PCORI Scientific Program Area: Assessment of Prevention ... · Research Prioritization Topic Briefs...

Research Prioritization Topic Briefs PCORI Scientific Program Area: Assessment of Prevention, Diagnosis, and Treatment Options Prepared for PCORI by Dr. Gillian Sanders Schmidler, PhD, and Team

April 18, 2013

The Duke Clinical Research Institute

Contents Topic 1: “Attention Deficit Hyperactivity Disorder (ADHD)” ........................................................................................... 2

Topic 2: “Bipolar Disorder” ........................................................................................................................................................... 9

Topic 3: “Hip Fracture” ................................................................................................................................................................. 15

Topic 4: “Carotid Artery Disease” ............................................................................................................................................. 21

Topic 5: “Cerebral Adrenoleukodystrophy (ALD )” ........................................................................................................... 28

Topic 6: “Coronary Artery Disease (CAD)” ............................................................................................................................ 35

Topic 7: “Ductal Carcinoma” ....................................................................................................................................................... 45

Topic 8: “Gestational Diabetes”.................................................................................................................................................. 51

Topic 9: “Eczema” ............................................................................................................................................................................ 61

Topic 11: “Generalized Anxiety Disorder (GAD)” ............................................................................................................... 77

Topic 12: “Hearing Loss” .............................................................................................................................................................. 84

Topic 13: “Chronic Kidney Disease” ......................................................................................................................................... 90

Topic 14: “Treatments for Liver Cancer” ............................................................................................................................... 97

Topic 15: “Macular Degeneration” ........................................................................................................................................ 105

Topic 16: “Melanoma” ................................................................................................................................................................ 111

Topic 17: “Migraine Headache” .............................................................................................................................................. 118

Topic 18: “Multiple Sclerosis” .................................................................................................................................................. 126

Topic 19: “Obstructive Sleep Apnea” .................................................................................................................................... 134

Topic 20: “Osteoarthritis” ......................................................................................................................................................... 143

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Topic 1: “Attention Deficit Hyperactivity Disorder (ADHD)” Comparative effectiveness of treatment options for attention deficit hyperactivity disorder (ADHD) in children.

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Criteria Brief Description Introduction Overview/definition

of topic DESCRIPTION OF CONDITION • Attention Deficit Hyperactivity Disorder (ADHD) is a neurobehavioral disorder ( ie, pertaining

to a person’s neurological state by observation of his/her behavior) that begins in childhood and could affect the entire lifespan

• ADHD is a highly heritable condition1 with genetic, biologic, and developmental factors all playing a role

• There is no single diagnostic or genetic test for ADHD, therefore early diagnosis is often impossible

• Diagnosis is based on behavioral signs or symptoms Relevance to

patient-centered outcomes

SYMPTOMS • Difficulties with paying attention, controlling impulsive behaviors, and/or being overly active PATIENT-CENTERED OUTCOMES2,3 • Children with ADHD are at increased risk of:

o Learning problems and academic underachievement o Difficulties relating to peers and forming friendships o Major injuries o Early sexual activity and pregnancy o Substance abuse and/or dependence o Legal difficulties o Occupational difficulties

Burden on Society Recent prevalence in

populations and subpopulations

PREVALENCE3 • One of the most common chronic health conditions affecting school-age children

o Approximately 9.5% of children ages 4-17 (5.4 million) diagnosed as of 2007 o Prevalence of reported cases is increasing

• Boys (13.2%) more likely to be affected than girls (5.6%) • Highest rates of ADHD are among children covered by Medicaid and multiracial children

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Effects on patients’

quality of life, productivity, functional capacity, mortality, use of health care services

QUALITY OF LIFE • When untreated, ADHD has a significant impact on quality of life, psychosocial functioning,

and family life PRODUCTIVITY • When untreated, ADHD significantly affects the productivity of both patients and their family

members HEALTH CARE SERVICE UTILIZATION • As of 2007, 2.7 million children ages 4-17 (66.3% of those diagnosed with ADHD) were

receiving drug treatment3 • Children with ADHD are more likely to have hospital inpatient, hospital outpatient, and

emergency department admissions3 • Children with ADHD are more likely to have contact with a mental health professional, use

prescription drugs, and have frequent health care visits3 • Average ADHD-related expenditures were $1,319 per patient in 200710

How strongly does this overall societal burden suggest that CER on alternative approaches to this problem should be given high priority?

ADHD is a common disorder affecting a large number of individuals that can have a significant impact on psychosocial, social, educational, and/or occupational functioning throughout the lifespan. While drug treatment is most often used, wider implementation of behavioral treatment with or without drug treatment may improve outcomes, reduce need for medication treatment, and reduce associated side effects.

Options for Addressing the Issue

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Based on recent

systematic reviews, what is known about the relative benefits and harms of the available management options?

For children under 6 years of age at risk of developing ADHD: • There is strong evidence for parent-administered behavior training (training parents to use

effective discipline strategies such as rewards and nonpunitive consequences to manage their child’s behavior). There are four different programs of behavior training interventions for parents, with some shared common therapeutic components.4 o Potential harms: no evidence4There is limited evidence for methylphenidate (MPH)

therapy (only one good study)4 Preschool ADHD Treatment Study (PATS) showed MPH to be effective5,6

o Potential harms: Young children have more dose-related side effects and interference with growth.4 In addition, MPH is less effective in children with three or more psychological conditions in addition to ADHD.4

For those 6 years of age and older with a diagnosis of ADHD: • Drugs used for controlling inattention, overactivity, and impulsivity have been shown to

maintain effectiveness and safety for 12 to 24 months.4 • It is less certain whether drugs are effective and safe over the longer term.4 • Drug treatments and interventions that combine drug and behavioral treatments are more

effective than behavioral treatments alone.4 This finding is based largely on the Multimodal Treatment Study of Children with ADHD (MTA).7

o The MTA study also suggests that (1) children with ADHD and comorbid anxiety respond equally well to behavioral treatment and medication; (2) children with ADHD and comorbid oppositional defiant disorder (ODD) or conduct disorder (CD) require medication for benefit; and (3) behavioral treatments in addition to medication may be most important for minorities8

• There is insufficient evidence to comment on longer-term outcomes for ADHD symptoms following behavioral training for parents, children, or for academic interventions4

What could new research contribute to achieving better patient-centered outcomes?

For children under 6 years of age: • There is a need for studies that compare drug treatments to behavioral treatments or

combined drug and behavioral treatment as in the MTA study (which looked at intensive medication management alone, intensive behavioral treatment alone, and a combination of both) in older children. For the youngest children, it would be beneficial to assess which strategies have the best patient-centered outcomes

• Since most studies have used different behavioral strategies it would also be beneficial to assess the relative efficacy of key components of behavioral treatment programs in an effort to see what strategies are most practical

For those over 6 years of age: • There is a need for more information on the long-term outcomes of behavioral and

pharmacologic therapies • The optimal follow-up and monitoring schedule for patients with ADHD is not known.9

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Have recent

innovations made research on this topic especially compelling?

• Existing studies of drug treatments tested older, short-acting stimulant medications, such as methylphenidate and amphetamine.

• Studies of newer, long-acting medications (eg extended release methylphenidate, extended release dextroamphetamine, extended release amphetamine, dextroamphetamine mixed salts, amphetamine, dextroamphetamine mixed salts atomoxetine, and lisdexamfetamine dimesylate) are needed. Such studies should ideally compare these medications to short-acting stimulant medications as well as behavioral therapies.

How widely does care now vary?

• Rates of diagnosis vary considerably in relation to access to local health care services and availability of medical providers.9

• Rates of drug usage vary by age and sex; children age 11-17 years are more likely than those age 4-10 to take medication; boys are 2.8 times more likely than girls to take medication.3

• Children of relatively low socioeconomic status are more likely to have ADHD and less likely to receive treatment than children of relatively high socioeconomic status9

• Low socioeconomic and minority status are both associated with shorter duration of drug use, thus reducing treatment efficacy.9

What is the pace of other research on this topic (as indicated by recent publications and ongoing trials)?

ClinicalTrials.gov: • Ongoing trials: 215 • Completed trials: 394 NIH reporter: 544 projects/ 307 publications

How likely is it that new CER on this topic would provide better information to guide clinical decision making?

For children under 6 years of age, new CER could provide better data on: • The comparative effectiveness of behavioral strategies versus drug versus a combination of

the two • The comparative effectiveness of newer ADHD medications, which are approved for children

over 6 years of age but are being prescribed off-label to children younger than 6, although they have not been studied in this population

• Which components of behavioral treatment programs are most practical For people over 6 years of age, new CER could provide better data on: • Long-term outcomes of behavioral versus drug therapies • Differences in outcomes based on age, sex, race, ethnicity, socioeconomic status, or other

comorbid conditions Potential for New Information to Improve Care and Patient-Centered Outcomes What are the

facilitators and barriers that would affect the implementation of new findings in practice?

FACILITATORS: • Large numbers of children and adults with ADHD • Significant impact on psychosocial function • Desire for alternatives to drug treatments because of concerns about side effects BARRIERS: • Lack of time for medical providers to adequately assess patients • Lack of training for medical providers in diagnosis and treatment of ADHD • Lack of availability of behavioral treatment programs in certain locations • Reimbursement for treatment • Cost and practicality of conducting long-term follow-up studies

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REFERENCES: 1. Larsson H, Lichtenstein P, Larsson JO. Genetic contributions to the development of ADHD subtypes from childhood

to adolescence. J Am Acad Child Adolesc Psychiatry. 2006;45(8):973-981. 2. Biel MG, McGee ME. Assessment of attention-deficit/hyperactivity disorder. Pediatr Ann. 2011;40(10):493-498. 3. Centers for Disease Control and Prevention. Attention-Deficit / Hyperactivity Disorder (ADHD): Data & Statistics.

Centers for Disease Control and Prevention. www.cdc.gov/ncbddd/adhd/data.html. Accessed April 10, 2013. 4. Charach A, Dashti B, Carson P, Booker L, Lim CG, Lillie E, Yeung E, Ma J, Raina P, Schachar R. Attention Deficit

Hyperactivity Disorder: Effectiveness of Treatment in At-Risk Preschoolers; Long-Term Effectiveness in All Ages; and Variability in Prevalence, Diagnosis, and Treatment. Comparative Effectiveness Review No. 44. (Prepared by the McMaster University Evidence-based Practice Center under Contract No. MME2202 290-02-0020.) AHRQ Publication No. 12-EHC003-EF. Rockville, MD: Agency for Healthcare Research and Quality; October 2011. www.effectivehealthcare.ahrq.gov/reports/final.cfm. Published October 2011. Accessed April 10, 2013.

5. Abikoff HB, Vitiello B, Riddle MA, Cunningham C, Greenhill LL, Swanson JM, Chuang SZ, Davies M, Kastelic E, Wigal SB, Evans L, Ghuman JK, Kollins SH, McCracken JT, McGough JJ, Murray DW, Posner K, Skrobala AM, Wigal T. Methylphenidate effects on functional outcomes in the Preschoolers with Attention-Deficit/Hyperactivity Disorder Treatment Study (PATS). J Child Adolesc Psychopharmacol. 2007;17(5):581-592.

6. Vitiello B, Abikoff HB, Chuang SZ, Kollins SH, McCracken JT, Riddle MA, Swanson JM, Wigal T, McGough JJ, Ghuman JK, Wigal SB, Skrobala AM, Davies M, Posner K, Cunningham C, Greenhill LL. Effectiveness of methylphenidate in the 1-month continuation phase of the Preschoolers with Attention-Deficit/Hyperactivity Disorder Treatment Study (PATS). J Child Adolesc Psychopharmacol. 2007;17(5):593-604.

How likely is it that the results of new research on this topic would be implemented in practice right away?

• It is likely that new data suggesting superiority of particular medications over others could be implemented quickly in people over the age of 6, as these medications are already approved for this age group

• It is likely that new data on the effectiveness of different drug treatments would not be implemented quickly in children under the age of 6, as these medications would need FDA approval in this age group and there is likely to be considerable concern regarding side effects. However, since many of these agents are already being used off-label in this age group, it may be possible to expedite this process.

• It is likely that new data on the effectiveness of different behavioral programs or their component parts could be implemented quickly if these programs are already available

• It is unlikely that new data on the effectiveness of different behavioral programs or their component parts could be implemented quickly if these programs are not already available as there would be delay while these programs are created

Would new information from CER on this topic remain current for several years, or would it be rendered obsolete quickly by subsequent studies?

• There are a large number of completed and ongoing studies in this topic area; however, many studies are small in size.

• Both the larger PATS and MTA studies have remained current for many years. It is likely that new information with more current therapies (medication and psychosocial) would remain relevant for many years.

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http://www.cdc.gov/ncbddd/adhd/data.html

http://www.effectivehealthcare.ahrq.gov/reports/final.cfm

7. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA

Cooperative Group. Multimodal Treatment Study of Children with ADHD. Arch Gen Psychiatry. 1999;56(12):1073-1086.

8. Murray DW, Arnold LE, Swanson J, Wells K, Burns K, Jensen P, Hechtman L, Paykina N, Legato L, Strauss T. A clinical review of outcomes of the multimodal treatment study of children with attention-deficit/hyperactivity disorder (MTA). Curr Psychiatry Rep. 2008;10(5):424-431.

9. Subcommittee on Attention-Deficit/Hyperactivity Disorder; Steering Committee on Quality Improvement and Management, Wolraich M, Brown L, Brown RT, DuPaul G, Earls M, Feldman HM, Ganiats TG, Kaplanek B, Meyer B, Perrin J, Pierce K, Reiff M, Stein MT, Visser S. ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2011;128(5):1007-1022.

10. Soni, A. Attention-Deficit Hyperactivity Disorder (ADHD) in children, ages 5-17: use and expenditures, 2007. Statistical Brief #276. Rockville, MD: Agency for Healthcare Research and Quality; 2009. www.meps.ahrq.gov/mepsweb/data_files/publications/st276/stat276.shtml. Published December 2009. Accessed April 10, 2013.

APPENDIX: TOPIC QUESTIONS

Nominated by Agency for Healthcare Research and Quality (AHRQ):

1) For children less than 6 years of age with disruptive behavior disorder or ADHD, what is the comparative efficacy and effectiveness of specific psychosocial treatments alone compared with pharmacological treatments alone or in combination with psychosocial treatments for patient outcomes?

2) For people ages 6 years or older with ADHD, what are the comparative long-term outcomes for the available psychosocial and pharmacological treatments?

3) Among children less than 6 years of age with disruptive behavior disorder or ADHD, what is the relative/comparative efficacy of key components of psychosocial treatment programs? These might include the relative efficacy of specific parent training compared with treatment components targeting the child, or the efficacy of variants in psychosocial treatment service delivery that allow flexibility for parental preferences compared with those that do not.

4) For people ages 6 years or older with ADHD, which specific sociodemographic, baseline clinical characteristics, and neurobiological features predict a positive treatment response with respect to patient outcomes?

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http://www.meps.ahrq.gov/mepsweb/data_files/publications/st276/stat276.shtml

Topic 2: “Bipolar Disorder” Comparative effectiveness of antipsychotics for adolescents and young adults with bipolar disorder.

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of topic DESCRIPTION OF CONDITION • Bipolar disorder, commonly called “manic depression,” is a serious brain disorder that

causes extreme and unusual changes in moods and behaviors. • Bipolar disorder that starts in childhood or the early teen years seems to be more severe

than when the disorder starts in older teens and adults.1,2 • There is no cure for bipolar disorder. • Antipsychotic medications are used to control symptoms of bipolar disorder and provide

symptom relieve compared to no treatment in adolescents and young adults (defined as youths under 25 years of age). However, antipsychotics carry significant side effects.

Relevance to patient-centered outcomes

SYMPTOMS/OUTCOMES • Symptoms

o Episodes of extreme elevated moods o Episodes of major depression

• Outcomes o Adolescents and young adults with bipolar disorder experience higher rates of

attempted and completed suicide, substance abuse, hospitalizations, legal issues, and poor academic and psychosocial functioning

• Worse outcomes are associated with patients who are an early age at first episode, who suffer long duration, who have comorbid disorders, are low socioeconomic status, or who have negative life events (like abuse)

Burden on Society Recent incidence

and prevalence in populations and subpopulations

BIPOLAR DISODER INCIDENCE (NEW CASES) & PREVALENCE (PROPORTION OF POPULATION LIVING WITH THE CONDITION) • A recent meta-analysis found that 2.7% of youths aged 12 to 21 have bipolar disorder.

Rates of bipolar disorder jump to as much as 5% when subsyndromal manic symptomatology is included in the estimates.3

• Recovery in most youths, defined as no significant symptoms for 2 months following first episode,4-7 is achievable

• Almost 80% of affected youth, however, will have a relapse of bipolar disorder within 2 to 5 years.6

Effects on patients’ quality of life, productivity, functional capacity, mortality, use of health care services

QUALITY OF LIFE • Affects family relationships and family’s overall financial security • Difficulties with interpersonal relationships • Antipsychotic drugs have side effects that negatively affect quality of life. PRODUCTIVITY • Poor school and social performance • Difficulties obtaining and retaining a job MORTALITY • Higher rates of attempted and completed suicide

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USE OF HEALTH CARE SERVICES • Higher number of hospitalizations compared to youths without bipolar disorder • Estimated $2.82 billion were spent in 2003 in the United States on antipsychotic

medications8 • Use of antipsychotics in youths has increased dramatically over the last 20 years9,10


This is a serious disorder affecting approximately 3% of adolescents and young adults, with significant implications for patients, families, and society. Antipsychotics have the potential to control symptoms but the majority of research has been conducted with adult populations. While there are multiple head-to-head comparison studies of the benefits and harms of antipsychotics for adults, few high-quality comparative effectiveness trials have tested these medications in younger populations.

Options for Addressing the Issue Based on recent


SCREENING/EARLY DIAGNOSIS • Diagnosing bipolar disorder in children and adolescents is complex and requires longitudinal

assessments • Psychiatric interviews and rating scales can be used by trained clinicians for screening • Parent-report instruments have also been used to screen for bipolar disorder in youths TREATMENT Overview • Antipsychotic drugs are one class of drugs used to treat bipolar disorder. These are

commonly categorized into two classes, which have different side-effect profiles. o First-generation antipsychotics (FGA) or typical antipsychotics (developed in the

1950s) Side effects: movement disorders (repetitive, involuntary muscle

movements: eye blinking, finger movement, lip smacking), uncontrollable muscle contractions, liver problems, irregular heartbeat, constipation, loss of appetite, and sedation

o Second-generation antipsychotics (SGA) or atypical antipsychotics (1980s) Side effects: weight gain, elevated lipids, increased risk for type 2 diabetes Lower risk of movement side effects with SGA than with FGA

Systematic Reviews • A recent systematic review identified only 11 randomized controlled trials (RCTs) evaluating

antipsychotic drugs in adolescents and young adults. These trials compared different doses of the same SGA (4 trials), one SGA versus another (2 trials), or an SGA versus placebo (8 trials).8 (Total number of comparisons exceeds 11 as some trials had 3 or 4 group designs that assessed multiple comparisons.)

o No studies compared FGAs to SGAs. o Few studies reported on important patient-centered outcomes (eg, sedation,

restlessness), even though they are vital to patient compliance

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o Few studies assessed long-term outcomes. o Little data on benefits and harms of antipsychotics among key subgroups of patients o Across all comparisons and outcomes the volume and quality of evidence were low.

What could new

research contribute to achieving better patient-centered outcomes?

New research could contribute to achieving better patient-centered outcomes: • Data on the relative benefits and harms of different treatments • Data on important patient and family outcomes

Have recent innovations made research on this topic especially compelling?

Recent innovations: • There have been multiple head-to-head comparison studies of the benefits and harms of

antipsychotics for adults, however, few high-quality comparative effectiveness trials have tested these medications in younger populations.


VARIABILITY IN CARE • Diagnosis is complex and requires ongoing evaluation which could lead to variability in care.

While relatively few antipsychotics are FDA-approved for use in youths with bipolar disorder, use of medications is often driven by side-effects leading to variability in care.


RECENT PUBLICATIONS • MEDLINE search from 1/1/2008-3/31/2013: total of 1250 citations

o 207 randomized controlled trials (RCTs) o 369 observational/cohort trials o 60 systematic reviews

ONGOING TRIALS • ClinicalTrials.gov: 254 ongoing trials • NIH Reporter: 570 projects


KEY UNCERTAINTIES IN CLINICAL DECISION MAKING • What are the comparative harms and benefits of FGAs and SGAs? • What are the long-term outcomes of these medications on youths across a wide variety of

clinical, developmental, and social domains? • Do effects of these treatments vary by important subgroups (age, sex)?

LIKELIHOOD THAT CER WOULD BE ABLE TO REDUCE THESE UNCERTAINTIES There is a high likelihood that CER would reduce uncertainly. • Few head-to-head comparisons of antipsychotics • Few high-quality longitudinal studies of antipsychotics • Little information to guide clinical practice on how treatment effects vary across key

subgroups Potential for New Information to Improve Care and Patient-Centered Outcomes What are the

facilitators and barriers that would

FACILITATORS • Few FDA-approved treatments at this time. CER could provide needed information on which

of the currently available treatments should be added to the FDA-approved list and give

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REFERENCES:

1. Perlis RH, Miyahara S, Marangell LB, Wisniewski SR, Ostacher M, DelBello MP, Bowden CL, Sachs GS, Nierenberg AA. Long-term implications of early onset in bipolar disorder: data from the first 1000 participants in the systematic treatment enhancement program for bipolar disorder (STEP-BD). Biol Psychiatry. 2004 May 1;55(9):875-881.

2. Birmaher B, Axelson D, Strober M, Gill MK, Valeri S, Chiappetta L, Ryan N, Leonard H, Hunt J, Iyengar S, Keller M. Clinical course of children and adolescents with bipolar spectrum disorders. Arch Gen Psychiatry. 2006 Feb;63(2):175-183.

3. Van Meter AR, Moreira AL, Youngstrom EA: Meta-analysis of epidemiological studies of pediatric bipolar disorder. J Clinical Psychiatry 72:1250–1256, 2011.

4. Birmaher B, Axelson D, Goldstein B, et al. Four-year longitudinal course of children and adolescents with bipolar spectrum disorders: the Course and Outcome of Bipolar Youth (COBY) study. Am J Psychiatry 2009; 166:795.

5. DelBello MP, Hanseman D, Adler CM, et al. Twelve-month outcome of adolescents with bipolar disorder following first hospitalization for a manic or mixed episode. Am J Psychiatry 2007; 164:582.

6. Birmaher B. Longitudinal course of pediatric bipolar disorder. Am J Psychiatry 2007; 164:537. 7. Geller B, Tillman R, Bolhofner K, Zimerman B. Child bipolar I disorder: prospective continuity with adult bipolar I

disorder; characteristics of second and third episodes; predictors of 8-year outcome. Arch Gen Psychiatry 2008; 65:1125.

8. Abou-Setta AM, Mousavi SS, Spooner C, Schouten JR, Pasichnyk D, Armijo-Olivo S, Beaith A, Seida JC, Dursun S, Newton AS, Hartling L. First-Generation Versus Second-Generation Antipsychotics in Adults: Comparative Effectiveness. Comparative Effectiveness Review No. 63. (Prepared by the University of Alberta Evidence-based Practice Center under Contract No. 290-2007-10021.) AHRQ Publication No. 12-EHC054-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2012. www.effectivehealthcare.ahrq.gov/reports/final.cfm. Published August 2012.

affect the implementation of new findings in practice?

needed comparative information on side-effect profiles. Expanding the choice of treatments with better side-effect profiles could potentially be embraced by clinical, patient, and caregiver populations.

BARRIERS • Social stigma associated with having a mental health disorder • Noncompliance with taking antipsychotics may occur for many reasons, including side

effects from medication and a lack of improvement in symptoms How likely is it that

the results of new research on this topic would be implemented in practice right away?

EVIDENCE OF BENEFIT • Highly likely that treatments with evidence of benefits would be implemented. EVIDENCE OF NO BENEFIT OR HARM • Highly likely that finding of no benefits or of greater harms would be implemented.

Would new information from CER on this topic remain current for several years?

Despite the sizable number of studies in this area, there are few head-to-head comparisons and the quality of these studies is generally low. Thus, high-quality, CER studies that report on important short- and long-term clinical and patient-centered outcomes are likely to be relevant for several years.

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http://www.uptodate.com/contents/bipolar-disorder-in-children-and-adolescents-epidemiology-pathogenesis-clinical-manifestations-and-course/abstract/3







9. Zito JM, Safer DJ, dosReis S, et al. Trends in the prescribing of psychotropic medications to preschoolers. JAMA 2000;238(8):1025-1030.

10. Pathak S AS, Danielyan A, et al. Psychotropic utilization and psychiatric presentation of hospitalized very young children. J Child Adolesc Psychopharmacol 2004;14(3):433-442.

Appendix: Topic Question

Nominated by Agency for Healthcare Research and Quality (AHRQ)

1) What is the efficacy and effectiveness of first or second generation antipsychotics for adolescents and young adults with bipolar disorder in the following outcome domains: core features of the disorder, its commonly associated comorbidities and behavioral features, social/occupational functioning, patient- and parent-reported outcomes, those related to high risk behaviors, and suicide-related behavior?

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Topic 3: “Hip Fracture” Comparative effectiveness of surgical options for hip fracture in the elderly.

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of topic DESCRIPTION OF CONDITION1,2,3 • “Hip fracture” refers to a break of the upper part of the femur (large bone of the upper thigh) • Classified into different types depending on location • Treatment options vary by fracture type • Two main causes:

o Simple falls (90%)—affect mostly the elderly, more common in women o Major trauma ( eg, motor vehicle accident)—mostly younger, more common in men

Patient-centered outcomes

SYMPTOMS/OUTCOMES1,2,3 • Hip fracture can result in:

o Pain o Functional impairment o Prolonged rehabilitation o Loss of ability to live independently o Premature death

• Goal of treatment usually to return patients to pre-fracture level of functioning Burden on Society Recent incidence


INCIDENCE (NEW CASES)1,2 • 957 per 100,000 for women and 414 per 100,000 for men from 1986 to 2005 • Increased risk in women due to changes in bone strength (osteoporosis) after menopause

o Unclear if decreased use of postmenopausal hormone replacement therapy after findings of Women’s Health Initiative in 2002 will lead to increased incidence in women


QUALITY OF LIFE1,2,3 • 80% of elderly women surveyed preferred death to a “bad” hip fracture that would result in

nursing home need FUNCTIONAL CAPACITY • 50% of previously independently living elderly patients able to walk unaided after fracture,

but many (25–75%) never completely recover full pre-injury functional status MORTALITY • 20% one-year mortality after a hip fracture • 2–3% in-hospital mortality among patients 65 and over4 USE OF HEALTH CARE SERVICES4 • 304,000 hospitalizations in the United States (in 2010) secondary to hip fractures

o Ages 65–84: 0.9% of all hospitalizations for men, 1.8% for women o Ages 85 and older: 2.7% of all hospitalizations for men, 4.5% for women

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• Common condition with potential for severe consequences and overall high societal burden • Also high potential for decreasing the incidence of hip fractures via fall prevention measures • Multiple different treatment options and potential for wide variety of different outcomes

depending on nature, quality, and extent of medical/surgical care provided • CER on alternative approaches may have significant impact on clinical outcomes, societal

costs, and patient and provider decision making



Four Key Questions in 2009 AHRQ “Treatment of Common Hip Fractures” report 3 1) Relationship between patient variables, fracture type, and patient outcomes 2) Relationship between fracture type and patient outcomes 3) Relationship between implant variables and patient outcomes 4) Relationship between intervention type and patient outcomes

Results: • Five of the included trials were conducted in the United States • Limited evidence to answer most of the key questions • High degree of uncertainty regarding the best way to treat unstable hip fractures and about

which treatment options are most appropriate for various clinical populations What could new


2010 AHRQ “Future Needs for the Treatment of Common Hip Fractures” report5 identified the following research gaps: • Predictors of short time-to-recovery and functional outcomes • Impact of suboptimal surgical quality on functional outcomes • Optimal treatment for different types of fractures ( eg, unstable intertrochanteric hip

fractures) or defined populations ( eg, frail elderly, patients with dementia) • Between-class and within-class comparisons ( eg, intramedullary nail vs. screws, cement vs.

not, number and placement of screws, plate length and position, nail length, and other parameters)


• Comanaged geriatric fracture centers and organized geriatric fracture programs represent novel approaches that are associated with shorter times to surgery, fewer postoperative infections, fewer complications overall, and shorter lengths of stay.6

• Further research on health care redesign involving multidisciplinary collaboration is timely and may result in both improved outcomes and more efficient use of health care resources.


VARIABILITY IN CARE • Very large variation in quality, nature, and extent of care provided across the many clinical

settings throughout the United States that offer hip fracture repair • High variability in training and quality of surgeons and hospital-based clinicians who provide

medical care to elderly patients with multiple comorbidities during hospitalization for hip fracture repair

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What is the pace of

other research on this topic (as indicated by recent publications and ongoing trials)?

RECENT PUBLICATIONS • Treatment of Common Hip Fractures (AHRQ, 2009)3 • Future Needs for the Treatment of Common Hip Fractures (AHRQ, 2010)5 • Pain Management Interventions for Hip Fractures (AHRQ, 2011)7 ONGOING TRIALS • FAITH (Fixation using Alternative Implants for the Treatment of Hip Fractures)8 • HEALTH (Comparing Total Hip Arthroplasty and Hemi-Arthroplasty on Revision Surgery and

Quality of Life in Adults with Displaced Hip Fractures)9 How likely is it that

new CER on this topic would provide better information to guide clinical decision making?

• The research gaps listed above were identified by key stakeholders. This suggests that CER on these topics is likely to inform stakeholder clinical decision making.

• Many areas of uncertainty involve technical issues regarding surgical management; relative involvement of patients/capacity for shared decision making may vary

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REFERENCES: 1. Brauer AC, Coca-Perraillon M, Cutler DM, Rosen AB. Incidence and mortality of hip fractures in the United States.

JAMA. 2009;302:1573-1579. 2. Braithwaite RS, Col NF, Wong JB. Estimating hip fracture morbidity, mortality and costs. J Am Geriatr Soc.

2003;51:364-70. 3. Butler M, Forte M, Kane RL, Joglekar S, Duval SJ, Swiontkowski M., Wilt T. Treatment of Common Hip Fractures.

Evidence Report/Technology Assessment No. 184 (Prepared by the Minnesota Evidence-based Practice Center under Contract No. HHSA 290 2007 10064 1.) AHRQ Publication No. 09-E013. Rockville, MD. Agency for Healthcare Research and Quality. 2009. www.ahrq.gov/research/findings/evidence-based-reports/hipfrac-evidence-report.pdf. Published August 2009. Accessed April 10, 2013.

4. HCUPnet, Healthcare Cost and Utilization Project. Agency for Healthcare Research and Quality, Rockville, MD. Available at: http://hcupnet.ahrq.gov. Accessed April 10, 2013.

Potential for New Information to Improve Care and Patient-Centered Outcomes What are the


FACILITATORS • The current lack of consensus on questions identified by stakeholders as being important is

likely to facilitate implementation of new, compelling findings. • 80% of hospitalizations have Medicare as primary payer—potential for CMS to help facilitate

implementation BARRIERS • Cost of implementation ( eg, to payers, providers, patients, caregivers, and others) • Lower barriers to market entry for surgical instruments and devices ( eg, hip implants), as

opposed to drugs • Reimbursement structure for providers and financial incentives/disincentives associated with

changing existing practices • Dissemination of findings across a large spectrum of providers, payers, and patients


EVIDENCE OF BENEFIT • Highly likely to be implemented because most stakeholders likely to be motivated to improve

decision making and patient outcomes • General sense that orthopedic surgeons are open to—and would welcome—greater clarity

on treatment options EVIDENCE OF NO BENEFIT OR HARM • Depending on balance, may be less likely to be implemented if findings do not provide

additional clarity o Especially true if current financial/other incentives favor continued use of intervention

with no benefit relative to other options Would new

information from CER on this topic remain current for several years?

• New information from CER on this topic may remain current if it is compelling and clear, and if it addresses questions deemed relevant by stakeholders.

• CER on certain technical questions may be rendered obsolete by unforeseeable technological advances ( eg, availability of new materials for hip replacement).

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http://hcupnet.ahrq.gov/

5. Butler M, Forte ML, Kane RL, Swiontkowski MF. Future Research Needs for the Treatment of Common Hip Fractures.

Future Research Needs Paper No. 2. (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-2007-10064-I.) AHRQ Publication No. 10-EHC071-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2010. www.effectivehealthcare.ahrq.gov/reports/final.cfm. Published September 2010. Accessed April 10, 2013.

6. Friedman, S.M., et al., Geriatric co-management of proximal femur fractures: total quality management and protocol-driven care result in better outcomes for a frail patient population. J Am Geriatr Soc. 2008;56:1349-1356.

7. Abou-Setta AM, Beaupre LA, Jones CA, Rashiq S, Hamm MP, Sadowski CA, Menon MR, Majumdar SR, Wilson MD, Karkhaneh M, Wong K, Mousavi SS, Tjosvold L, Dryden DM. Pain Management Interventions for Hip Fracture. Comparative Effectiveness Review No. 30. (Prepared by the University of Alberta Evidence-based Practice Center under Contract No. 290-02-0023.) AHRQ Publication No. 11-EHC022-EF. Rockville, MD: Agency for Healthcare Research and Quality. 2011. www.effectivehealthcare.ahrq.gov/reports/final.cfm. Published May 2011. Accessed April 10, 2013.

8. Fixation Using Alternative Implants for the Treatment of Hip Fractures [FAITH]: A Multi-Centre Randomized Trial Comparing Sliding Hip Screws and Cancellous Screws on Revision Surgery Rates and Quality of Life in the Treatment of Femoral Neck Fractures. ClinicalTrials.gov ID: NCT00761813. http://clinicaltrials.gov/ct2/show/NCT00761813. Accessed April 10, 2013.

9. Comparing Total Hip Arthroplasty and Hemi-Arthroplasty on Revision Surgery and Quality of Life in Adults With Displaced Hip Fractures (The HEALTH Study). ClinicalTrials.gov ID: NCT00556842. http://clinicaltrials.gov/ct2/show/NCT00556842. Accessed April 10, 2013.


Nominated by the Agency for Healthcare Research and Quality (AHRQ)

1. What predicts short time-to-recovery after hip fracture? 2. What predicts functional outcomes after one year, especially one to two years after hip fracture? 3. What is the impact of suboptimal surgical quality on functional outcomes? 4. Do certain procedures ( eg, internal fixation) work better than others for frail older patients? 5. Are most fragile patients more or less likely to have suboptimal fracture reduction/implant position than the

most active, mobile patients (making them higher risk for implant failure?) 6. Which procedures are better for patients with dementia? 7. What is the optimal treatment for displaced femoral neck fractures? 8. What is the optimal treatment for unstable‖ intertrochanteric hip fractures? 9. What is the optimal treatment for subtrochanteric hip fractures? 10. Between class comparisons ( eg, IM nail vs. screws) 11. Within-class comparison of arthroplasty—c ement vs. not 12. Within-class comparison of number and placement of screws 13. Within-class comparison of plate length, position 14. Within-class comparison of nail length (IMN)

20



http://clinicaltrials.gov/ct2/show/NCT00761813

http://clinicaltrials.gov/ct2/show/NCT00556842

Topic 4: “Carotid Artery Disease” Comparative effectiveness of medical and surgical treatment options of patients with asymptomatic carotid artery stenosis.

21


of topic DESCRIPTION OF CONDITION Overview • The carotid arteries, which carry blood to the brain, are prone to blockage from

arteriosclerosis (thickening/hardening of the arteries). Atherosclerotic plaque in the carotid arteries can lead to ischemic strokes or transient ischemic attacks (TIAs).

• The risk of stroke related to carotid artery disease is higher with: o Higher degrees of stenosis (narrowing of the carotid artery) o Neurologic symptoms o Evidence of asymptomatic cerebral embolism or presence of ulcerations of carotid artery

• Peripheral vascular disease and ischemic heart disease are common comorbid conditions. Screening/Diagnosis • Carotid stenosis can be identified through diagnostic evaluation:

o In persons with neurologic symptoms o By hearing a neck bruit (abnormal sound) o Via screening tests (Doppler ultrasound)

Treatment • Three main treatments are used to prevent stroke in patients with carotid artery disease: (1)

medical therapy (using various drugs) for risk factor reduction, (2) carotid endarterectomy (CEA) or, more recently, (3) percutaneous carotid artery angioplasty and stenting (CAS). CEA and CAS are two different types of revascularization procedures.


SYMPTOMS/OUTCOMES • Neurologic symptoms sometimes last <24 hours. • For patients who progress to a stroke, outcomes include:

o Loss of use of arms or legs o Loss of ability to speak (aphasia) o Functional deficits, including in relation to ambulation or ability to care for self o Death (with large severe strokes)



PREVALENCE (PROPORTION OF POPULATION LIVING WITH THE CONDITION) • Prevalence of asymptomatic carotid artery stenosis is up to 7.5%, with higher prevalence in

men and in older patients1

22



QUALITY OF LIFE • Quality-of-life benefit from CEA is delayed, with initial risk of perioperative morbidity

(including strokes caused by the surgery), but with benefit that is significant at two years and longer after procedure. Limited data are available on CAS.

PRODUCTIVITY • Stroke is the leading cause of serious long-term disability in the United States. MORTALITY • 30-day mortality rates directly related to CEA and CAS among Medicare patients were 1.2%

for CEA and 2.3% for CAS in 2005.2 USE OF HEALTH CARE SERVICES AND COSTS • In 2008, total direct and indirect costs related to stroke in the United States were over $65

billion. • The majority of direct medical costs arise during the first few months after a stroke and

include acute hospital costs (~50%), nursing home, and home health care costs (35%).3 • The majority of lifetime stroke-related costs are from indirect costs, including lost earnings,

informal care, or the care required for assistance in the home by a relative or unpaid nonrelative.3

• Among Medicare beneficiaries, CEA was performed on over 66,000 patients for symptomatic or asymptomatic indication in 2005;CAS in over 7000 patients.2

• Given the success of medical therapy and risk factor reduction, the overall rate of carotid revascularization procedures (CEA and CAS) has declined between 1998 and 2008. A large decrease in the use of CEA during this period has been accompanied by a sharp increase in the use of CAS.4


The detection of asymptomatic carotid artery stenosis provides an opportunity to avoid many of the costs associated with a stroke through prevention, particularly the lifetime indirect costs associated with lost productivity and informal care. However, detection and management of this asymptomatic condition also impose direct and indirect costs associated with the screening process, treatment, and lost productivity associated with both of these.



SCREENING/DIAGNOSIS • The United States Preventive Services Task Force (USPSTF) does not recommend screening

by ultrasound for the general population.5 TREATMENT Medical Therapy • Medical therapy with antiplatelet agents (aspirin, ticlopidine, clopidogrel, or aspirin and

dipyridamole) and risk factor reduction are generally accepted as being effective for all patients with carotid artery disease.

• Medical therapy is preferred for symptomatic patients with <50% stenosis. • One systematic review of 11 prospective studies (but no random controlled trials [RCTs])

23

found that treatment with medical therapy led to stroke rates in follow-up that are comparable to rates achieved with CEA.6

Carotid Endarterectomy (CEA) • CEA is recommended for patients who have experienced symptoms (stroke or TIA)

associated with carotid stenosis of 70-99% (strongly recommended) or 50-69% (when life expectancy is >5 years and probability of stroke during surgery is <6%).7

• CEA is also a consideration for appropriate patients who are asymptomatic with 60-99% stenosis (when life expectancy is >5 years and probability of stroke during surgery is <3%).

• Trials comparing CEA to medical therapy (aspirin) concluded that patients undergoing CEA for asymptomatic carotid artery disease should have the procedure done in centers with a perioperative rate of death and stroke of <3% and with surgeons whose complication rates are <3%.8-10

• Certain subgroups of patient are shown not to benefit from CEA (compared to aspirin therapy) including patients with: o Significant comorbidity o Prior stroke and persistent neurologic deficits on the same side o Total occlusion of the internal carotid artery (same side CEA) o Total occlusion of contralateral internal carotid artery (opposite side CEA)

• Based on data from meta-analysis, women may not benefit from CEA for asymptomatic carotid artery disease, based on five-year risk of stroke or perioperative death, whereas men do seem to benefit from CEA, especially if their life expectancy is ≥5 years.11

• Patients with evidence of asymptomatic cerebral embolism, presence of ulcerations of carotid artery plaques, and higher degrees of stenosis are at higher risk of stroke and may benefit more from CEA.

Percutaneous Carotid Artery Angioplasty and Stenting (CAS) • There is an overall similar risk of stroke or death with CEA and CAS. • CEA is favored over CAS for patients older than 70 years of age, with higher rates of stroke

especially associated with age ≥80. • Based on observational data, CAS may be appropriate for patients with prior neck radiation

therapy, high cervical carotid bifurcations, and those with complete occlusion of contralateral internal carotid artery.

• A systematic review in patients with symptomatic and asymptomatic carotid artery disease found that CAS had a higher risk of stroke at 30 days compared to CEA, lower risk of MI, and no significant difference in mortality at 30 days.12 Other systematic reviews confirm the higher risk of stroke and lower risk of MI with CAS compared to CEA.

• A recent Cochrane review13 found: o Among asymptomatic patients, no statistically significant difference was found between

CEA and CAS for the primary safety outcome of stroke or death at 30 days, or for combined efficacy and safety outcomes including MI, cranial nerve palsy, and access-site hematomas.

o Among symptomatic patients, there was a higher risk of the composite outcome of stroke or death associated with CAS only among older patients (≥70 years old).

o In patients not suitable for CEA, there was no significant difference between CAS and 24

medical therapy. What could new


• Current optimal medical therapy has been shown to be as good as or superior to CAS and CEA in two recent RCTs in patients with symptomatic carotid artery disease.14-15 However, trials comparing CEA or CAS to optimal medical therapy in patients with significant asymptomatic carotid artery disease have not been done.

• Trials comparing CEA and CAS in specific subgroups of patients based on sex, race, and comorbidities, all which have been found to affect outcome of the invasive procedures, have not been done.

• Better evidence based on RCTs to determine if medical therapy is adequate or even better compared to CEA and CAS would be very important to the care of patients with asymptomatic carotid artery disease. It could potentially expose patients to less risk and improve outcomes; it could also lead to decreased health care costs.


• Improved medical therapy for atherosclerotic disease has been developed, including the widespread use of statins and more aggressive risk factor management. These improvements in medical therapy have rendered landmark trials comparing CEA with medical therapy possibly obsolete.

• Recent data suggest that stroke rates are lower with more aggressive risk factor reduction, potentially reducing or eliminating the benefit of CEA (or CAS) over medical therapy14-15


• Based on Medicare beneficiaries data from 2004-2006:2 o CEA and CAS were performed more often in men than women; both were performed

more often in patients with peripheral vascular disease. o CEA and CAS were performed more often in the East North Central region than in New

England. What is the pace of


RECENT PUBLICATIONS • The USPSTF is updating its 2007 guidance5 with a new review of evidence in 2013. ONGOING TRIALS • ClinicalTrials.gov lists 68 trials of CEA and 81 trials of CAS as completed or ongoing, but only

one is a comparative trial (CAS vs. CEA, still recruiting), and none compares medical treatment with CAS or CEA.

• Multiple technology evaluations of devices to reduce embolization associated with CAS procedures are underway.


• New comparative-effectiveness research (CER) evaluating current aggressive medical therapy and risk factor reduction vs. procedure-based management (CEA or CAS), particularly for patients with asymptomatic carotid artery stenosis and possibly for patients with noncritical (50-69%) symptomatic stenosis, would help to resolve uncertainty.

• Trials comparing these treatments in specific subgroups of patients based on sex, race, and comorbidities, all which have been found to affect outcome of the invasive procedures, have not been done.

Potential for New Information to Improve Care and Patient-Centered Outcomes

25

REFERENCES:

1. de Weerd M, Greving JP, Hedblad B, et al. Prevalence of asymptomatic carotid artery stenosis in the general population: an individual participant data meta-analysis. Stroke. 2010;41(6):1294-1297.

2. Patel MR, Greiner MA, DiMartino LD, et al. Geographic variation in carotid revascularization among Medicare beneficiaries, 2003-2006. Arch Intern Med. 2010;170(14):1218-1225.

3. Demaerschalk BM, Hwang HM, Leung G. US cost burden of ischemic stroke: a systematic literature review. Am J Manag Care 2010;16(7):525-533.

4. Goodney PP, Travis L, Lucas FL, et al. Trends and regional variation in carotid revascularization. The Dartmouth Institute for Health Policy and Clinical Practice. A Dartmouth Atlas Surgery Report. Jan 26, 2010.

5. U.S. Preventive Services Task Force. Screening for Carotid Artery Stenosis: Clinical Summary of U.S. Preventive Services Task Force Recommendation. AHRQ Publication No. 08-05102-EF-3. Rockville, MD: U.S. Preventive Services Task Force; 2007. www.uspreventiveservicestaskforce.org/uspstf07/cas/cassum.htm. Published December 2007. Accessed April 11, 2013.

What are the facilitators and barriers that would affect the implementation of new findings in practice?

FACILITATORS • Implementation of medical therapy to treat asymptomatic carotid artery disease could likely

be easy, as similar treatments are already used for other atherosclerotic diseases. • Medical therapy vs. a procedure would result in less stress to patients, lower risk of

procedure-related complications, and reduced direct and indirect health care costs. BARRIERS • Existing referral patterns and recently expanded use of CAS among interventional

cardiologists, radiologists, and neurologists may be resistant to change. • There are no definite recommendations regarding screening procedures for asymptomatic

carotid artery disease, which may prevent eligible patients from receiving the best treatment.


• Implementation of medical therapy to treat asymptomatic carotid artery disease could likely be easy, as similar treatments are already used for other atherosclerotic diseases.

• Similarly, research supporting expanded indications for revascularization procedures would likely be easily and quickly implemented as the relatively rapid uptake of CAS illustrates.


New research comparing medical and revascularization procedures for asymptomatic stenosis, particularly in those subgroups of patients at high or low risk, for complications related to these procedures have a great potential benefit to patients and the health care system and would likely be relevant for several years.

26

http://www.uspreventiveservicestaskforce.org/uspstf07/cas/cassum.htm

6. Abbott AL. Medical (nonsurgical) intervention alone is now best for prevention of stroke associated with asymptomatic severe carotid stenosis: results of a systematic review and analysis. Stroke 2009; 40(10):e573-583.

7. Brott TG, Halperin JL, Abbara S, et al. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/ SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease: executive summary. Stroke. 2011;42(8):e420-463.

8. Gorelick PB. Carotid endarterectomy: where do we draw the line? Stroke 1999;30(9):1745-1750. 9. Goldstein LB, Moore WS, Robertson JT, et al. Complication rates for carotid endarterectomy. A call to action.

Stroke 1991; 22(11):1353-1357. 10. Barnett HJ. The inappropriate use of carotid endarterectomy. CMAJ 2004;171(5):473-474. 11. Rothwell PM, Goldstein LB. Carotid endarterectomy for asymptomatic carotid stenosis: asymptomatic carotid

surgery trial. Stroke 2004;35(10):2425-2427. 12. Guay J. Endovascular stenting or carotid endarterectomy for treatment of carotid stenosis: a meta-analysis. J

Cardiothorac Vasc Anesth. 2011;25(6):1024-1029. 13. Bonati LH, Lyrer P, Ederle J, et al. Percutaneous transluminal balloon angioplasty and stenting for carotid artery

stenosis. Cochrane Database Syst. Rev. 2012;9:CD000515. 14. Chimowitz MI, Lynn MJ, Derdeyn CP, et al.; SAMMPRIS Trial Investigators. Stenting versus aggressive medical

therapy for intracranial arterial stenosis. N Engl J Med. 2011;365(11):993-1003. 15. Powers WJ, Clarke WR, Grubb RL Jr, et al; COSS Investigators. Extracranial-intracranial bypass surgery for stroke

prevention in hemodynamic cerebral ischemia: the Carotid Occlusion Surgery Study randomized trial. JAMA. 2011;306(18):1983-1992.

APPENDIX: TOPIC QUESTIONS Nominated by ‘Web’

1) What is the optimal management of patients with asymptomatic carotid artery stenosis?

Population: Older patients of both genders and any ethnicity should be included in studies

Importance: The most relevant randomized trial addressing asymptomatic carotid disease is arguably obsolete (ACAS, 1995) since it was completed before use of statin agents became widespread. Because the margin of benefit of intervention over medical therapy was already narrow at that time, more effective medical therapy may have made intervention equivalent to medical therapy.

Nominated by National Institute of Health (NIH)

1) Revascularization vs. intensive medical management of asymptomatic carotid disease.

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http://www.ncbi.nlm.nih.gov/pubmed/21398144



Topic 5: “Cerebral Adrenoleukodystrophy (ALD )”

Comparative effectiveness of early versus late bone marrow transplant treatment for children affected by adrenoleukodystrophy (ALD).

28


of topic

DESCRIPTION OF CONDITION • Adrenoleukodystrophy (ALD) is an inherited disorder that affects how cells break down

nutrients called very long chain fatty acids. These acids accumulate in cells and affect organs including the brain, adrenal glands, and testes. The childhood cerebral form of the disease is the most severe form.

• ALD may be familiar from the movie “Lorenzo’s Oil.” • ALD is linked to the X chromosome:

o Boys have only one X chromosome, so carriers almost always develop symptoms. o Girls have two X chromosomes, but 50-65% of carriers may still develop symptoms later

in life. Relevance to


SYMPTOMS/OUTCOMES • Symptoms vary in severity and timing:

o 35% of male patients develop severe nerve symptoms during childhood, starting with behavioral problems and progressing to cognitive deficits, blindness, and quadriplegia. The adrenal glands are often affected. Average age of onset is 7 years. Progresses to vegetative state (similar to a coma) within one to two years. Death occurs within five to ten years.

o 45-50% of male patients develop a less severe form of the disease during adulthood (called adrenomyeloneuropathy or AMN). This causes a slowly progressing paralysis and can affect the adrenal glands. When female patients develop symptoms, it resembles AMN.

o 5-10% of patients develop adrenal gland problems only. • Other outcomes:

o Decreased quality of life for both patient and family o Reproductive concerns (female carrier has 50% chance of having an affected son and a

50% chance of passing the gene to a daughter) o Considerable uncertainty about benefits and harms of screening (among male patients,

there is no good way to predict who is going to develop symptoms, when they will occur, or their severity)



INCIDENCE (NEW CASES)1 o 1 in 42,000: hemizygotes (having only one of a given pair of genes, ie, males) o 1 in 16,800: including both hemizygotes and heterozygotes (having two different forms of

the gene, ie, females) PREVALENCE (PROPORTION OF POPULATION LIVING WITH THE CONDITION) o Approximately 27,000 people in the United States (0.001-0.009% of population)

Effects on patients’ quality of life, productivity, functional

QUALITY OF LIFE • Severity of ALD varies, but all patients who develop symptoms experience some decrease in

quality of life. In the severe childhood form (30-35% of patients), the impact on quality of life is major.

29

capacity, mortality, use of health care services

• Like all childhood illnesses, cerebral ALD has substantial effects on the whole family. PRODUCTIVITY • Affected children have an impact on parents’ productivity. • The impact for affected adults depends on the severity of symptoms. FUNCTIONAL CAPACITY • The severe childhood form limits patients’ ability to do normal daily activities. • The less severe form (AMN) can lead to total disability in up to 20% of cases. MORTALITY • Mortality is close to 100% within five to ten years of diagnosis for the severe childhood form.

AMN is also associated with early death in up to 20% of cases. How strongly does

this overall societal burden suggest that CER on alternative approaches to this problem should be given high priority?

Though ALD is rare, it carries a severe burden for people who have it and their families.



There are no systematic reviews on the severe childhood form of ALD, although there was a narrative review in 2012 of hematopoietic stem cell transplantation (HSCT) as a treatment in pediatric populations.2 This report attempted to conduct a systematic review of AMN, but pediatric data were too limited. A summary of the available evidence follows. SCREENING/EARLY DIAGNOSIS • Tests are available, but there is no direct evidence of improved outcomes for symptoms or

mortality based on identification of ALD in newborns. o Potential benefits include family planning, avoiding a lengthy process of diagnosis after

symptoms develop. o Potential harms include false-positive results, identification of newborns who will not

develop symptoms until later in life, complications of unproven therapies, identification of carriers and the resulting potential negative impact on quality of life.

TREATMENT o Replacement of adrenal gland hormones3,4

o No uncertainty; benefits (prevention of mortality) greatly outweigh harms when adrenal insufficiency is present (70% of patients with ALD).

o Dietary therapy (Lorenzo’s oil)3,5 o Uncontrolled studies have been conducted in asymptomatic boys discovered on

screening, boys with the severe childhood form, and adults with AMN. o Potential benefits include a reduction or delay in onset of developing cerebral disease in

asymptomatic patients (but no benefit if already present); may also slow pace of symptom progression in AMN.

o Potential harms include causing low platelet count, abnormal liver tests.

30

o HSCT3,6-11 o Potential benefits include improving neurologic symptoms and mortality in boys with

early symptoms or mild abnormalities on MRI: Little evidence for benefit in patients with advanced symptoms or MRI findings. Not recommended for patients with no abnormality on MRI, since half will not

develop brain disease. o Potential harms include death, severe infections, graft-versus-host disease, need for

immunosuppression drugs. o Medical treatments with lovastatin or phenylacetate show minimal evidence of benefits and

harms. o Gene therapy shows minimal evidence of benefits and harms.


New research in three main areas could contribute to better patient-centered outcomes: 1) Better understanding of benefits, harms, and costs associated with screening for ALD in

newborn males would potentially facilitate starting dietary therapy early and improving survival and neurologic outcomes. Additional outcomes to study could be patient and family quality of life and reproductive decisionmaking.

2) Further study is needed to define which patient subgroups benefit most from HSCT in terms of neurologic symptoms and survival. Existing data are limited to case series studies.6-9 Clinical trials to evaluate HSCT in predefined patient subgroups (for example, patients with severe childhood ALD with minimal symptoms, patients with severe childhood ALD with moderate-to-severe symptoms, and patients with less severe forms such as AMN) could examine outcomes such as survival, neurologic symptoms, and quality of life.

3) Research comparing novel, less-established therapies (gene therapy, treatment with lovastatin) to better established therapies (HSCT, dietary therapy) in predefined patient subgroups is needed to increase understanding of whether and how these therapies improve patient-centered outcomes.


The development of gene therapy as an option for treating ALD is a promising innovation and merits further research.


VARIABILITY IN CARE o Because ALD is a rare disease with variable presentation among patients, care requires

special expertise. Variability in care exists now but likely is appropriate given that patients present very differently.


RECENT PUBLICATIONS o In 2012 there was a comparative effectiveness review2 that evaluated four case-series

studies of HSCT in pediatric patients with severe childhood form of ALD.6-9 One additional case-series report of HSCT on the severe form of ALD has since been published.

ONGOING TRIALS o There are at least eight ongoing studies in ClinicalTrials.gov relating to ALD, three of which

address HSCT, and two which address dietary or medical therapies. There is a recently completed study comparing Lorenzo’s oil with placebo in adults with AMN, but results are not yet available. Outcomes assessed in these studies include neurological function and survival.

31

How likely is it that


The greatest limitation is the lack of randomized controlled trials and other controlled studies of HSCT, dietary therapy, gene therapy, and other treatments. Carrying out controlled studies may be difficult, however, due to the rarity of ALD and ethical concerns about withholding treatment in control patients for this often-fatal disease. Another limitation is that variation in disease symptoms from patient to patient makes it difficult to generalize findings of existing studies to all patients. KEY UNCERTAINTIES IN CLINICAL DECISIONMAKING: • What are the comparative benefits and harms of screening with different tests compared

with each other and with no screening? • Do the benefits of HSCT outweigh the potential harms in specific subgroups of patients with

ALD? • What is the role of newer therapies for ALD, such as gene therapy, compared with other

therapies? LIKELIHOOD THAT CER WOULD BE ABLE TO REDUCE THESE UNCERTAINTIES: o Because accurate screening tests exist, additional well-designed studies would likely be able

to reduce uncertainty in the area of ALD screening. Well-designed studies comparing different therapies (HSCT, dietary therapy, gene therapy) in different patient subgroups would help reduce uncertainty in treating ALD.



FACILITATORS o Technical experience with HSCT at specialized centers for ALD and other conditions o Potential high degree of acceptance for positive findings since ALD is a condition with

extremely poor prognosis and high impact on families BARRIERS • Variability in clinical presentation making it difficult to generalize findings to all patients • Costs of treatment • Availability of donor stem cells and access to specialized therapies such as HSCT o Potential for reluctance to accept negative findings since ALD is a condition with extremely

poor prognosis and high impact on families How likely is it that


EVIDENCE OF BENEFIT o If there is evidence of benefit, it is extremely likely that research results would be

implemented quickly. EVIDENCE OF NO BENEFIT OR HARM o Depending on the balance of benefits and harms, implementation may be less likely if there

is insufficient patient demand or provider uncertainty.

Would new information from CER on this topic remain current for several years, or would it be

Because ALD is a rare disease, often having a long delay between diagnosis and outcomes, the number of studies is necessarily small, and so findings from completed studies are likely to be relevant for a relatively long period compared with more common diseases having a shorter time to measurement of outcomes.

32

rendered obsolete quickly by subsequent studies?

REFERENCES: 1. Bezman L, Moser AB, Raymond GV, Rinaldo P, Watkins PA, Smith KD, Kass NE, Moser HW. Adrenoleukodystrophy:

incidence, new mutation rate, and results of extended family screening. Ann Neurol. 2001;49(4):512-517. 2. Ratko TA, Belinson SE, Brown HM, Noorani HZ, Chopra RD, Marbella A, Samson DJ, Bonnell CJ, Ziegler KM, Aronson

N. Hematopoietic Stem-Cell Transplantation in the Pediatric Population. Comparative Effectiveness Review No. 48. (Prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. HHSA 290-2007-10058.) AHRQ Publication No. 12-EHC018-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2012. www.effectivehealthcare.ahrq.gov/reports/final.cfm. Published February 2012. Accessed datexx.

3. Moser HW, Raymond GV, Dubey P. Adrenoleukodystrophy: new approaches to a neurodegenerative disease. JAMA. 2005;294(24):3131-3134.

4. Dubey P, Raymond G, Moser AB, Kharkar S, Bezman L, Moser HW. Adrenal insufficiency in asymptomatic adrenoleukodystrophy patients identified by very long chain fatty acid screening. J Pediatr. 2005;146:528-532.

5. Moser HW, Raymond GV, Lu SE, Muenz LR, Moser AB, Xu J, Jones RO, Loes DJ, Melhem ER, Dubey P, Bezman L, Brereton NH, Odone A. Follow-up of 89 asymptomatic patients with adrenoleukodystrophy treated with Lorenzo’s oil. Arch Neurol. 2005;62:1073-1080.

6. Aubourg P, Blanche S, JambaquéI, Rocchiccioli F, Kalifa G, Naud-Saudreau C, Rolland MO, DebréM, Chaussain JL, Griscelli C. Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation. N Engl J Med. 1990;322(26):1860-1866.

7. Loes DJ, Stillman AE, Hite S, Shapiro E, Lockman L, Latchaw RE, Moser H, Krivit W. Childhood cerebral form of adrenoleukodystrophy: short-term effect of bone marrow transplantation on brain MR observations. AJNR Am J Neuroradiol 1994;15(9):1767-1771.

8. Shapiro E, Krivit W, Lockman L, Jambaqué I, Peters C, Cowan M, Harris R, Blanche S, Bordigoni P, Loes D, Ziegler R, Crittenden M, Ris D, Berg B, Cox C, Moser H, Fischer A, Aubourg P. Long-term effect of bone-marrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy. Lancet. 2000;356:713-718.

9. Peters C, Charnas LR, Tan Y, Ziegler RS, Shapiro EG, DeFor T, Grewal SS, Orchard PJ, Abel SL, Goldman AI, Ramsay NK, Dusenbery KE, Loes DJ, Lockman LA, Kato S, Aubourg PR, Moser HW, Krivit W. Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999. Blood. 2004;104:881-888.

10. Miller WP, Rothman SM, Nascene D, Kivisto T, DeFor TE, Ziegler RS, Eisengart J, Leiser K, Raymond G, Lund TC, Tolar J, Orchard PJ. Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report. Blood. 2011;118(7):1971-1978.

11. Mahmood A, Dubey P, Moser HW, Moser A. X-linked adrenoleukodystrophy: therapeutic approaches to distinct phenotypes. Pediatr Transplant. 2005;9 Suppl 7:55-62.

Appendix: Topic Question Nominated by ‘Web’

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1) Adrenoleukodystrophy (ALD) is an X-linked disorder with an incidence of 1 in 17,000 males. It is characterized by an increase in very long chain fatty acids (VLCFA) in plasma and brain. In approximately 40% of boys with ALD, an acute inflammatory process develops within the central nervous system (CNS). The median age of onset of this neuroinflammatory process is age 7. Untreated, it is rapidly progressive and lethal, generally within several years of onset. Early in the course of cerebral ALD (C-ALD), bone marrow transplantation is effective in achieving disease stabilization. While patients early in the course of their disease have good outcomes with transplantation, many boys are not diagnosed until they are more advanced, limiting the ability of transplantation to stabilize the disease process. The question therefore becomes “Can we tell parents making decisions for their affected boys who is likely to have a reasonable outcome, and who is not?”

a. Population: This disease is limited to boys, based on how it is inherited. In regards to demographics, it

affects all ethnic groups relatively similarly.

b. Importance: Imagine that you have a boy that you have always thought is absolutely healthy, but he starts doing worse in school, is complaining of vision issues or hearing issues, and at some point an MRI is done. The MRI scan suggests ALD and the disease is confirmed with a blood test. Then the parents learn that not only does their son have an inherited disease affecting the brain, but that it is progressive and will be lethal within a few years. There is one potential intervention, which is bone marrow transplantation. However, in some situations, a transplant may stop the disease from getting worse, but in others a transplant may lead to a boy that is devastated neurologically and will require virtually total care, possibly for decades. It is extremely important to develop methods to determine who should be transplanted and who should not. This is the goal of our proposed study.

34

Topic 6: “Coronary Artery Disease (CAD)” Comparative effectiveness of coronary artery bypass surgery (CABG) and percutaneous coronary intervention (PCI) for treatment of adults with coronary artery disease.

35


of topic DESCRIPTION OF CONDITION • Coronary artery disease (CAD) is caused by atherosclerosis, a thickening or hardening of the

coronary arteries, which can lead to narrowing and obstruction of blood flow to the heart muscle.

• CAD can be present but not cause symptoms (asymptomatic).

• CAD can result in chest pain (angina) or a heart attack (myocardial infarction or MI for short).

• Treatment of CAD depends on the individual patient:

o All patients are given medications as needed for conditions they have that contribute to CAD, such as medications to prevent blood clots (blood thinners), treat high blood pressure, treat diabetes, and lower their cholesterol if it is too high.

o As the disease progresses, some patients require invasive treatments, such as percutaneous coronary interventions (PCI), or coronary artery bypass graft (CABG) surgery, which is even more invasive and with a longer recovery.1


SYMPTOMS • Shortness of breath

• Chest pain (angina)

• Heart attack (or MI), symptoms of which can include chest pain or crushing chest pain, pain and numbness down an arm, neck pain, back pain, jaw pain, nausea, sweating

OUTCOMES • Quality of life (freedom from chest pain, ability to do self-care and activities), prevention of

future heart attacks or strokes, survival, and prevention of complications (such as prolonged hospital stay, infection, bleeding) from the invasive treatments of PCI and CABG

PATIENT CHARACTERISTICS • Characteristics include, sex, race, age, comorbidities (hypertension, diabetes, high

cholesterol, chronic kidney disease, congestive heart failure), and lifestyle choices (heavy alcohol consumption, tobacco use, sedentary lifestyle).

• These characteristics affect disease progression and thus treatment of the patient.

SEVERITY OF CAD 36

• Determined by assessing the number and location of vessels with CAD and the degree of constriction (stenosis) of the diseased vessels

PROCEDURE/HEALTH CARE CENTER VARIABLES • PCI variables include choice of opening a vessel with balloon angioplasty or placing a stent

(small device to help hold vessels open)

• CABG variables include open-bypass (chest bone is opened), performed either

o “On pump” (heart is stopped, heart-lung bypass machine is used)

o “Off pump” (heart remains beating, no pump needed, heart does not need to be restarted but is technically more difficult for surgeon)

• MIDCAB procedure, a relatively new type of bypass, is less invasive (chest bone is not opened); it involves:

o Small cuts made on the left side of the chest between the ribs

o Repair limited to one or two coronary arteries

o Performing “on pump” or “off pump”

• Centers where more PCI and CABG procedures are performed have better outcomes, suggesting that experience is an important factor in improving how well a patient does after the procedure.

Burden on Society Recent incidence and

prevalence in populations and subpopulations

INCIDENCE (NEW CASES) • Rates of first heart attack or stroke in men rise from 3 per 1000 (aged 35-44) to 74 per

1000 (aged 85 to 94).2

• For women, comparable rates occur 10 years later in life.

• The gap between men and women narrows with advancing age.2

• 600,000 Americans die from heart disease each year, which is one in every four deaths.3

• CAD is the most common type of heart disease, killing more than 385,000 people annually.3

PREVALENCE (PROPORTION OF POPULATION LIVING WITH THE CONDITION) • Age-adjusted prevalence of CAD in a general US population was estimated at about 6%

in 2010, with higher prevalence in certain subgroups including patients over 65 years of age (19.8%), patients with diabetes (35%), and patients with chronic kidney disease (38-

37

65%).


QUALITY OF LIFE • Quality of life is associated with not having chest pain (known as angina).

o Patients undergoing CABG (rather than PCI) had less angina during the period from six months to three years after the procedure.

o The amount of chest pain was the same for both procedures after three years.

o Older patients had less angina in general.

PRODUCTIVITY • Lost productivity cost about $172 billion in 2010.4

FUNCTIONAL CAPACITY • CAD is one of the top three conditions causing disability in the United States.

MORTALITY • CAD is the leading cause of death in the United States in both men and women.

• Rate of death attributable to CAD decreased by 30% (from 1999 to 2009).

• African Americans with CAD die at a faster rate than Caucasians with CAD.

USE OF HEALTH CARE SERVICES • In the United States in 2009, ~596,000 patients underwent PCI, and ~242,000 patients

underwent CABG.

• PCI usually involves placement of a stent to keep a diseased vessel open.

• In 2010, CAD was the leading diagnosis across US hospitalized patients.


BURDEN • Given the large number of CAD patients and the aging society, priority should be given to

comparative-effectiveness research to determine the treatments with the best outcomes based on patient characteristics and severity of CAD.

38



Knowledge about benefits and harms of treatment options, based on a recent systematic review,5 include: BENEFITS

• Overall survival after PCI and CABG are now quite similar, with PCI being the less invasive option.

• Patients with 1-vessel disease (non-left anterior descending vessel) have better survival with PCI.

• Patients with 3-vessel, or left main, disease have better survival with CABG.

• In patients with diabetes and heart failure, there was no clear difference between PCI and CABG in terms of survival.

HARMS

• Risk of periprocedural heart attack was not significantly different with CABG compared to PCI.

• Risk of periprocedural stroke was higher with CABG compared to PCI.

• Complications were higher in older patients for both CABG and PCI.

• Patient results were worse for both procedures at hospitals where they were performed infrequently.


An AHRQ report in 20106 identified four areas where future research is indicated to answer areas of uncertainty: 1 Studies of the comparative effectiveness and safety of PCI vs. CABG should be done using

existing data (performing meta-analyses of individual patient data available from prior research projects).

2 Studies should evaluate the ability of tests to predict how well a person will do with different types of revascularization procedures. Such tests would include both invasive tests (arteriography) and noninvasive tests (magnetic resonance [MRI or computed tomography angiography], CT scan, and exercise treadmill testing).

3 Studies should enhance patient participation by asking for and measuring patient preferences as well as involving patients in decisions regarding their care.

4 Studies should develop performance measures that provide feedback to health care providers in order to improve outcomes for their patients.

39

Have recent


• Drug-eluting stents (DES) are a newer technology than bare-metal stents (BMS).

• Use of DES with PCI has increased markedly over the past decade.

• Most doctors who do PCI and CABG believe that there are fewer heart attacks and strokes in patients who receive DES (compared with BMS), but there are not enough data to support this belief.

• A 2007 AHRQ report5 included only one DES trial, but there are now six DES vs. CABG studies completed, with additional available data.

• An updated comparative-effectiveness report comparing DES with CABG could help determine whether DES is truly superior to BMS and further help define which populations of CAD patients do better with the less invasive PCI treatment (rather than CABG).


VARIABILITY IN CARE • Overall, there are fewer invasive procedures being done, and of those performed, rates for

the less invasive PCI have increased.

o An analysis of Medicare patients from 2001 to 2009 showed an increase for PCI of 1.3% per 1000 beneficiaries.

o During the same period, there was an annual decrease of CABG by 5%.

• An analysis of North Carolina data from 2003 to 20097 showed that rates of all invasive

procedures per 100,000 population declined:

o 24% decrease in catheterization rates

o 16% decrease in PCI rates

o 35% decrease in CABG rates


RECENT PUBLICATIONS • In a MEDLINE search over the past 5 years, 26,550 citations were identified related to

treatment of CAD:

o Randomized controlled trials (RCTs): 2853

o Cohort studies: 9831

o Systematic reviews: 1827

• In 2007, AHRQ published a comparative-effectiveness report of PCI vs. CABG for CAD5; an

40

addendum was published in February 2010 with meta-analysis of individual patient data from 10 of the 12 trials included in the 2007 report.

• In September 2010, AHRQ published a future research needs report about PCI vs. CABG for CAD.6

ONGOING TRIALS • A search of ClinicalTrials.gov lists 167 ongoing trials.

• Several projects are evaluating comparisons of single modalities; for example, DES vs. BMS in subgroups (elderly, diabetes); off-pump vs. on-pump CABG.

• There are few RCTs of PCI vs. CABG due to the difficulty in recruiting cardiologists and cardiac surgeons who are willing to randomize patients.

• An indirect or network meta-analysis combining single-modality studies of DES vs. BMS and the various CABG modalities could be performed to increase the number of PCI vs. CABG studies available for comparison.


KEY UNCERTAINTIES IN CLINICAL DECISION MAKING • Previous systematic reviews were based on older technologies (balloon angioplasty or

BMS).

• DES use has increased over the past decade.

• Findings from RCTs may not translate to results in real-world settings, where patients with multiple comorbidities are treated for CAD.

• RCTs have not been large enough to evaluate effectiveness in subgroups.

• Provider and patient preferences—rather than evidence—are used in determining the choice of invasive therapy to treat individual CAD patients.

REDUCING UNCERTAINTIES • Updated CER comparing DES and BMS, by looking at earlier data from BMS vs. CABG

studies and then newer data comparing DES vs. CABG, would reduce uncertainty about newer technologies.

• Pooling patient-level data would make it possible to have more information about optimal care for certain patient subgroups.

• Providers may be able to help patients make more informed decisions with better evidence.

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FACILITATORS • Professional societies and patient advocacy groups help to implement new guidelines as

more information is obtained.

• Educational initiatives, similar to “Get With the Guidelines” for MI and heart failure care, could be implemented.

BARRIERS • Physician and patient preferences, regardless of what the evidence may show, will always

factor into decisions about the use of invasive procedures.

• Some patients may choose a certain procedure due to insurance requirements, fear of surgery, or inability to take time away from work and caregiver responsibilities.


• Physician and patient preferences influence much of the variability in PCI and CABG use across the nation. This situation mandates additional research to increase our understanding of how particular types of disease, demographics, and comorbidities affect outcomes. This knowledge will help patients to optimize their treatments.

• Implementation would require collaborative effort among professional societies and patient advocacy groups as well as health care providers in order to educate patients and determine the best care for them.


• PCI and CABG have been the main invasive treatments for over two decades.

• While advances in PCI and CABG techniques are still being developed, it is likely that results from CER on this topic will be relevant for several years.

• Further, this is a prime group to work on this type of shared decision making model, because there are already strong professional societies and guideline groups in place.

References:

1. Incidence and Prevalence: 2006 Chart Book on Cardiovascular and Lung Diseases. Bethesda, MD: National Heart, Lung, and Blood Institute; 2006.

2. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation. 2013;2127(1):e6-e245. PMID: 23239837.

42

3. Kochanek KD, Xu JQ, Murphy SL, Miniño AM, Kung HC. Deaths: final data for 2009. National vital statistics reports. 2011;60(3).

4. Fang J, Shaw, KM, Keenan NL. Prevalence of Coronary Heart Disease – United States, 2006-2010. MMWR October 14, 2011;60(40):1377-1381.

5. Bravata DM, McDonald KM, Gienger AL, et al. Comparative Effectiveness of Percutaneous Coronary Interventions and Coronary Artery Bypass Grafting for Coronary Artery Disease. Comparative Effectiveness Review No. 9. (Prepared by Stanford-UCSF Evidence-based Practice Center under Contract No. 290-02-0017.) Rockville, MD: Agency for Healthcare Research and Quality; 2007. www.effectivehealthcare.ahrq.gov/reports/final.cfm. Published October 2007.

6. Trikalinos TA, Dahabreh IJ, Wong J, et al. Future Research Needs for the Comparison of Percutaneous Coronary Interventions with Bypass Graft Surgery in Nonacute Coronary Artery Disease. Future Research Needs Paper No. 1. (Prepared by the Tufts Evidence-based Practice Center under Contract No. 290-2007-10055-I.) AHRQ Publication No. 10-EHC068-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2010. www.effectivehealthcare.ahrq.gov/reports/final.cfm. Published September 2010.

7. Jones WS, Patel MR, Holleran SA, et al. Trends in the use of diagnostic coronary angiography, percutaneous coronary intervention, and coronary artery bypass graft surgery across North Carolina. Am Heart J. 2011;162(5):932-937. PMID: 22093211.

APPENDIX: Topic Questions Nominated by ‘Web’

1) How can we be certain that patients are being offered the proper treatment for coronary artery disease … percutaneous coronary intervention vs. coronary artery bypass surgery? How can we know whether guidelines are being followed in every institution? Population: All patients who have coronary artery disease, which would affect men and women of all ethnicities, but usually in the relatively elderly population. Importance: We know outcomes are affected by approach ... PCI vs. CABG. Are we using concordant decision making to assure that patients are being referred for the proper treatment? Best care would be most cost-effective in the long run.

Nominated by NIH

Comparative effectiveness of PCI vs. CABG [specifically for]:

Subpopulations:

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http://www.effectivehealthcare.ahrq.gov/reports/final.cfm.%20Published%20September%202010

• Age >75 years • Prior PCI • Diabetes • Women • Congestive heart failure • Stage 3 or 4 of chronic kidney disease

Comparisons: • BMS vs. on-pump traditional CABG with arterial grafts • DES vs. on-pump traditional CABG with arterial grafts

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Topic 7: “Ductal Carcinoma” Comparative effectiveness of management strategies for ductal carcinoma in situ (DCIS) among women who have had screening mammography.

45


of topic DESCRIPTION OF CONDITION • Ductal carcinoma in situ (DCIS):

o Abnormal cells that look like cancer cells lining the milk ducts of the breast that have not invaded the underlying breast tissue

• DCIS itself is not an invasive cancer, but may become an invasive breast cancer • Main clinical issue is that there is no reliable way to predict which patients with DCIS will go

on to develop invasive cancer and which will not Relevance to



o Most DCIS is asymptomatic and detected through screening mammography o Some women have nipple discharge or feel a lump

• Outcomes o Various treatment options for DCIS present trade-offs relevant to patient-centered

outcomes such as symptoms, function, and well-being Burden on Society Recent incidence


• INCIDENCE (NEW CASES) & PREVALENCE (PROPORTION OF POPULATION LIVING WITH THE CONDITION) o Approximately 54,944 new cases of DCIS are expected to occur among US women in

2013 o While the annual incidence of DCIS is less than that of invasive breast cancers, expanded

use of screening mammography has led to a dramatic increase in the diagnosis of DCIS (32.5 cases per 100,000 women).1 25% of all breast “cancers” diagnosed in the United States are DCIS

• KEY SUBPOPULATIONS o Increased risk of DCIS is associated with:1

Use of screening mammography Older age (peaks at ages 60-74) Race (Caucasian vs. African American) Family history of DCIS or positive for BRCA 1/2 genes Increased breast density None or one child and older age at birth of first child


QUALITY OF LIFE • Anxiety/uncertainty surrounding significance of diagnosis • Need for long-term follow-up • Treatments may have impact on body image, sexual functioning • Other potential side effects include lymphedema (swelling of arm because of blockage of

lymphatic flow) if extensive lymph node biopsy performed MORTALITY • 98% survival after diagnosis of DCIS

46


• Continued use of screening mammography, along with increasing prevalence of risk factors (baby boom population in highest risk group, later age at first birth) suggests overall incidence is likely to rise

• Low effect on mortality means that number of women living with diagnosis of DCIS will be very high



Four recent systematic reviews explored diagnosis and treatment options.1-4 They found: SCREENING/EARLY DIAGNOSIS • DCIS is primarily detected through screening mammography • There are no reliable methods for distinguishing clinically-relevant DCIS (likely to progress to

invasive cancer) from DCIS that would never become symptomatic or develop into invasive cancer

CLINICAL MANAGEMENT AND TREATMENT • Decisions about clinical management and treatment (and evaluation of harms and benefits)

are complicated by the fact that the proportion of untreated DCIS that would develop into invasive cancers of the breast is not known.

• Current clinical options include: o Mastectomy o Breast-conserving therapy alone o Breast-conserving therapy plus radiation therapy o Breast-conserving therapy plus radiation therapy, plus tamoxifen

• Benefits: o Most important potential benefit for any treatment is prevention of mortality from

invasive breast cancer, but without knowing prognosis for individual cases of DCIS, this is difficult to evaluate

o Additional potential benefits include: For DCIS destined to become invasive cancer, earlier treatments may be less

disfiguring and/or have fewer side effects Prevention of recurrence of DCIS (but if DCIS was never going to become invasive

cancer, this may not really be a benefit) • Harms:

o Effects of mastectomy on body image, relationships, and other factors o Lymphedema o Menopausal symptoms from tamoxifen o Increased risk of abnormal growth of lining of uterus with tamoxifen, leading to

abnormal bleeding or endometrial cancer What could new There are limited randomized studies of DCIS treatment on which to base decisions regarding the

47


trade-offs between the various treatment options.


No recent innovations, but to date there have been limited randomized studies of existing DCIS management and treatment options


VARIABILITY IN CARE • Variability in both surgical and postoperative management, with resulting variability in

outcomes5-11 What is the pace of


RECENT PUBLICATIONS • MEDLINE search from 1/1/2008–3/27/2013: total 136

o 6 randomized controlled trials/therapy o 65 cohort studies o 12 meta-analyses or systematic reviews

ONGOING TRIALS • There are at least 25 ongoing studies listed in ClinicalTrials.gov • NIH Reporter (a database of NIH funded studies) lists:

o 89 projects o 43 publications

How likely it is that new CER on this topic would provide better information to guide clinical decision making?

KEY UNCERTAINTIES IN CLINICAL DECISION MAKING • Biggest uncertainty in clinical decision making is which DCIS cases are truly “pre-cancers” • Patient preferences for different outcomes also unclear LIKELIHOOD THAT CER WOULD BE ABLE TO REDUCE THESE UNCERTAINTIES • There are few randomized controlled trials of promising treatments for women with DCIS. • CER unlikely to reduce uncertainty about clinical significance—identifying biomarkers, impact

of management on invasive cancer/mortality more of a basic science, NIH issue • Patient-centered CER could be highly useful if it focused on patient preferences, quality-of-

life, and anxiety issues rather than on traditional cancer outcomes Potential for New Information to Improve Care and Patient-Centered Outcomes What are the


FACILITATORS • High degree of uncertainty • Given the high survival rate, many of the most important outcomes relevant to CER are

related specifically to patient preferences BARRIERS • Significant anxiety about potential breast cancer diagnosis may contribute to preferences for

overly aggressive treatment options • Possibly provider incentives/disincentives for maintaining current practice patterns

How likely is it that the results of new

EVIDENCE OF BENEFIT • High likelihood of implementation if evidence of benefit

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REFERENCES: 1. Virnig BA, Tuttle TM, Shamliyan T, Kane RL. Ductal carcinoma in situ of the breast: a systematic review of incidence,

treatment, and outcomes. J Natl Cancer Inst. 2010;102(3):170-178. 2. Early and locally advanced breast cancer: diagnosis and treatment. Clinical guidelines CG80. UK National Institute for

Health and Care Excellence (NICE); February 2009. 3. Goodwin A, Parker S, Ghersi D, Wilcken N. Post-operative radiotherapy for ductal carcinoma in situ of the breast.

Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD000563. DOI:10.1002/14651858.CD000563.pub6.

4. Staley H, McCallum I, Bruce J. Postoperative tamoxifen for ductal carcinoma in situ. Cochrane Database of Systematic Reviews 2012, Issue 10. Art. No.: CD007847. DOI: 10.1002/14651858.CD007847.pub2.

5. Baxter NN, Virnig BA, Durham SB, Tuttle TM. Trends in the treatment of ductal carcinoma in situ of the breast. J Natl Cancer Inst. 2004;96(6):443–448.

6. Katz J, Lantz PM, Janz NK, et al. Patterns and correlates of local therapy for women with ductal carcinoma-in-situ. J Clin Oncol. 2005;23(13):3001–3007.

7. Partridge A, Winer JP, Golshan M, et al. Perceptions and management approaches of physicians who care for women with ductal carcinoma in situ. Clin Breast Cancer. 2008;8(3):275-280

8. Rakovitch E, Pignol JP, Chartier C, et al. The management of ductal carcinoma in situ of the breast: a screened population-based analysis. Breast Cancer Res Treat. 2007;101(3):335–347.

9. Tuttle TM, Jarosek S, Habermann EB, et al. Increasing rates of contralateral prophylactic mastectomy among patients with ductal carcinoma in situ. J Clin Oncol. 2009;27(9):1362–1367.

10. Gold HT, Dick AW. Variations in treatment for ductal carcinoma in situ in elderly women. Med Care. 2004;42(3):267-275.

11. Dick AW, Sorbero MS, Ahrendt GM, et al. Comparative effectiveness of ductal carcinoma in situ management and the roles of margins and surgeons. J Natl Cancer Inst. 2011;103(2):92-104.


research on this topic would be implemented in practice right away?

EVIDENCE OF NO BENEFIT OR HARM • Implementation of less aggressive practices related to screening/treatment often more

difficult because of residual patient anxieties about risk and potential provider incentives for recommending specific treatments

• Relative weighting of harms may also create barriers (eg, some patients/providers may feel that “over-diagnosis” is worth preventing cancer)


There are few randomized controlled trials of promising treatments for women with DCIS. It is highly likely that new information on the management of DCIS will be current for several years.

49

Nominated by the Institute of Medicine (IOM):

• Compare the effectiveness of management strategies for ductal carcinoma in situ (DCIS).

50

Topic 8: “Gestational Diabetes” Comparative effectiveness of medical, surgical and lifestyle treatment options in the prevention and treatment of gestational diabetes.

51


of topic DESCRIPTION OF CONDITION • Normal pregnancy increases the body’s need for insulin, resulting in increases in blood sugar. • Some women do not produce enough insulin, or their bodies cannot use the insulin well

enough. • As blood sugar rises, the risk of certain adverse outcomes for mother and infant increase. • Although the association between increasing blood sugar and increasing risk of adverse

outcomes is continuous, there are different definitions for the threshold for distinguishing “gestational diabetes” (GDM) from “normal” elevations in blood sugar.


SYMPTOMS/OUTCOMES • Increased blood sugar more sugar available to the baby larger baby than normal

(relative proportions of different parts of baby’s body also different, affecting labor and delivery)

• Most common adverse outcomes of GDM related to larger babies • Outcomes for babies

o Short term Shoulder dystocia

During labor, the head delivers but the baby’s shoulders get stuck—this is potentially fatal. However, the most common adverse outcome is injury to the nerves around the baby’s neck/shoulders, which can result in permanent disability to the baby.

Postdelivery hypoglycemia (low blood sugar) Other respiratory and metabolic complications

o Long term Higher rates of obesity, hyperactivity/attention disorders, diabetes later in life

(although unclear if treatment during pregnancy affects these outcomes) • Outcomes for mothers

o Short term Association with preeclampsia (high blood pressure and protein in the urine,

occasionally leading to seizures); increases risk of death for both mother and baby, sometimes necessitating premature delivery of the baby

Increased risk of Cesarean section (C-section), both because of difficult labor due to large baby and lower physician threshold regarding performing C-sections because of concerns about shoulder dystocia

Injury to the vagina, bladder, and/or rectum from large baby, which may lead to problems with incontinence, prolapse

NIH Consensus Panel noted paucity of data on quality of life, particularly anxiety1 o Long term2 5-10% of women diagnosed with GDM have overt diabetes, usually type 2, diagnosed

immediately after pregnancy 35-60% chance of developing overt diabetes in next 10-20 years

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INCIDENCE (NEW CASES) & PREVALENCE (PROPORTION OF POPULATION LIVING WITH THE CONDITION) • Rates of GDM vary across studies (in part due to varying definitions for GDM) • Using older definitions, rates of GDM range from 2-10% of pregnancies in the United States

(of the approximately four million deliveries, 80,000-400,000 women, annually)2 • New proposed definition would increase proportion of women diagnosed with GDM to 15-

20% of pregnancies (600,000-800,000 women annually)3 • Risk increased in some ethnic populations

o African American o Hispanic/Latino American o Native American o Pacific Islander

• Risk increased in older women, obese women, and women with family history of diabetes o Incidence increasing over time as average age of pregnancy increases and prevalence of

obesity in population increases Effects on patients’


• QUALITY OF LIFE o Diagnosis of GDM carries significant self-management burden for mothers (checking

sugar levels multiple times a day) o Having a larger baby can cause birth trauma or more C-sections, which impact mother’s

quality of life and recovery from birth o History of GDM is linked to a greater risk of the mother developing type 2 diabetes, type

1 diabetes, and cardiovascular disease later in life o Diagnosis of GDM may cause significant anxiety/concern over and above normal

concerns about pregnancy • PRODUCTIVITY

o In the short term, C-sections have longer recovery than vaginal delivery and may interfere with mother-infant interaction in the delivery room.

o In the longer term, a history of GDM increases the risk of other chronic illnesses (diabetes, cardiovascular disease). Developing these chronic conditions may impact mother’s future productivity.

• FUNCTIONAL CAPACITY o C-sections is associated with a higher rate of injury to some organs (bladder, bowel,

blood vessels), infections (wound, uterus, urinary tract), and blood clotting complications (although absolute risks are low).

o Children of mothers with GDM have higher rates of childhood obesity, hyperactivity/inattention disorders, and higher rates of developing diabetes later in life.

• MORTALITY o For fetus, greater risk of death near time of delivery o For mothers, greater risk life-threatening preeclampsia o Absolute risk for death in both mother and infant low

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How strongly does


• GDM is relatively common, and new definitions may make it even more common • Short- and long-term effects on mother and infant

o Significant impact on C-section utilization alone • Major source of uncertainty is effect of changing screening practices/definitions, with –two-

to three-fold increase in number of women diagnosed with GDM and relative lack of data on benefits and harms in this broader population



SYSTEMATIC REVIEWS/AVAILABLE DATA • Ample systematic review data available regarding screening/diagnosis, prevention, and

treatment of GDM • However, available data based on studies conducted using different screening/diagnostic

criteria—unclear how they would apply if criteria change SCREENING/EARLY DIAGNOSIS • Two main options for screening (usually between 24-28 weeks gestation, earlier for high-risk

women) o “Two-step” approach traditional in the United States, recommended by American

Congress of Obstetricians and Gynecologists (ACOG)4-5 50 grams of glucose taken orally without regard to whether woman has recently

eaten Blood glucose (sugar) measured 1 hour later

− If less than cutoff, patient is “negative” and no further testing − If above cutoff, a second step (on another day) is performed, using 100 grams of

glucose while patient is fasting; blood glucose measured before the dose and 1, 2, and 3 hours after and compared to cutoffs to make diagnosis.

This approach was originally developed to identify women at risk for developing diabetes later in life, not to identify women at high risk for GDM-related complications during pregnancy

Minimizes the number of women needed to fast for testing (can be difficulty/inconvenient during pregnancy)

o “One-step” approach used internationally, recommended by International Association of Diabetes and Pregnancy Study Group (IADPSG) and American Diabetes Association (ADA)3,6 75 grams of glucose given while fasting Fasting, 1-, and 2-hour levels compared against criteria Some minor differences in definitions between two groups IADPSG cutoffs based on pregnancy outcomes (glucose values associated with 1.75-

fold increase in selected adverse outcomes) o Adoption of “one-step” approach would make US practice consistent with rest of world,

but would increase number of women with diagnosis of GDM two- to three-fold o Recent NIH Consensus Conference (March 2013) concluded too little data about relative

benefits and harms to recommend change1 PREVENTION OF GDM

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• Lack of clear evidence on weight loss, diet, or physical activity before or during pregnancy to prevent GDM

TREATMENT • According to a recent AHRQ-sponsored systematic review, there is moderate evidence for

reduction of preeclampsia, macrosomia (big baby), and shoulder dystocia with receipt of treatment for GDM (defined as treatments reducing maternal blood sugar levels)7 o Diet/activity may be sufficient o If no response, insulin is standard of care, but uncertainty about safety of some

preparations o Limited data on oral agents in the United States, none FDA-approved o Limited data on harms/benefits of different delivery management strategies (eg,

induction of labor) PREVENTION OF LONG-TERM MATERNAL DIABETES • No data on effectiveness of strategies aimed at preventing long-term development of

diabetes in women

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What could new


New research could contribute to achieving better patient-centered outcomes in certain key areas: • Diagnosis/screening:

o Further comparative-effectiveness research (CER) evaluating the timing of assessment for GDM could improve patient-centered outcomes (for both mothers and babies)

o Further CER evaluating strategies for assessment of GDM (for example one-step vs. two-step strategy, 100 gram vs. 75 gram glucose tolerance tests) could improve patient-centered outcomes for both mothers and babies

• Prevention o Further CER exploring prevention of GDM through nutritional, exercise, and drug

treatment strategies could improve patient-centered outcomes for both mothers and babies

• Treatment o Further CER exploring treatment of GDM through nutritional, exercise, and different

pharmacologic strategies (including insulin, more established medications like glyburide and metformin, and newer medication classes) could improve patient-centered outcomes for both mothers and babies

o In particular, further CER to identify safe and effective alternatives to insulin could improve patient-centered outcomes such as quality of life (because insulin imposes a greater self-management burden on mothers)

• Development of GDM and overt diabetes o Research to identify risk factors for GDM and subsequent development of overt diabetes

could improve patient-centered outcomes for both mothers and babies o Potential risk factors could include maternal health behaviors (such as diet, physical

activity, or breastfeeding), maternal metabolic measures (such as glucose tolerance test, insulin levels, or cortisol levels), comorbid conditions (such as advanced maternal age, hypertension, or hyperlipidemia), genetic factors (such as gene mutations, epigenetic factors, and gene-environment interactions)

o Further CER exploring prevention of subsequent development of overt diabetes following GDM (through behavioral change strategies, lifestyle interventions, or pharmacologic strategies) could improve patient-centered outcomes for both mothers and babies


Recent innovations: • With the availability of new classes of non-insulin-dependent diabetes medications in

addition to better-established non-insulin-dependent diabetes medications, research on prevention and non-insulin-dependent treatment of GDM using these therapies is compelling

• As our understanding of the role of genetic factors in development of disease expands, new opportunities exist to explore novel questions about risk factors for the development of GDM and the development of overt diabetes after GDM (including gene mutations, epigenetic factors, and gene-environment interactions)


VARIABILITY IN CARE • Widespread variation in delivery practices between types of providers (obstetricians, family

practice physicians, nurse midwives) and within different groups • Variability in postdelivery screening/testing

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What is the pace of


RECENT PUBLICATIONS • MEDLINE search, 1/1/2008 – 4/3/2013: total 575

o 53 randomized controlled trials (RCTs) o 58 meta-analyses or systematic reviews



How likely is it that


KEY UNCERTAINTIES IN CLINICAL DECISION MAKING • What is the optimal timing and mode of GDM screening? • What are the comparative benefits and harms of different behavioral strategies (diet,

exercise) and drug treatments on mother and child outcomes? • What is the optimal management of women diagnosed with GDM after delivery? • What is the optimal management of children born to women with GDM? LIKELIHOOD THAT CER WOULD BE ABLE TO REDUCE THESE UNCERTAINTIES • While there have been many systematic reviews on GDM, most point to a lack of well-

designed, higher-quality studies. New, high-quality CER could contribute significantly to this area and provide needed guidance for clinical decision making.



FACILITATORS • Common condition with serious outcomes that impact both mother and child. • Pregnancy is a time of heightened patient activation. Thus, patient may be adherent to new

behaviors at this time if prompted by physician.

BARRIERS • Variability in screening and diagnostic criteria may lead to differential implementation • Cost of treatments • Patient compliance with taking medications during pregnancy • Uncertain how patients and providers weigh relative benefits/harms to mother vs. infant in

event of competing risks; further research on this alone would be critical and have applicability beyond management of GDM


EVIDENCE OF BENEFIT • Likely to be implemented if clear evidence of better mother-child outcomes EVIDENCE OF NO BENEFIT OR HARM • Depending on practice, likelihood of stopping/decreasing practice may be variable. For

example, to the extent that C-section rates are driven by provider concern about adverse outcomes and subsequent malpractice litigation, lack of evidence of benefit may still not lead to changes in practice.

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REFERENCES:

1. National Institutes of Health Consensus Development Conference: Diagnosing Gestational Diabetes Mellitus Conference; March 4–6, 2013. Draft Statement. http://prevention.nih.gov/cdp/conferences/2013/gdm/resources.aspx. Published March 2013. Accessed April 11, 2013.

2. Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2011. http://www.cdc.gov/diabetes/pubs/factsheet11.htm. Published 2011. Accessed April 11, 2013.

3. Metzger BE, Gabbe SG, Persson B, Buchanan TA, Catalano PA, Damm P, Dyer AR, Leiva A, Hod M, Kitzmiler JL, Lowe LP, McIntyre HD, Oats JJ, Omori Y, Schmidt MI. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010;33(3):676-682.

4. Anonymous. Committee opinion no. 504: screening and diagnosis of gestational diabetes mellitus. Obstet Gynecol. 2011;118(3):751-753.

5. American College of Obstetricians and Gynecologists Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists. Number 30, September 2001 (replaces Technical Bulletin Number 200, December 1994). Gestational diabetes. Obstet Gynecol. 2001;98(3):525-538.

6. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2013;36 Suppl 1:S67-74.

7. Hartling L, Dryden DM, Guthrie A, Muise M, Vandermeer B, Aktary WM, Pasichnyk D, Seida JC, Donovan L. Screening and Diagnosing Gestational Diabetes Mellitus. Evidence Report/Technology Assessment No. 210. (Prepared by the University of Alberta Evidence-based Practice Center under Contract No. 290-2007-10021-I.) AHRQ Publication No. 12(13)-E021-EF. Rockville, MD: Agency for Healthcare Research and Quality;2012.www.effectivehealthcare.ahrq.gov/reports/final.cfm. Published October 2012. Accessed April 11, 2013.


• GDM is a relatively common condition with multiple uncertainties in diagnosis and treatment. It is likely that high-quality RCT evidence would remain current for several years.

• At current time, greatest controversy in this field is whether to adapt one-step screening, with consequent two- to three-fold increase in number of women diagnosed with GDM o Because the likelihood of benefits and harms and the ratio of benefits and harms will

vary based on the underlying population, new research on prevention, treatment, and postpregnancy management would all need to be conducted.

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http://prevention.nih.gov/cdp/conferences/2013/gdm/resources.aspx

http://www.cdc.gov/diabetes/pubs/factsheet11.htm


APPENDIX: TOPIC QUESTIONS Nominated by AHRQ

1. What are the effectiveness and safety of any of the second generation sulfonylureas compared to any insulin in the treatment of gestational diabetes with regard to the following: short- and long-term maternal outcomes, neonatal outcomes, and long-term offspring outcomes?

2. What are the effectiveness and safety of metformin compared to any insulin in the treatment of gestational diabetes with regard to the following: short- and long-term maternal outcomes, neonatal outcomes, and long-term offspring outcomes?

3. What are the comparative effectiveness and safety of various insulin regimens in terms of type/duration, dosing, and frequency of administration in the treatment of gestational diabetes with regard to the following: short- and long-term maternal outcomes, neonatal outcomes, and long-term offspring outcomes?

4. What are the effectiveness and safety of other hypoglycemic drug classes (eg, thiazolidinediones, DPP-4 inhibitors, GLP-1 agonists, meglitinides) compared to any insulin or other hypoglycemic drugs in the treatment of gestational diabetes with regard to the following: short- and long-term maternal outcomes, neonatal outcomes, and long-term offspring outcomes?

5. What are the effectiveness and safety of elective labor induction at 40 weeks compared to expectant management in women with gestational diabetes with regard to the following: maternal and neonatal outcomes?

6. What are the effectiveness and safety of elective cesarean delivery at 40 weeks compared to expectant management in women with gestational diabetes with regard to the following: maternal and neonatal outcomes?

7. What is the evidence that maternal health behaviors (such as breastfeeding, physical activity, diet) are associated with the risk of developing type 2 diabetes or glucose intolerance/ impaired fasting glucose following a pregnancy with gestational diabetes?

8. What is the evidence that maternal metabolic measures (eg, fasting insulin levels, OGTT measures, HPA axis stress (subclinical hypercortisolism)) are associated with the risk of developing type 2 diabetes or glucose intolerance/impaired fasting glucose following a pregnancy with gestational diabetes?

9. What is the evidence that comorbid conditions (eg, advanced maternal age, obesity, hypertension, hypercholesterolemia) are associated with the risk of developing type 2 diabetes or glucose intolerance/impaired fasting glucose following a pregnancy with gestational diabetes?

10. What is the evidence that family history, gene mutations, genotypes, gene-environment interactions, epigenetic modifications, or other biomarkers are associated with the risk of developing type 2 diabetes or glucose intolerance/impaired fasting glucose among women with gestational diabetes? Are there differences in these associations by race or ethnic group?

11. What is the comparative effectiveness of various lifestyle interventions (eg, diet, physical activity, smoking) for prevention of type 2 diabetes, glucose intolerance/impaired fasting glucose, and obesity in women with a history of gestational diabetes?

12. What is the comparative effectiveness of various educational and behavioral change strategies (eg, patient education about diabetes risk, lactation support, diet, physical activity) for prevention of type 2 diabetes and glucose intolerance/impaired fasting glucose in women with a history of gestational diabetes?

13. What are the performance characteristics (sensitivity, specificity, and reproducibility) of a single fasting blood glucose test compared to the full 2-hour 75-gm OGTT in screening for type 2 diabetes and glucose intolerance/impaired fasting glucose following a pregnancy with gestational diabetes? Does the accuracy of the

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fasting blood glucose test compared to the full 2-hour 75-gm OGTT vary with the postpartum testing interval in screening for type 2 diabetes and glucose intolerance/impaired fasting glucose following a pregnancy with gestational diabetes?

14. What are the performance characteristics (sensitivity, specificity, and reproducibility) of the HbA1c test compared to the 2-hour 75-gm OGTT in screening for type 2 diabetes and glucose intolerance/impaired fasting glucose following a pregnancy with gestational diabetes? Does the accuracy of the HbA1c test compared to the full 2 hour 75- gm OGTT vary with the postpartum testing interval in screening for type 2 diabetes and glucose intolerance/impaired fasting glucose following a pregnancy with gestational diabetes?

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Topic 9: “Eczema” Comparative effectiveness of treatment options for topical or systemic eczema in children and adults.

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of topic DESCRIPTION OF CONDITION1,2 • Eczema (also known as atopic dermatitis) is a chronic inflammatory skin condition. • It is often the first manifestation of other allergic diseases (allergic rhinitis or hay fever,

asthma, food allergy). • It typically presents in early childhood but can develop in adulthood. • It is characterized by defects in the skin’s protective outer layer. These defects can either

develop over time (acquired) or be something a patient is born with (genetic). • An inadequate immune response may increase one’s susceptibility to infections.


SYMPTOMS1,2 • Three recurring phases of itchy skin lesions:

o Acute—weeping, crusted skin lesions o Subacute—dry, scaly, red skin lesions o Chronic—thickened skin lesions from scratching

• Can be exacerbated by temperature, humidity, irritants, infections, food, allergens and emotional stress.

DIAGNOSIS • No objective diagnostic test • Diagnosis based on clinical features COMPLICATIONS • Sleep disturbance • Chronic skin changes • Scarring from picking and scratching • Secondary skin infections (bacterial and viral)



PREVALENCE2,3 • 17.8 million people in the United States are living with eczema • 10-20% of US children • Prevalence is increasing • Study of US children 17 years of age or younger:

o Prevalence ranged from 8.7% to 18.1% from state to state o Higher disease prevalence associated with metropolitan living, African American

population, and educational levels in the household greater than high school Effects on patients’


QUALITY OF LIFE1,4 • Significant impact on patients (and difficult for caregivers to manage in children) • Sleep disruption (from itching) • Inhibited bonding and touching between parent and affected infant • Parental feelings of inadequacy about caring for their affected child • Embarrassment and avoidance of daily activities • Emotional distress and at risk for behavioral problems, anxiety, and depression • Financial costs, time demands, and lifestyle changes associated with disease management

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PRODUCTIVITY4 • Missed school or work days • Lost work days for medical appointments and when children miss school

USE OF HEALTH CARE SERVICES4 • Moderate disease—13 physician visits per year and annual cost of $1700 for family • Severe disease—23 physician visits per year and annual cost of $2500 or more


US costs are estimated between $364 million and $3.8 billion annually.5



MANAGEMENT OPTIONS Standard therapy for eczema includes skin hydration, topical corticosteroids, and antihistamines. Studies comparing topical corticosteroids with calcineurin inhibitors have shown that calcineurin inhibitors are more effective at reducing skin inflammation than low-potency topical corticosteroids; but have similar efficacy to mid-potency topical corticosteroids. Other therapies are introduced if the eczema does not respond to standard therapy. Costs and side effects influence the choice of therapy. For example, calcineurin inhibitors are expensive, and the side effect profile includes immunosuppression and increased risk of skin cancer. Brief descriptions of the benefits and harms of routine therapies follow.1,2

• Skin hydration: Warm, soaking baths and application of a moisturizer:

o Potential benefits are improvement of skin-barrier function, decreased itching, maintenance of skin texture, decreased need to use corticosteroids.

o Potential harms are skin irritation or drying (if lotion or cream) and interfering with sweat ducts (if occlusive ointment).

• Topical corticosteroids: Seven levels of medication strength, which should be tailored to disease severity: o Potential benefits include effective treatment (low potency used for maintenance, high

potency for treatment of exacerbations over short periods). o Potential harms are systemic and local: Systemic (suppression of hypothalamic-pituitary-adrenal axis) harms vary with

potency, application site, percent of body covered, and duration of use (and is more likely in small children and infants (who have a higher body surface area ratio than adults).

Local harms are thinning of the skin; rash around mouth; bumpy, acne-like rash on nose; and contact dermatitis.

• Calcineurin inhibitors: Tacrolimus and pimecrolimus, approved for use in patients older than

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2 years of age. These are particularly useful for eczema on the face that is not responsive to low-potency topical steroids: o Potential benefits include reduced itchiness, no skin atrophy, and greater therapeutic

margin of safety than medium-strength glucocorticoids for facial and eyelid eczema. o Potential harms are transient local burning and itching in the first week, facial flushing

after drinking alcoholic beverages, possible increase in viral skin infections (herpes simplex, molluscum contagiosum), possible immunosuppression, and possible link to lymphoma and skin cancer (but no conclusive evidence for lymphoma and skin cancer).

• Tar preparations: No randomized controlled studies demonstrating efficacy; tar preparations can potentially irritate the skin.

• Antihistamines: Little objective evidence demonstrating relief of itching for sedating or nonsedating oral antihistamines. Additionally, topical antihistamines can potentially cause skin to become increasingly inflamed and reactive to irritants.

• Food allergy testing: Recommended only if patient has persistent eczema despite optimal management, or if there is a reliable history of an immediate allergic reaction after ingestion of food.

• Extensive elimination diets: Based on positive skin tests or specific immunoglobulin-E test results, not recommended because of potential development of nutritional deficiencies.

• Nutritional supplementation and Probiotics: Fish oil, zinc sulphate, selenium, vitamin E, vitamin D, pyridoxine, buckthorn seed oil, buckthorn pulp oil, hempseed oil, sunflower oil, DHA, and probiotics:1,2,6,7 o There is no convincing evidence for benefits of nutritional supplements or existing

probiotics. o Nutritional studies were small with low numbers of participants and of poor quality. o Two trials of fish oil found some slight improvement in terms of itchiness and quality of

life; but these were small trials and larger trials are needed before recommendations can be made.

o There is also ongoing research regarding giving supplemental Vitamin D if the patient has low vitamin D levels confirmed by a blood test.

o There is no evidence for harms in nutritional supplementation studies except: There is a potential for vitamin D toxicity if taken in high doses. Probiotics can cause infections and digestion problems.

• Therapies for difficult-to-manage patients:1,2 o Systemic immunomodulating agents (medications that help regulate your immunity)

include cyclosporine A, mycophenolate mofetil, azathioprine, interferon-gamma, systemic corticosteroids, and methotrexate.

All have potential for serious adverse effects. o Phototherapy (ultraviolet therapy, made up of mostly UVA rays), the benefit has to be

weighed against the potential skin damage caused by these treatments (similar to sun exposure and tanning beds).

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What could new


• Itching is the most significant complaint of patients with eczema; therefore improved patient outcomes must include evaluating therapies that can control itching.

• A recent meta-analysis8 suggests that topical therapies were preferable to systemic therapies at controlling itching. o Further, calcineurin inhibitors were the most effective agent at controlling itching. o Studies designed to evaluate the safe use of these agents in children and patients

younger than two years of age are needed. • The role of omega-3 fatty acids in the treatment of eczema symptoms has been evaluated

only in small studies. Larger studies are needed that assess the potential role of these dietary supplements.


• The most recent innovation has been the approval of calcineurin inhibitors. • However, the black-box warning for these topical agents (lack of long-term safety data and

the potential risk of the development of skin cancer) has likely limited their use, particularly in children.

• Attempting to better define the role of calcineurin inhibitors in treating childhood eczema is compelling.


Care varies widely: • Eczema is a common condition for which patients seek care from health care providers

representing a wide variety of different specialties. • Many patients self-treat with over-the-counter creams without consultation from health care

professionals. What is the pace of


Clinicaltrials.gov: Search: Eczema Total ongoing trials: 75 Completed trials: 122

Clinicaltrials.gov: Search: Dermatitis Total ongoing trials: 139 Completed trials: 339


• New comparative-effectiveness research (CER) that provides compelling information about treatment or prevention approaches that can be easily understood and implemented by patients or caregivers is likely to guide patient-driven clinical decisions.

• There is a need for better, faster ways to identify the allergen causing the eczema to reduce a patient’s exposure to the allergen or to identify a medication that will treat the reaction. Until we have better diagnostic methods, clinical treatments are chosen by trial and error (that is, “Let’s see if this works, and if not, we’ll try something else”).



FACILITATORS • Desire by stakeholders to improve care • Generally well-informed patients who may be able to access new findings via the Internet BARRIERS • Diversity of health care providers (dermatologists, general internists, family physicians,

gynecologists, alternative medicine practitioners, and the like) who treat eczema • Large amount of currently available information on the Internet • Wide variation of beliefs about what causes eczema and what are plausibly effective

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treatment options How likely is it that


• Results of new research on this topic would need to be disseminated to a diverse group of stakeholders.

• However, with targeted efforts towards dermatologists and allergists (who see a large volume of eczema in their practices), this information would be helpful for discussing the risks and benefits of treatment options with those who suffer with eczema.

Would new information from CER remain current, or would it be rendered obsolete quickly by subsequent studies?

• Eczema seems to be a relatively active topic in ongoing research. • Many different claims of efficacy and harms associated with a variety of different treatment

approaches are readily available on the Internet. • In order for new CER information on this topic to remain current, it would have to be

perceived by stakeholders as compelling in order to compete with existing and future information (substantiated by evidence or not).

REFERENCES

1) Schneider L, Tilles S, Lio P et al. Atopic dermatitis: A practice parameter update 2012. J Allergy Clin Immunol 2013;131:295-299.

2) Berke R, Singh A, Guralnick M et al. Atopic dermatitis: An overview. Am Fam Physician. 2012;86(1)35-42. 3) Eichenfield LF, Ellis CN, Mancinin AJ, Paller AS, Simpson EL. Atopic dermatitis. Epidemiology and Pathogenesis

Update. 2012 Semin Cutan Med Surg 31 (suppl 3):S3-5. 4) O’Connell EJ. The burden of atopy and asthma in children. Allergy 2004 59 (Suppl.78):7-11. 5) Mancini AJ. Kaulback K, Chamlin SL. The socioeconomic impact of atopic dermatitis in the United States: A

systematic review. Pediatric Dermatology 2008;25(1) 1-6. 6) Bath-Hextall FJ, Jenkinson C, Humphreys R, Williams HC. Dietary supplements for established atopic eczema.

2012 The Cochrane Collaboration. 7) Boyle RJ, Bath-Hextall FJ, Leonardi-Bee J, Murrell DF, Tang MLK. Probiotics for treating eczema (Review). 2008.

The Cochrane Collaboration. 8) Sher LG, Chang J, Patel IB, Balkrishnan R, Fleischer AB Jr. Relieving the pruritis of atopic dermatitis: a meta-

analysis. Acta Derm Venereol. 2012 Sep;92(5):455-461.

APPENDIX: Topic Question

Nominated over the Web 1) What safe therapies are there to stop the itch associated with eczema, either topical or systemic? Topical

corticosteroids do not work for everyone, and they are not appropriate for the face. For infants, it is not always a great option to cover the entire body and does not stop the itching.

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http://www.ncbi.nlm.nih.gov/pubmed?term=Sher%20LG%5BAuthor%5D&cauthor=true&cauthor_uid=22773026

http://www.ncbi.nlm.nih.gov/pubmed?term=Chang%20J%5BAuthor%5D&cauthor=true&cauthor_uid=22773026

http://www.ncbi.nlm.nih.gov/pubmed?term=Patel%20IB%5BAuthor%5D&cauthor=true&cauthor_uid=22773026

http://www.ncbi.nlm.nih.gov/pubmed?term=Balkrishnan%20R%5BAuthor%5D&cauthor=true&cauthor_uid=22773026

http://www.ncbi.nlm.nih.gov/pubmed?term=Fleischer%20AB%20Jr%5BAuthor%5D&cauthor=true&cauthor_uid=22773026

http://www.ncbi.nlm.nih.gov/pubmed/?term=Relieving+the+pruritus+of+atopic+dermatitis%3A+a+meta-analysis.

Population: All ages and ethnic groups.

Importance: Because there are so many people still suffering with eczema. 2) I would like to see more research on eczema, what causes it, and most importantly nonmedication treatment

options. I am particularly interested in the link between nutrition, omega-3 fatty acids and eczema. Thank you! Population: Adults and children

Importance: Both my daughter and I suffer from eczema and have spent countless hours researching this very common condition. We accidentally discovered a link between fats and eczema, and use a self-prescribed treatment, consisting of bumping up fatty acids in our diet. I would like to see a more scientific study on this topic. It seems, at least based on our experiences, and those of the many people posting in Internet forums, that the omega-3 could be a cure for eczema! Much simpler and probably safer than the many medications (creams) that we have been prescribed, unsuccessfully, over the years.

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Research Prioritization Topic Brief Topic 10: “Epilepsy” Comparative effectiveness of treatment options for epilepsy in adults. PCORI Scientific Program Area: Assessment of Prevention, Diagnosis and Treatment Options Dr. Gillian Sanders Schmidler, PhD and Team The Duke Clinical Research Institute

April 18, 2013

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of topic DESCRIPTION OF CONDITION • Epilepsy is a condition in which a person experiences recurrent seizures1 • Seizures are temporary disturbances in brain function in which groups of nerve cells in the

brain signal abnormally and excessively1-2 • People with epilepsy are at special risk for status epilepticus (a potentially life-threatening

condition in which a person either has an abnormally prolonged seizure or does not fully regain consciousness between recurring seizures) and sudden unexplained death in epilepsy (SUDEP)2



o Seizures may cause change in awareness or sensation, involuntary movements, or other changes in behavior1-2

o There are two main types of seizures: Primary generalized seizures—begin with widespread involvement of both sides of

the brain Partial seizures—begin with involvement of a smaller, localized area of the brain

o 30-40% of people with epilepsy continue to have seizures even when treated with antiepileptic drugs3

• Other outcomes o People with severe seizures that resist treatment have, on average, a shorter life

expectancy and an increased risk of cognitive impairment, particularly if the seizures developed in early childhood.2

o It is not uncommon for people with epilepsy, especially children, to develop behavioral and emotional problems.2

o Epilepsy can affect both school and work performance.2 o Even when seizures are controlled, side effects of drugs or surgical interventions can

further diminish quality of life. Burden on Society Recent incidence


• INCIDENCE (NEW CASES)3 o 200,000 people in the United States develop epilepsy each year.

• PREVALENCE (PROPORTION OF POPULATION LIVING WITH THE CONDITION)3 o Third most common neurological disorder in the United States o 2.5 million people in the United States have epilepsy o Affects more than 300,000 children under the age of 15, more than 90,000 of whom

have seizures that cannot be adequately treated Effects on patients’

quality of life, productivity, functional capacity, mortality, use of

• QUALITY OF LIFE o People with epilepsy have an increased risk of poor self-esteem, depression, and

suicide.2 o Most states and the District of Columbia will not issue a driver's license to someone with

epilepsy unless the person can document that they have gone a specific amount of time without a seizure.1-2

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health care services

• PRODUCTIVITY o According to one survey, only about 56% of people with epilepsy finish high school, and

about 15% finish college (rates much lower than those for the general population), and about 25% of working-age people with epilepsy are unemployed2

• FUNCTIONAL CAPACITY o Cognitive impairment, behavioral and emotional problems o Environmental restrictions (eg, no driving, work at heights, use of heavy equipment or

hazardous machinery) • MORTALITY

o Mortality rate among people with epilepsy is 2-3 times higher than the general population, and the risk of sudden death is 24 times higher3


• This is a common neurological disorder that can have a significant impact on psychosocial, social and/or educational or occupational functioning throughout the lifespan.



SYSTEMATIC REVIEWS • 381 MEDLINE; 107 Cochrane reviews SCREENING/EARLY DIAGNOSIS • People are usually not screened or tested for epilepsy unless they have an unexplained loss

of consciousness or a strong family history of epilepsy. However, research into finding genes and genetic disorders that cause epilepsy may allow genetic screening and prenatal diagnosis of epilepsy in the future.

TREATMENT • Newer antiepileptic drugs significantly reduce the risk of mortality compared to older drugs

(carbamazepine, phenytoin, or valproic acid).4 • Based on four controlled clinical trials:4

o Switching from a brand name to a generic antiepileptic drug may increase the risk of hospitalization and hospital stay duration, but may not increase outpatient service utilization.

o When comparing brand name antiepileptic drugs with their respective generic versions, seizure occurrence and frequency were not significantly different between groups.

o There were no significant differences between brand name antiepileptic drugs and their respective generic versions in terms of total withdrawals or withdrawals due to lack of efficacy.

o No significant differences were noted between brand name and generic antiepileptic drugs for evaluated side effects, including headache, somnolence, diplopia, or skin rash.

• In children, the ketogenic diet (high-fat, adequate-protein, low-carbohydrate diet) results in short- to medium-term benefits in seizure control, the effects of which are comparable to

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modern antiepileptic drugs. Limited data are available for adults.5 • A meta-analysis of surgery for epilepsy reported median proportions of long-term (>5 years)

seizure remission of 27% for frontal lobe resections, 46% for occipital or parietal resections, and 66% for temporal lobe resections.6

• For nonresective surgeries, callostomy (a procedure that severs the fiber bundle connection between the right and left cerebral hemispheres) resulted in 35% freedom from seizures and subpial transections (cutting nerve fibers in the outer layers of the brain) a 16% freedom from seizures.6

• The only complete randomized controlled trial (RCT) of epilepsy surgery showed a statistically significant advantage of surgery over medical management in seizure remission (58 vs. 8%, respectively).7 A systematic review of nonrandomized comparative studies and an RCT that was terminated early also reported significant improvements in the seizure frequency in the surgery group compared with nonsurgery group.8

• In the Nationwide Inpatient Sample hospital discharge database, anterior temporal lobectomy for epilepsy performed between 1988 and 2003 was associated with a 10.8% overall morbidity and no mortality.9

• Early antiepileptic drug withdrawal resulted in a 32% increase in seizure relapse compared with late withdrawal. Early discontinuation was also associated with greater relapse rates in people with partial seizures or an abnormal EEG.10


New research could contribute to achieving better patient-centered outcomes: • What is the comparative effectiveness of early surgery vs. medical management in patients

with difficult-to-control seizures? Or, what is the comparative effectiveness of early surgery vs. later surgery in seizure remission and quality of life? [To date, only one RCT looking at comparative-effectiveness research (CER) between the surgery vs. medical management strongly favoring surgery, but there could be benefit in conducting studies looking at the timing of referral for surgical evaluation.]

• What is the comparative effectiveness of different surgical methods in remission of seizures? [Studies comparing different surgical interventions and/or preoperative screening methods to determine the most appropriate surgical intervention may be useful.]

• What is the comparative effectiveness of different generic versions of seizure medications? [No studies available comparing generic medications made by different manufacturers but anecdotal evidence suggests people may respond differently.]

• What is the comparative effectiveness of different treatments for mood disorders associated with seizure disorders? [Given the significant association between epilepsy and mood disorders, it would be helpful to know if certain treatments are more effective than others in this population.]

• What is the optimal timing of antiepileptic drug withdrawal and what are the risk factors predictive of relapse among seizure-free adults?


Recent innovations: • The use of preoperative imaging and EEG monitoring has helped to identify those patients

with the highest likelihood of benefit from surgical resection. • Improvements in drugs and drug delivery methods (providing potentially more effective

alternatives to current oral or IV routes).

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How widely does

care now vary? VARIABILITY IN CARE11 • According to a recent study (Quality Indicators in Epilepsy Treatment [QUIET]), patients with

epilepsy received 40.9% of recommended care • Black patients were two times more likely to receive 50% or more recommended care

compared with non-Hispanic whites • Black patients scored significantly worse than non-Hispanic whites for two patient-reported

measures: perceived racial/ethnic disparities and difficulties getting follow-up appointments What is the pace of


ONGOING TRIALS • ClinicalTrials.gov lists 300 Ongoing Trials and 432 Completed trials. • Phase II/III clinical trials are ongoing for several antiepileptic drugs.12 • RCTs are underway for few alternative, non-drug therapies, e.g., ketogenic diet (high-fat,

adequate-protein, low-carbohydrate), yoga, P- glycoprotein blockers, and polyunsaturated fatty acids.12


KEY UNCERTAINTIES IN CLINICAL DECISION MAKING • Do outcomes differ based on timing of referral for surgical evaluation? • What is the optimal timing for discontinuing antiepileptic drugs in patients who have been

free of seizures? • Do different surgical techniques result in different outcomes? • What are the most effective techniques for identifying epileptic foci prior to surgery? • What are the predictors of response to surgery? • Is the ketogenic diet effective in controlling seizures in the adult population? • Are there any medications to treat mood disorders that are more effective than others in

patients with seizures? • Do generic antiepileptic drugs differ in their effectiveness? LIKELIHOOD THAT CER WOULD BE ABLE TO REDUCE THESE UNCERTAINTIES • CER looking at early referral vs. late referral for surgical evaluation could provide useful

information if outcomes do differ • New CER may provide useful information regarding which surgical techniques are more

effective than others • New CER may provide useful information regarding which techniques best identify the areas

of focus for surgical intervention • It is unlikely that even if it were feasible to do a study comparing generic medications from

different manufacturers that this would change clinical care • New CER research looking at various medications to treat mood disorders may provide useful

information regarding which medications may be more effective in patients with epilepsy • New CER on specialized diets (such as the ketogenic diet) in the adult population may

provide useful information to determine if this is an effective treatment • New CER on discontinuation of antiepileptic drugs in seizure-free patients may help to

identify the ideal timing to stop these medications Potential for New Information to Improve Care and Patient-Centered Outcomes What are the

facilitators and barriers that

FACILITATORS • Effective surgical interventions for intractable epilepsy already in use • Multiple medications for treating mood disorders currently available

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REFERENCES: 1. Centers for Disease Control and Prevention. Epilepsy Basics. www.cdc.gov/epilepsy/basics/faqs.htm. Accessed April

11, 2013. 2. National Institute of Neurological Disorders and Stroke. Seizures and Epilepsy: Hope Through Research.

www.ninds.nih.gov/disorders/epilepsy/detail_epilepsy.htm. Accessed April 11, 2013. 3. National Clearinghouse Quality Measures, Epilepsy: percentage of visits for patients with a diagnosis of epilepsy who

had the type(s) of seizure(s) and current seizure frequency for each seizure type documented in medical record. 2009 Aug. NQMC: 006895. American Academy of Neurology—Medical Specialty Society. www.qualitymeasures.ahrq.gov/content.aspx?id=32700&search=epilepsy. Published 2009. Accessed April 11, 2013.

4. Talati R, Scholle JM, Phung OJ, et al. Effectiveness and Safety of Antiepileptic Medications in Patients with Epilepsy. Comparative Effectiveness Review No. 40. (Prepared by the University of Connecticut/Hartford Hospital Evidence-based Practice Center under Contract No. 20-2007-10067-I.) AHRQ Publication No. 11(12)-EHC082-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2011. www.effectivehealthcare.ahrq.gov/reports/final.cfm. Published December 2011. Accessed April 11, 2013.

5. Levy RG, Cooper PN, Giri P, Pulman J. Ketogenic diet and other dietary treatments for epilepsy. Cochrane Database of Systematic Reviews 2012, Issue 3. Art. No.: CD001903. DOI: 10.1002/14651858.C D001903.pub2.

would affect the implementation of new findings in practice?

BARRIERS • Insurance coverage • Education of providers • Inability of providers to direct which manufacturers’ generic medication is used • Even if determined to be effective in adults, studies have shown poor compliance with a

ketogenic diet, so its utility may be limited How likely is it that


• It is very likely that information regarding significant differences in medications to treat mood disorders associated with epilepsy could be implemented right away as these medications are available and most are covered by most insurance plans

• It is likely that with appropriate education, changes in timing of referral for surgical intervention could be implemented if significant differences were found

• It is unlikely that even if significant differences were found between generic medications from different manufacturers that providers will have the liberty to prescribe a specific manufacturer’s medications


• It is likely that any new information from CER on this topic would stay current for several years, as it will provide information on the appropriate use of existing treatments (surgery for epilepsy, medications for mood disorders) and no significant changes in these treatments are expected in the near future

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http://www.cdc.gov/epilepsy/basics/faqs.htm

http://www.ninds.nih.gov/disorders/epilepsy/detail_epilepsy.htm

http://www.qualitymeasures.ahrq.gov/content.aspx?id=32700&search=epilepsy


6. Tellez-Zenteno JF, Dhar R, Wiebe S. Long-term seizure outcomes following epilepsy surgery: a systematic review and

meta-analysis. Brain 2005;128:1188-1198. 7. Wiebe S, Blume WT, Girvin JP, et al. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J

Med 2001;345:311-318. 8. Health Quality Ontario. Epilepsy surgery: an evidence summary. Ont Health Technol Assess Ser [Internet].

2012;12(17):1-28. http://www.hqontario.ca/en/documents/eds/2012/full-report-epil-surg.pdf. Published 2012. Accessed April 11, 2013.

9. McClelland S III, Guo H, Okuyemi KS. Population-based analysis of morbidity and mortality following surgery for intractable temporal lobe epilepsy in the United States. Arch Neurol 2011;68:725-729.

10. Sirven J, Sperling MR, Wingerchuk DM. Early versus late antiepileptic drug withdrawal for people with epilepsy in remission. Cochrane Database of Systematic Reviews 2001, Issue 3. Art. No.: CD001902. DOI: 10.1002/14651858. CD001902.

11. Avetisyan R, Cabral H, Montouris G, et al. Evaluating racial/ethnic variations in outpatient epilepsy care. Epilepsy Behav 2013;27:95-101.

12. Epilepsy Research Benchmarks Progress Update (2007-2009). National Institute of Neurological Disorders and Stroke. www.ninds.nih.gov/research/epilepsyweb/2010_benchmarks.htm. Accessed: April 11, 2013.

APPENDIX: TOPIC QUESTIONS Nominated by Institute of Medicine (IOM)

1. Compare the effectiveness of monotherapy and polytherapy (ie, use of two or more drugs) on seizure frequency, adverse events, quality of life, and cost in patients with intractable epilepsy.

Nominated by National Institute of Health (NIH)

2. Quality of life for patients with difficult to control epilepsy: comparison of surgery vs. medical management. Nominated by ‘Web’

3. Should I go to my neurologist, therapist, or primary health physician when finding out if panic attacks are really seizures or just panic attacks?

• Population: Younger patients. • Importance: It's what I've been experiencing myself recently. The Internet is not giving any help and it is

a question that, when answered, will give me a lot of help and peace of mind. 4. My grand mal and complex partial seizures, which come from my left temporal lobe, have re-emerged back into

my life after being dormant for 9.5 years. The neurologist wants to do the research to see if I am a good candidate for surgery. Should I proceed with the research or continue on the drugs that he has me on? I can still function fine, but the occasional seizure is holding me back.

• Population: This would help everyone (from all backgrounds) who has to face the same decision I do. There are risks of the surgery but there are also risks of continuing regular drugs or something else as treatment, but everyone must weigh the pros and cons. If I go through with it and come out fine, I would love to be a voice for the Epilepsy Foundation to help support the idea of people doing the testing. Right now I am leaning towards going forward with the research.

5. How many different medications have you taken? Which ones? What dosage? Where they brand name, generic, or have they been changed from brand name to generic? Did they cause side effects, if so what? If you changed to generic, could you feel a difference between the medications? While taking the generic did the pharmacy change the manufacturer? After changing manufacturer of the medication, did this change the outcome,

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http://www.hqontario.ca/en/documents/eds/2012/full-report-epil-surg.pdf

http://www.ninds.nih.gov/research/epilepsyweb/2010_benchmarks.htm

reasons, or "feelings" the medication was used for? I want to be able to prove there is a difference between manufacturer's generic medication in the way they treat patient's need for the medication.

• Population: This will include anyone that is able to switch brand name medication with generic medication. Over a period of time, we will switch one generic manufacturer with another generic manufacturer. This will prove which generic is the closest to the brand name for treatment.

• Importance: I was able to take a generic (Teva) brand Epilepsy medication. The pharmacy switched brands to another generic (Mylan). I was able to drive because I was epilepsy free for five years. Since the pharmacy switched generic brands I had a seizure while driving. My fourteen your old daughter was with me. She had to have her ankle fused after three surgeries. After this, I want know if generic medications cause differences in other health issues.

6. I am caregiver for my 60-year-old sister, diagnosed with Lennox-Gastaut seizure disorder. Because of multiple foci in the brain from which seizures precipitate, current meds are not effective for total seizure control. Currently, she has the best seizure control since the age of 11. but it has been a "hit and miss" project over the years trying different meds and wondering if we were missing just the right combination of meds that would be effective for her. Onfi, the latest addition to her regime (Lamictal, Keppra, and Banzel) has resulted in the most notable seizure reduction. She now averages a 3-10 partial seizures weekly and 1-2 cluster seizures monthly. It would be helpful to be able to access information from other patients with the same diagnosis regarding meds, diet, exercise, and prevention techniques that have been effective as well as "triggers" for seizure activity. Although each patient is different, I suspect there are some similarities within similar diagnoses. Thank you.

• Population: It would help all patients with epilepsy to have access to information about what has been effective for other patients with similar seizure disorders.

Importance: It is important because the information is not currently available and choosing the best med is largely trial and error process, even for neurologists.

7. How does the ketogenic diet control seizures in epilepsy? • Population: All patients affected by seizures, especially children. • Importance: The diet has been used for many years with great success, yet only a superficial

understanding of its exact mechanism exists. This information could be used to develop safer antiepileptic medications and permit more patients to improve their seizure control.

8. Is there evidence that any specific diet controls seizures better for different causes of epilepsy? Low glycemic index, modified Atkins, ketogenic diet...

• Population: Severe drug resistant epilepsy, children • Importance: Lack of funding for diet studies, avoids drug toxicity issues

9. Do anti-suffocation pillows effectively prevent hypoxia during nocturnal seizures? • Population: All ages, especially cognitively impaired, residential community dwelling • Importance: Class 1 medical device in the UK, not approved in the US, lack of information

10. Improve health care and community services for persons with epilepsy in rural and underserved populations. • Population: Patients residing in rural areas. Patients of low socioeconomic status • Importance: Although many new treatments have been developed for epilepsy, people residing in

underserved rural areas lack access to specialty care or specialty care is delayed due to lack of health professional knowledge about epilepsy. Through expansion of access to comprehensive epilepsy care and timely diagnosis can improve patient health outcomes, potentially reduce mortality, improve quality of life and ultimately reduce the burden of epilepsy.

11. Patients with epilepsy often experience changes in mood and psychoses from the anti-seizure drugs they take. Is it correct to identify these as "side effects," or would it be better to view the changes as symptoms of what Hans Landolt called "forced normalization"?

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• Population: younger. Refractory epileptics • Importance: Doctors would better know what to expect from treatments a patient has not yet tried.

Doctor and patient could make better choices in treatment. Identifying "forced normalization" as a serious problem would indicate the need for complete seizure control earlier in childhood. Patients' self-esteem may be less damaged by understanding the causes of multiple drug failures and uncontrolled mood.

12. How many patients with epilepsy are able to take one generic brand medication that keeps their seizures under control, then start having seizures when the medication is switched to another generic brand medication? What is the difference between the generic brand medications that make patients start having the seizures? Is there a difference in the type of seizures that they were having previously?

• Population: Patients with all types of epilepsy and are able to keep track of their seizures or have someone with them who can for them. Patients or people who stay with them that are able to tell to the difference between their seizures. Patients of all ages, race, and sex.

• Importance: I was able to take one generic brand medication then was switched another brand generic. I had been able to drive for five years because I had been seizure free. The drug store switched my generic brand medication to another company that made that medication. While I was driving, I had a seizure which was not like my others that I had before. This caused me to have a wreck and with my daughters in the car. One had to have surgery on her ankle. This is why I am working hard on discovering more information on generic medications. Thank You

13. What should patients with epilepsy (children and adolescents) do about the conflicting information about suicidality induced by the antidepressants and the antiepileptics: If the patient is diagnosed with MDD, and you look on the Internet, there are two black box warnings about the AED and the SSRIs. It is really hard for parents to make an informed decision when they have to deal with this, is it the medication that makes them suicidal or the disease??

• Population: Younger, adolescents, early adults • Importance: I deal with this question every day, suicidality is very frequent in patients with epilepsy and

parents feel with the information out there is really hard for them to make an informed decision

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Topic 11: “Generalized Anxiety Disorder (GAD)”

Comparative effectiveness of treatment options for generalized anxiety disorder (GAD) in adults.

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of topic DESCRIPTION OF CONDITION • Generalized anxiety disorder (GAD) is a clinical condition characterized by excessive and

persistent worry or anxiety that is difficult to control. • GAD can be chronic (always feel anxiety) or the symptoms can come and go (remittent). • 66% of people with GAD have other disorders, such as social phobia, panic disorder,

substance abuse, or posttraumatic stress disorder. Relevance to patient-

centered outcomes SYMPTOMS • People with GAD may have similar symptoms to those experienced by people with panic

disorder, and these symptoms are often their presenting issues that make them seek medical care.

• According to the psychological classification system (DSM-IV-TR1), diagnosis of GAD requires the presence of excessive worry accompanied by three or more of the following symptoms: restlessness, fatigue, difficulty concentrating, irritability, muscle tension, sleep disturbance.



• Lifetime prevalence of GAD is 5-12% in the United States.2,3 • GAD is about twice as common among women compared with men. • GAD is more common in middle age, with prevalence rates rising after age 35 in women and

age 45 in men. • Nearly 8% of patients consulting a primary care physician have GAD.4


QUALITY OF LIFE • GAD can be debilitating and lead to agoraphobia and other avoidance behaviors. • GAD has been associated with impaired social functioning and quality of life.5 PRODUCTIVITY • GAD can result in decreased productivity due to days missed from work. FUNCTIONAL CAPACITY • GAD is associated with a significant degree of functional impairment, similar to that seen

with major depression.6 MORTALITY • GAD may be associated with severe mental illness (eg, major depression), which can lead to

premature death. USE OF HEALTH CARE SERVICES • GAD has been shown to be associated with increased use of health care services.


GAD is a highly prevalent condition with significant overall societal burden due to the persistent nature of impairments.

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There are few randomized controlled trials (RCTs) comparing treatment options, including both medication and nonmedication interventions for GAD. Systematic reviews in this field have primarily evaluated comparisons either with placebo (in medication trials) or with no-treatment controls (for instance, in psychological treatment options). Many systematic reviews have combined pretreatment-to-posttreatment improvements in the same patient, in order to estimate the effect of treatment. TREATMENT • Medication treatments for GAD:

o A systematic review concluded that selective serotonin reuptake inhibitors (SSRIs)—the usual first-line medication treatment for GAD—were effective in one out of every five patients treated. 7

o There are few trials comparing different medication treatments, but an indirect comparison in a meta-analysis of placebo-controlled trials of patients with GAD reported similar effect sizes for SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), benzodiazepines, buspirone, and hydroxyzine.8

o The effect of the medications was higher for children and adolescents than for adults.8 o Another meta-analysis assessed remission rates for first-, second-, and third-line

medication treatments in patients with GAD and showed that higher remission rates were reported in studies of first-line SSRI and SNRIs compared with second-line tricyclic antidepressants, benzodiazepines, buspirone, and pregabalin.9

• Psychological treatment for GAD: o Cognitive behavioral therapy (CBT) is the most studied and appears to be most effective

psychotherapy for GAD.10,11 Meta-analyses of RCTs and nonrandomized controlled trials have found that CBT was superior to no treatment or placebo controls for improvement in anxiety and depressive symptom severity measures.12-14

o One meta-analysis that compared medications and CBT found mostly the same results, but this was based on indirect comparisons. 12

• Complementary and alternative therapies for GAD: o Mindfulness- and acceptance-based interventions:

In a 19-study meta-analysis of within-group pretreatment-to-posttreatment effects showed substantial reductions in anxiety and depression symptoms.15

o Meditative therapies: A meta-analysis showed effect sizes for reducing anxiety symptoms of -0.52

compared with wait-list control (25 RCTs); -0.59 compared with attention control (7 RCTs); and -0.27 compared with alternative treatments (10 RCTs). However, most studies measured only improvement in anxiety symptoms.16

o Lifestyle modifications: There is strong support for lifestyle modifications including moderate

exercise and mindfulness meditation. 17 There is also some support for the herbal medicine kava. 17 There is currently little evidence for naturopathic medicine; acupuncture;

yoga; tai chi; dietary improvement; and avoidance of caffeine, alcohol, and nicotine. 17

Homeopathy was not supported.17

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What could new


• New research on nonmedication treatment options for GAD may contribute to better patient-centered outcomes among people for whom medical management is not sufficiently effective or who have intolerable side effects to the prescribed medication.

• New research on the efficacy of medication or nonmedication treatment for subgroups of patients could contribute to better patient-centered outcomes.


There is preliminary evidence showing several complementary and alternative approaches for the treatment of GAD and its associated symptoms (eg, mindfulness meditation, acupuncture, exercise, yoga, herbal therapies) may be effective.15-17


VARIABILITY IN CARE • A large proportion of cases of GAD are undiagnosed; many people try to alleviate symptoms

using home remedies, over-the-counter medications, self-medicating with alcohol and tobacco, and/or by using other alternative medicine approaches (yoga, meditation, and so forth).

• In a longitudinal study in primary care of patients with anxiety disorders, including 25% with GAD, almost half (47%) of patients were untreated. When patients did receive treatment, the most common approach involved a combination of medication and psychotherapy (25%), with 21% receiving medication alone and 7% receiving psychotherapy alone.18

• People who seek health care for GAD do so through a wide range of medical specialties, resulting in highly variable types and quality of care.


RECENT PUBLICATIONS (Medline Search of Past five years) Total: 2,185 citations Citations labeled as RCT: 653 Citations labeled as Meta-Analysis or Systematic Reviews: 265 ONGOING TRIALS (Search on ‘clinicaltrials.gov’) Search: Generalized Anxiety Disorder Ongoing Trials: 113 trials that are recruiting subjects and therefore do not have results published yet nor are included in any of the above mentioned meta-analyses


KEY UNCERTAINTIES IN CLINICAL DECISION MAKING • There are many uncertainties pertaining to the comparative effectiveness and safety of

nonmedication treatment options for GAD, especially for the comparative effectiveness of medication and nonmedication treatments (with very few direct comparison studies).

• There is also uncertainty pertaining to patient preference for treatment options, as well as patients’ willingness and ability to engage in lifestyle modifications or behavioral interventions that could prove to be potentially effective.

LIKELIHOOD THAT CER WOULD BE ABLE TO REDUCE THESE UNCERTAINTIES • There is a high likelihood that new comparative-effectiveness research (CER) on

nonmedication approaches to GAD could help inform patients and health care providers about treatment options and facilitate decision making.


facilitators and FACILITATORS • GAD is a highly prevalent condition, and patients do often seek relief from unpleasant

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barriers that would affect the implementation of new findings in practice?

symptoms. • There are increasing numbers of patients interested in nonmedication approaches to disease

management and relief of symptoms. • No obvious avenue exists for disseminating findings to patients and health care providers,

however professional societies related to psychiatry/psychology and support and advocacy groups for those who have GAD should be potential resources to facilitate dissemination.

BARRIERS • There is a general lack of industry support for nonmedication approaches to treating clinical

conditions. How likely is it that


EVIDENCE OF BENEFIT • The apparently growing population of those seeking information from sources other than

conventional health care providers might access and implement results of new research right away.

• Physicians and other health care providers, however, may tend to wait for additional information about nonmedication approaches before changing their recommendations.

• Insurance companies may also be relatively slow to implement changes involving nonmedication treatments.

EVIDENCE OF NO BENEFIT OR HARM • Evidence of no benefit may be largely overlooked by patients, providers, and payers. • Evidence of harm associated with nonmedication approaches is likely to be addressed

quickly by health care providers and have bearings on their recommendations regarding treatment options for an individual patient.


There are many important clinical uncertainties associated with this topic. New information may be rendered obsolete quickly, but may also encourage further research that may ultimately have an impact on patient-centered outcomes.

REFERENCES 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.) (DSM-

IV-TR). Washington, DC: American Psychiatric Press Inc, 2000. 2. Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in

the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005; 62:593. 3. Kessler RC, Gruber M, Hettema JM, et al. Co-morbid major depression and generalized anxiety disorders in the

National Comorbidity Survey follow-up. Psychol Med. 2008; 38:365. 4. Üstün TB, Sartorius N. Mental Illness in General Health Care: An International Study. Chichester, United Kingdom:

Wiley; 1995. pp. 323–335. 5. Massion AO, Warshaw MG, Keller MB. Quality of life and psychiatric morbidity in panic disorder and generalized

anxiety disorder. Am J Psychiatry. 1993;150(4):600–607.

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6. Wittchen HU, Carter RM, Pfister H, et al. Disabilities and quality of life in pure and comorbid generalized anxiety

disorder and major depression in a national survey. Int Clin Psychopharmacol. 2000; 15:319. 7. Kapczinski F, Lima MS, Souza JS, Schmitt R. Antidepressants for generalized anxiety disorder. Cochrane Database

Syst Rev. 2003; CD003592. 8. Hidalgo RB, Tupler LA, Davidson JR. An effect-size analysis of pharmacologic treatments for generalized anxiety

disorder. J Psychopharmacol. 2007; 21:864. 9. Bereza BG, Machado M, Ravindran AV, Einarson TR. Evidence-based review of clinical outcomes of guideline-

recommended pharmacotherapies for generalized anxiety disorder. Can J Psychiatry. 2012 Aug;57(8):470-478. 10. Hunot V, Churchill R, Silva de Lima M, Teixeira V. Psychological therapies for generalised anxiety disorder.

Cochrane Database Syst Rev. 2007; CD001848. 11. Hendriks GJ, Oude Voshaar RC, Keijsers GP, et al. Cognitive-behavioural therapy for late-life anxiety disorders: a

systematic review and meta-analysis. Acta Psychiatr Scand. 2008; 117:403. 12. Mitte K. Meta-analysis of cognitive-behavioral treatments for generalized anxiety disorder: a comparison with

pharmacotherapy. Psychol Bull. 2005; 131:785. 13. Norton PJ, Price EC. A meta-analytic review of adult cognitive-behavioral treatment outcome across the anxiety

disorders. J Nerv Ment Dis. 2007; 195:521. 14. Hofmann SG, Smits JA. Cognitive-behavioral therapy for adult anxiety disorders: a meta-analysis of randomized

placebo-controlled trials. J Clin Psychiatry. 2008; 69:621. 15. Vøllestad J, Nielsen MB, Nielsen GH. Mindfulness- and acceptance-based interventions for anxiety disorders: a

systematic review and meta-analysis. Br J Clin Psychol. 2012 Sep;51(3):239-60. doi: 10.1111/j.2044-8260.2011.02024.x. Epub 2011 Sep 9.

16. Chen KW, Berger CC, Manheimer E, Forde D, Magidson J, Dachman L, Lejuez CW. Meditative therapies for reducing anxiety: a systematic review and meta-analysis of randomized controlled trials. Depress Anxiety. 2012 Jul;29(7):545-62. doi: 10.1002/da.21964. Epub 2012 Jun 14.

17. Sarris J, Moylan S, Camfield DA, Pase MP, Mischoulon D, Berk M, Jacka FN, Schweitzer I. Complementary medicine, exercise, meditation, diet, and lifestyle modification for anxiety disorders: a review of current evidence. Evid Based Complement Alternat Med. 2012;2012:809653. doi: 10.1155/2012/809653. Epub 2012 Aug 27.

18. Weisberg RB, Dyck I, Culpepper L, et al. Psychiatric treatment in primary care patients with anxiety disorders: a comparison of care received from primary care providers and psychiatrists. Am J Psychiatry. 2007;164(2):276–282.

APPENDIX: Topic Questions Nominated by ‘Web’ 1) What other options for treatment are there for GAD besides pills, if a person also suffers from GERD, or other

intestinal disorders which prevent digestion of pills?

Population: Patients who suffer from gastrointestinal disorders. Importance: This question is important, because taking pills is impeding the speed at which I can respond to a pill-oriented treatment regimen.

Note: We could find no specific link between GERD and GAD, other than the higher rate of somatic (bodily) complaints in people with GAD. Furthermore, there is no evidence that GERD prevents the digestion of pills which might be used for

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treatment of GAD. Hence, we focused this topic brief on the comparison between medication and nonmedication treatment for GAD

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Topic 12: “Hearing Loss” Comparative effectiveness of treatments for hearing loss in children and adults.

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Criteria Brief Description Introduction Overview/definition of

topic

DESCRIPTION OF CONDITION • There are three types of hearing loss.1

o Sensorineural hearing loss (SNHL) involves inner ear, cochlea, and auditory nerve o Conductive hearing loss involves middle ear bones or other processes that prevent

sound from being transmitted from external ear to inner ear. o Mixed loss is a combination of sensorineural and conductive causes of hearing loss

• In children, there is a fourth type of hearing loss, auditory neuropathy spectrum disorder, which, because of damage to the inner ear or the hearing nerve, sound is not organized in a way that the brain can understand.

CAUSES • Hearing loss can result from genetic causes, trauma, infections, and other exposures.2

TREATMENTS • Treatments vary depending on the type and cause of hearing loss, as well as a patient’s

culture, language, medical, and developmental backgrounds.2 • Treatments for hearing loss include:

o Antibiotics (for external or middle ear infections) o Oral corticosteroids (for inflammatory or sudden hearing loss) o Conventional hearing aids o Contralateral routing of signals (CROS) hearing aids, which transmit sound from a

microphone in the hearing-impaired ear to a receiver in the hearing ear o Bone-anchored hearing aids (BAHA), which involve a sound processor implanted in the

skull behind the ear that carries sound vibrations directly to the cochlear nerve o Cochlear implant devices, which involve an externally worn microphone, sound

processor and transmitter system, and implanted receiver and electrode system containing the electronic circuits that receive signals from the external system and send electrical currents to the inner ear


Hearing loss has a significant effect on the ability to communicate, work, and learn. Comparative-effectiveness research (CER) to identify the most effective treatments could lead to dramatic improvements in functioning and quality of life for patients.



PREVALENCE • Hearing loss affects 360 million people worldwide.2 • Approximately two to three out of every 1,000 children in the United States are born deaf

or hard-of-hearing.3 • Approximately 17% (36 million) of American adults report some degree of hearing loss.3 • There is a strong relationship between age and reported hearing loss: 18% of American

adults 45-64 years old, 30% of adults 65-74 years old, and 47% of adults 75 years old or older report hearing loss.3

• The prevalence of hearing loss is higher among people who are male, white, older, less educated, diabetic, hypertensive, or, are a long-time smoker.4

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QUALITY OF LIFE/PRODUCTIVITY/FUNCTIONAL CAPACITY/MORTALITY • Spoken language development is often delayed in children with deafness.2 • Hearing loss can have a significantly adverse effect on the academic performance of

children.2 • Exclusion from communication can cause feelings of loneliness, isolation, and frustration,

particularly among older people with hearing loss.2 • If a person with congenital deafness has not been given the opportunity to learn sign

language as a child, they may feel excluded from social interaction.2 • Sensorineural hearing loss is the third leading cause worldwide of years lived with

disability.5 • Adults with hearing loss have a much higher unemployment rate.2 • Among those who are employed, a higher percentage of people with hearing loss are in

the lower grades of employment compared with the general workforce.2 • In the United States, severe to profound hearing loss is expected to cost society

$297,000 over the lifetime of an individual. Most of these losses (67%) are due to reduced work productivity; the use of special education resources for children contributes an additional 21%.6

• People with severe hearing loss in the workplace are expected to earn only 50-70% of their non-hearing-impaired peers and lose between $220,000 and $440,000 in earnings over their working life.6

• Lifetime costs for those with prelingual onset exceed $1 million.6 • The lifetime educational cost of hearing loss (more than 40 decibels permanent loss

without other disabilities) has been estimated at $115,600 per child (year 2007 value).1 USE OF HEALTH CARE SERVICES • Only one out of five people who could benefit from a hearing aid actually wears one.3 • Approximately 188,000 people worldwide have received cochlear implants. In the United

States, roughly 41,500 adults and 25,500 children have received them.3 In adults and children, both multichannel and bilateral cochlear implants were rated as cost-effective treatments for hearing loss.7

• Cochlear implants yielded a calculated net savings of $53,198 per child in indirect costs such as reduced educational expenses.7


Hearing loss can have a profound effect on an individual’s ability to achieve his or her full potential, which in turn can result in significant overall economic and societal costs to the larger community. This very common disorder should be given high priority in the research agenda.


systematic reviews, what is known about the relative benefits and harms of the available management

• Corticosteroids are a validated treatment of hearing loss caused by autoimmune and inflammatory disease; they also remain the primary treatment of idiopathic sudden SNHL.8

• There is limited evidence that hyperbaric therapy improves hearing in patients with idiopathic sudden SNHL and no evidence of a functionally significant improvement.9

• BAHA surgery may be preferred by patients over air-conduction CROS hearing aids for 86

options?

asymmetric hearing loss.10

• There is no significant improvement in auditory localization with either BAHA or CROS hearing aids, but BAHA provides an advantage with both speech discrimination in noise and subjective auditory abilities.11

• There is significant improvement in auditory localization with bilateral cochlear implantation compared with unilateral cochlear implantation.12

• Bilateral cochlear implants were beneficial for speech perception in noise under certain conditions and several self-reported measures.12

• Statistically significant improvement in mean speech scores as measured by open-set sentence or multisyllable word tests in most studies looking at unilateral implantation.5

• There is significant improvement in quality of life after unilateral implantation.5 • Results from studies assessing bilateral implantation showed improvement in

communication-related outcomes compared with unilateral implantation and additional improvements in sound localization compared with unilateral device use or implantation only.5

• Based on a few studies, quality-of-life outcomes varied across tests after bilateral implantation.5

• Bilateral BAHA provides additional objective and subjective benefit compared with unilateral BAHA.13


• Comparative effectiveness of long-term outcomes for unilateral vs. bilateral cochlear implants

• Comparative effectiveness of BAHA vs. CROS in a randomized controlled trial format • Comparative effectiveness of long-term outcomes for BAHA vs. CROS • Comparative effectiveness of unilateral or bilateral cochlear implant devices vs. assistive

listening devices • Comparative effectiveness of unilateral or bilateral cochlear implant devices vs. electric-

acoustic devices • Comparative effectiveness of unilateral or bilateral cochlear implant devices vs.

habilitation/rehabilitation therapy Have recent innovations

made research on this topic especially compelling?

Increased numbers of patients are receiving bilateral cochlear implants; studies to date have shown significant benefit over unilateral implantation. There is ongoing research that continues attempts to improve the technology of existing hearing devices.14


We were unable to find any publications describing the variation in care for hearing loss treatment. There were a few publications on quality improvement strategies to improve newborn screening of hearing as well as a few publications describing primary care referral patterns to audiology and otolaryngology for hearing loss.


ClincalTrials.gov: Search: Hearing Loss Total ongoing trials: 186 Completed trials: 154 Search: Deafness Total ongoing trials: 183 Completed trials: 149

NIH Reporter: Projects: 743 Publications: 436

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New CER could provide useful information regarding the comparative effectiveness of unilateral vs. bilateral cochlear implants as well as useful information comparing these devices with other treatment modalities for hearing loss. New CER could provide additional information comparing the BAHA cochlear stimulator with the CROS hearing aid.

Potential for New Information to Improve Care and Patient-Centered Outcomes What are the facilitators

and barriers that would affect the implementation of new findings in practice?

FACILITATORS • Existing technology will allow easier implementation if specific devices are found to be

more effective. BARRIERS • Uncertain coverage by insurance for some devices makes it hard for patients to know

what to do if the device that is recommended by the specialist is not covered by their insurance (should they pay for the out-of-pocket cost, or ask the specialist to recommend a different one that is covered?).

• Experts (audiologists and otolaryngologists) understand the advantages/disadvantages and differences among these devices, but patients have little information to make decisions on which devices are best for their hearing loss.

• Primary care providers are focused on screening for hearing loss and referrals to specialists; therefore their knowledge of appropriate treatment options for specific patients is limited.


It is likely that if covered by insurance, more effective devices or practices (such as bilateral cochlear implantation) would be adopted readily because the technology and expertise already exist.


There is ongoing research to improve hearing aid technology to provide better speech discrimination and better discrimination in noisy environments which could help to improve existing hearing devices, but not necessarily render any results regarding comparative effectiveness obsolete.14

REFERENCES 1. Centers for Disease Control. http://www.cdc.gov/ncbddd/hearingloss/types.html. Accessed 4/2/2013. 2. World Health Organization. http://www.who.int/mediacentre/factsheets/fs300/en/. Accessed 4/1/2013. 3. National Institute for Deafness and other Communication Disorders.

http://www.nidcd.nih.gov/health/statistics/Pages/quick.aspx. Accessed 4/1/2013. 4. Agrawal Y, Platz EA, Niparko JK. Prevalence of Hearing Loss and Differences by Demographic Characteristics Among

US Adults Data From the National Health and Nutrition Examination Survey, 1999-2004. Arch Intern Med. 2008;168(14):1522-1530.

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http://www.cdc.gov/ncbddd/hearingloss/types.html

http://www.who.int/mediacentre/factsheets/fs300/en/

http://www.nidcd.nih.gov/health/statistics/Pages/quick.aspx

5. Gaylor JM, Raman G, Chung M, et al. Cochlear Implantation in Adults: A Systematic Review and Meta-analysis. JAMA

Otolaryngol Head Neck Surg. 2013 Mar 1;139(3):265-72. DOI: 10.1001/jamaoto.2013.1744. 6. Mohr PE, Feldman JJ, Dunbar JL, et al. The societal costs of severe to profound hearing loss in the United States. Am

J Audiol. 2012 Dec;21(2):329-330. 7. Semenov YR, Martinez-Monedero R, Niparko JK. Cochlear Implants Clinical and Societal Outcomes. Otolaryngol Clin

N Am 2012;45:959–981. 8. Chau JK, Cho JJ, Fritz DK. Evidence-based practice: management of adult sensorineural hearing loss. Otolaryngol Clin

North Am. 2012 Oct;45(5):941-958 9. Bennett MH, Kertesz T, Yeung P. Hyperbaric oxygen for idiopathic sudden sensorineural hearing loss and tinnitus.

Cochrane Database Syst Rev. 2007;(1):CD004739. 10. Bishop CE, Eby TL. The current status of audiologic rehabilitation for profound unilateral sensorineural hearing loss.

Laryngoscope. 2010;120(3):552–556. 11. Baguley DM, Bird J, Humphriss RL, et al. The evidence base for the application of contralateral bone anchored

hearing aids in acquired unilateral sensorineural hearing loss in adults. Clin Otolaryngol. 2005;31(1):6–14. 12. van Schoonhoven J, Sparreboom M, van Zanten BG, et al. The effectiveness of bilateral cochlear implants for severe-

to-profound deafness in adults: a systematic review. Otol Neurotol. 2013 Feb;34(2):190-198. 13. Janssen RM, Hong P, Chadha NK. Bilateral bone-anchored hearing aids for bilateral permanent conductive hearing

loss: a systematic review. Otolaryngol Head Neck Surg. 2012 Sep;147(3):412-22. 14. National Institutes of Health.http://report.nih.gov/nihfactsheets/viewfactsheet.aspx?csid=95. Accessed 4/2/2013.

APPENDIX: Topic Question Nominated by Institute of Medicine (IOM) 1) Compare the effectiveness of the different treatments (eg, assistive listening devices, cochlear implants, electric-acoustic devices, habilitation and rehabilitation methods [auditory/oral, sign language, and total communication]) for hearing loss in children and adults, especially individuals with diverse cultural, language, medical, and developmental backgrounds.

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http://www.ncbi.nlm.nih.gov/pubmed?term=Gaylor%20JM%5BAuthor%5D&cauthor=true&cauthor_uid=23429927

http://www.ncbi.nlm.nih.gov/pubmed?term=Raman%20G%5BAuthor%5D&cauthor=true&cauthor_uid=23429927

http://www.ncbi.nlm.nih.gov/pubmed?term=Chung%20M%5BAuthor%5D&cauthor=true&cauthor_uid=23429927



http://www.ncbi.nlm.nih.gov/pubmed?term=Mohr%20PE%5BAuthor%5D&cauthor=true&cauthor_uid=11155832

http://www.ncbi.nlm.nih.gov/pubmed?term=Feldman%20JJ%5BAuthor%5D&cauthor=true&cauthor_uid=11155832

http://www.ncbi.nlm.nih.gov/pubmed?term=Dunbar%20JL%5BAuthor%5D&cauthor=true&cauthor_uid=11155832



http://www.ncbi.nlm.nih.gov/pubmed?term=Chau%20JK%5BAuthor%5D&cauthor=true&cauthor_uid=22980677

http://www.ncbi.nlm.nih.gov/pubmed?term=Cho%20JJ%5BAuthor%5D&cauthor=true&cauthor_uid=22980677

http://www.ncbi.nlm.nih.gov/pubmed?term=Fritz%20DK%5BAuthor%5D&cauthor=true&cauthor_uid=22980677



http://www.ncbi.nlm.nih.gov/pubmed?term=van%20Schoonhoven%20J%5BAuthor%5D&cauthor=true&cauthor_uid=23444466

http://www.ncbi.nlm.nih.gov/pubmed?term=Sparreboom%20M%5BAuthor%5D&cauthor=true&cauthor_uid=23444466

http://www.ncbi.nlm.nih.gov/pubmed?term=van%20Zanten%20BG%5BAuthor%5D&cauthor=true&cauthor_uid=23444466


http://www.ncbi.nlm.nih.gov/pubmed?term=Janssen%20RM%5BAuthor%5D&cauthor=true&cauthor_uid=22714424

http://www.ncbi.nlm.nih.gov/pubmed?term=Hong%20P%5BAuthor%5D&cauthor=true&cauthor_uid=22714424

http://www.ncbi.nlm.nih.gov/pubmed?term=Chadha%20NK%5BAuthor%5D&cauthor=true&cauthor_uid=22714424


http://report.nih.gov/nihfactsheets/viewfactsheet.aspx?csid=95

Topic 13: “Chronic Kidney Disease”

Comparative effectiveness of treatment and prevention options for patients with chronic kidney disease.

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Criteria Brief Description Introduction Overview/definition of

topic DESCRIPTION OF CONDITION • Chronic kidney disease (CKD) is a condition in which the kidneys are damaged and cannot

filter blood as well as in normal functioning kidneys.1 • There are five stages of CKD based on level of functional impairment.


SYMPTOMS • CKD is usually asymptomatic in the early stages.1 • In more advanced kidney disease stages, symptoms can include lack of energy, difficulty

concentrating, poor appetite, insomnia, muscle cramping, edema (swelling), dry skin, increased urinary frequency, bruising, shortness of breath, and bone pain.2

OUTCOMES • CKD can cause wastes to build up in the body and lead to other health problems,

including cardiovascular disease, anemia (low red blood cells), and bone deformities and weakening.1

• CKD is usually irreversible and progressive. • If not treated, over time it can lead to kidney failure, also called end-stage kidney disease

(ESKD).1 Burden on Society Recent incidence and


INCIDENCE (NEW CASES) • The incidence of CKD is increasing most rapidly in people aged 65 and older—more than

doubling in this age group between 2000 and 2008, to nearly 4.5%.3 • The incidence of recognized CKD among 20-64 year olds is 0.5%.3

PREVALENCE (PROPORTION OF POPULATION LIVING WITH THE CONDITION)1 • In the United States, more than 20 million people aged 20 years or older (>10%) have

CKD. • CKD is more common among women than men. • African Americans were nearly four times more likely to develop ESKD than whites in

2007; however, this disparity in ESKD incidence had narrowed from 1998 to 2005. • The Hispanic population has 1.5 times the rate of kidney failure compared to the non-

Hispanic white population. Effects on patients’


QUALITY OF LIFE • Multiple studies have shown that CKD is associated with decreased health-related quality

of life (QOL), most showing a worse QOL decreasing with progressive kidney disease.4-6 PRODUCTIVITY o One study showed that patients with CKD reported 18% absenteeism and 35%

productivity loss.7 MORTALITY o Premature death from both cardiovascular disease and from all causes is higher in adults

with CKD compared to adults without CKD.1 o Individuals with CKD are 16-40 times more likely to die before progressing to ESKD.1 o The number of annual deaths from ESKD increased from 10,478 in 1980 to 90,118 in

2009.3 91

COST o The overall medical and economic cost of CKD in the United States was approximately

$82.9 billion in 2007.8 o Expenditures for patients with CKD accounts for nearly 28% of all Medicare spending.8


CKD is an increasingly common medical condition, which results in significant economic costs to society and impact on the quality of life of individual who have it. High priority should be given to this research topic.



• For CKD patients with large amounts of protein in their urine—nearly all with diabetes and hypertension—angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) significantly reduced the risk of progressing to ESKD compared with placebo.9

• For CKD patients with small amounts of protein in their urine who have cardiovascular disease or diabetes with other cardiovascular risk factors, ACEIs treatment reduced mortality risk compared with placebo.9

• In randomized controlled trials that directly compared different treatments for hypertension, diabetes, and high cholesterol, it was unclear whether increasing treatment improves clinical outcomes.9

• Despite substantial focus on the early identification and proactive management of CKD in the last few years, there are significant areas where more research is needed in order to know how best to manage people with CKD.10


• Examining different strategies to screen for CKD or monitor CKD progression could lead to earlier detection of kidney disease, faster initiation of preventive medicine, and better patient-centered outcomes (such as QOL and delayed progression of CKD).

• Evaluating the comparative effectiveness of various treatments for CKD risk factors such as hypertension, diabetes, and high cholesterol could help to determine the best treatment of these conditions to prevent progression of CKD and improve patient-centered outcomes.

• Evaluating available treatment for slowing progression of CKD at different stages could help determine the optimal timing for initiation of treatment to slow CKD progression and improve patient-centered outcomes.

• Evaluating available treatment for slowing progression of CKD among patients in different demographic subgroups and with different comorbidities could lead to more effective and better tolerated treatment, thus improving patient-centered outcomes.

• Evaluating harms of treatments to slow progression of CKD could potentially improve patient adherence and quality of life.

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• Although research exists showing improvement in diabetes treatment (a known risk factor for CKD) with medical nutrition therapy (MNT), additional research assessing the comparative effectiveness of MNT vs. (or in addition to) other treatments for diabetes may provide useful information for determining how to best manage diabetes in order to optimize kidney functioning.


Newer drug classes, several of them “first-in-class” drugs (ie, drugs which, for example, use a new and unique mechanism of action for treatment) that are being tested have less supportive data and would make compelling areas for additional research.


VARIABILITY IN CARE • Among people with CKD in the United States, lower socioeconomic status is associated

with greater risk of disability. This is found regardless of a patient’s race or ethnicity, health care access, and comorbid conditions.11

• The mechanisms by which socioeconomic status influences the development of risk factors for CKD throughout the course of an individual’s life are not entirely clear.11


Clinicaltrials.gov: o Total ongoing trials: 548 o Completed trials: 778

NIH Reporter: o Projects: 250 o Publications: 596


KEY UNCERTAINTIES IN CLINICAL DECISION MAKING • Does systematic CKD screening improve clinical outcomes? • Does systematic CKD monitoring for worsened kidney function or damage improve

clinical outcomes? • What medications used to treat diabetes, hypertension, and high cholesterol have an

effect on progression of renal disease? • Does the effectiveness of available medical treatments differ based on severity of CKD

stage? • Do medical treatments have different risks vs. benefits in clinical outcomes for patients

with recently worsened kidney function or damage (as detectable by monitoring) compared with those with stable CKD?

• Do medical treatments improve outcomes in CKD subgroups for which treatment is not already indicated?

• How effective is MNT alone or in combination with other treatment in preventing or slowing progression of CKD?

• What is the effect of MNT on clinical outcomes in patients with CKD stages 1–3 vs. later stage CKD?

• Does effectiveness of medical treatments vary based on stage of kidney disease? • What is the optimal timing (stage of kidney disease) of referral to a nephrologist (kidney

specialist) for management of CKD? LIKELIHOOD THAT CER WOULD BE ABLE TO REDUCE THESE UNCERTAINTIES • New research would likely be able to identify ideal screening and monitoring strategies. • New research could clarify ideal treatment for those risk factors such as diabetes,

hypertension, and high cholesterol that would prevent progression of kidney disease.

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• New research could clarify effectiveness of treatment in different stages of kidney disease.

• New research could clarify the comparative effectiveness of MNT in preventing or slowing progression of kidney disease.

Potential for New Information to Improve Care and Patient-Centered Outcomes What are the facilitators

and barriers that would affect the implementation of new findings in practice?

FACILITATORS • Diabetes, hypertension, and high cholesterol are all already high-priority conditions. • Many medications exist to treat these conditions and potentially prevent complications. • MNT is covered by Medicare. • Most patients with kidney disease are on Medicare and/or Medicaid, so some

information may be able to be obtained from their databases. BARRIERS • Studies of earlier stage CKD would require years of follow-up, which could be expensive. • The number of available treatments and many different patient subgroups could make

designing generalizable studies challenging. • There is a potential lack of workers to provide MNT to all qualified patients. • There is a potential lack of coverage for MNT by insurance plans other than Medicare. • Providers lack knowledge about MNT. • Providers lack knowledge about current CKD management guidelines.


• It is likely that new information regarding optimal treatments for diabetes, hypertension, and high cholesterol in patients with CKD could be implemented quickly with education.

• If MNT were shown to be effective in preventing or slowing progression of kidney disease, it is likely that new information could be implemented quickly if there is an adequate number of trained workers to provide nutrition counseling.


It is likely that new information from comparative-effectiveness research (CER) would remain current for several years.

REFERENCES 1. Centers for Disease Control and Prevention. National Chronic Kidney Disease Fact Sheet: General Information and

National Estimates on Chronic Kidney Disease in the United States, 2010. Atlanta, GA: U.S. Department of Health and Human Services, CDC; 2010. http://www.ihpm.org/pdf/CKD_HPM%20_2010.pdf. Published 2010.

2. Chronic Kidney Disease. Institute for Health and Productivity Management. http://www.ihpm.org/pdf/CKD_HPM%20_2010.pdf. Published 2010. Accessed 4/8/2013.

3. Kidney Disease Statistics for the United States. National Kidney and Urologic Diseases Information Clearinghouse (NKUDIC). http://kidney.niddk.nih.gov/kudiseases/pubs/kustats/. Accessed 4/6/2013.

4. Perlman RL, Finkelstein FO, Liu L, et al. Quality of life in chronic kidney disease (CKD): a cross-sectional analysis in the Renal Research Institute-CKD study. Am J Kidney Dis. 2005 Apr; 45(4):658-666.

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http://www.ihpm.org/pdf/CKD_HPM%20_2010.pdf

http://www.ihpm.org/pdf/CKD_HPM%20_2010.pdf

http://kidney.niddk.nih.gov/kudiseases/pubs/kustats/

http://www.ncbi.nlm.nih.gov/pubmed?term=Perlman%20RL%5BAuthor%5D&cauthor=true&cauthor_uid=15806468

http://www.ncbi.nlm.nih.gov/pubmed?term=Finkelstein%20FO%5BAuthor%5D&cauthor=true&cauthor_uid=15806468

http://www.ncbi.nlm.nih.gov/pubmed?term=Liu%20L%5BAuthor%5D&cauthor=true&cauthor_uid=15806468


5. Mujais SK, Story K, Brouillette J, et al. Health-related Quality of Life in CKD Patients: Correlates and Evolution over

Time. Clin J of the Am Soc of Nephrology. 2009 Aug; 4(8): 1293–1301. 6. Pagels AA, Soderkvist BK, Medin C, et al. Health-related quality of life in different stages of chronic kidney disease

and at initiation of dialysis treatment. Health and Quality of Life Outcomes. 2012 Jun;10:71. 7. Assessing Work Productivity Loss and Disability Among Chronic Kidney Disease Sufferers in the United States.

Poster presentation at the American Occupational Health Conference. 2010 May. 8. U.S. Renal Data System. USRDS 2009 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal

Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2009.

9. Fink HA, Ishani A, Taylor BC, et al. Chronic Kidney Disease Stages 1–3: Screening, Monitoring and Treatment. Comparative Effectiveness Review No. 37. (Prepared by the Minnesota Evidence-based Practice Center under Contract No. HHSA 290-2007-10064-I.) AHRQ Publication No. 11(12)-EHC075-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2012. www.effectivehealthcare.ahrq.gov/reports/final.cfm. Published January 2012.

10. Black C, Sharma P, Scotland G, et al. Early referral strategies for management of people with markers of renal disease: a systematic review of the evidence of clinical effectiveness, cost-effectiveness and economic analysis. Health Technology Assessment. 2010; 14(21): 1-184

11. Plantinga LC, Johansen KL, Schillinger D, Powe NR. Lower Socioeconomic Status and Disability Among US Adults With Chronic Kidney Disease, 1999-2008. Prev Chronic Dis. 2012;9:E12.

APPENDIX: Topic Questions

Nominated by ‘Web’ 1) What are the best strategies for delaying the progression of chronic kidney disease, maintaining the patient's

quality of life, and decreasing morbidity?

Importance: Chronic kidney disease (CKD) is common, affecting approximately 20 million (one out of every nine) people in the United States.

2) Is Diabetes Self-Management Training (DSMT) and/or dietetic consultation (including, but not limited to,

Medicare Medical Nutrition Therapy) effective in empowering patients to avoid morbidity/mortality from chronic kidney disease (CKD) associated with diabetes? Population: The burden of CKD is greatest among senior citizens, including Medicare beneficiaries, as well as among members of racial and ethnic minority groups, and among populations with lower socioeconomic status. The growth of CKD in the United States is related to the increase in both diabetes and hypertension at the population level. Importance: Medical Nutrition Therapy (MNT) is Medicare coverage for consultation with a nutritionist that was authorized by the Benefits Improvement and Protection Act of 2000 and is available to individuals with diabetes and/or impaired kidney function (eGFR below 50). Utilization of MNT benefits has been far below expectations. However, MNT and DSMT provide excellent opportunities for patient empowerment. Proof that DSMT and MNT are effective in improving outcomes (eg, preventing/delaying End Stage Renal Disease, improving blood pressure control, enhancing glycemic control, reducing avoidable hospitalizations from CKD associated with diabetes)

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should enhance utilization of these benefits. In addition, this kind of research could incentivize group health plans to include similar initiatives as part of the wellness programs they provide pursuant to the Affordable Care Act.

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Topic 14: “Treatments for Liver Cancer” Comparative effectiveness of medical and surgical treatment options in patients with primary or metastatic malignancies of the liver in adults.

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of topic DESCRIPTION OF CONDITION • Two different types of liver cancer: primary and secondary • Primary liver cancer (cancer arising from the cells of the liver)

o Most commonly hepatocellular carcinoma (HCC) o HCC almost always arises in patients with chronic liver disease (from other causes):1-2 Alcohol addiction/abuse/overuse Chronic infection with Hepatitis B or C Nonalcoholic fatty liver disease (associated with obesity and Type 2 diabetes) Less common exposures such as arsenic, certain chemicals in plastics, abuse of

anabolic steroids (testosterone derivatives), rare metabolic/genetic conditions • Secondary liver cancer (other cancer has spread to liver; called liver metastases)

o Cancer cells from another organ cause tumors in the liver o Most common original cancer site is the colon3 60-70% of colon cancer patients eventually develop liver metastases

20-25% have liver metastases at time of diagnosis 40-50% develop liver metastases despite colon cancer treatment

o Other cancers that spread to the liver include breast, esophagus, stomach, pancreas, skin, and lung

o Treatment of secondary liver cancer is based on treatment of original cancer Relevance to


• Symptoms o Primary liver cancer (HCC) Jaundice (skin and whites of eyes become yellow, urine darkens, color of stool

becomes lighter than normal) General feelings of poor health, weakness, and fatigue Loss of appetite and/or weight loss Abdominal bloating Itching of skin Abdominal pain or discomfort Swelling of legs

o Secondary liver cancer (liver metastases) Similar to HCC May have symptoms related to original type of cancer or from its treatment

• Other outcomes

o Mortality o Quality of life (affected both by underlying disease and by treatments)



INCIDENCE (new cases)/PREVALENCE (proportion of population with condition) • Incidence approximates prevalence for both primary and secondary liver cancer due to high

mortality rates • Primary liver cancer (HCC)

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o Age-adjusted incidence 3.2 per 100,000 in the United States in 2006 and increasing due to rise in rate of hepatitis B and C (present in 80% of HCC cases)4

o Incidence and prevalence are much higher in other parts of the world (eg, Asia, Africa), mirroring higher rates of hepatitis B and C5

o In the United States, more common in men than women and more common among Asian/Pacific Islanders, Native Americans/Alaska Natives, blacks, and Hispanic people than in whites (age-adjusted incidence per 100,000)6

• Secondary liver cancer (liver metastases): Difficult to estimate overall, as multiple cancers

can cause liver metastasis o Overall incidence of colon cancer is 46.3 per 100,000, and about 20-25% of these

patients have metastases7-8 o Assuming 65% of all cases eventually develop liver metastases (age-adjusted incidence

per 100,000)6 o By race/sex, secondary liver cancer (liver metastases) are between 1.5 to more than 10

times more likely than primary liver cancer (HCC) o Metastases at time of diagnosis are slightly more common in blacks than in whites


QUALITY OF LIFE • Both primary (HCC) and secondary liver cancer (liver metastases) have a major impact on

quality of life, with impact increasing with worsened tumor cancer stage8-9 FUNCTIONAL CAPACITY/PRODUCTIVITY • Primary liver cancer/HCC: Functional capacity reduced; impact on functional capacity often

worse among patients with advanced liver disease due to hepatitis B or C infections and/or other illnesses10-11

• Secondary liver cancer (liver metastases): Major impact on functional capacity; patients often debilitated from their cancer treatments (which can include surgery, chemotherapy, and radiation) as well as from underlying illness8,10

MORTALITY • Primary liver cancer (HCC):

o One-year survival rate remains <50%, five-year survival rate 14.4%11-12 o Age-adjusted death rate is estimated at 5.2 per 100,000 people per year in the United

States7 • Secondary liver cancer: Varies by tumor type; for colon cancer that spreads to the liver, one-

year survival is ~40%, and five-year survival is ~6-8%8,13 How strongly does


• Incidence of primary liver cancer (HCC) is increasing as prevalence of hepatitis B and hepatitis C increase o Primary liver cancer (HCC) is a high-mortality condition There is a range of available treatments, lending high priority to CER However, relative burden of primary liver cancer much smaller than for secondary

liver cancer Other strategies available for preventing morbidity/mortality from primary liver

cancer • Primary prevention of hepatitis B and C through vaccination (currently available

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only for hepatitis B), screening, measures to prevent the spread of hepatitis infections between people, improved treatments for chronic hepatitis infection

• Prevention and treatment of other conditions (alcoholism, type 2 diabetes, and other liver diseases)

o Secondary liver cancer (liver metastases) can result from multiple other types of cancers Colon cancer with associated liver metastasis is a relatively common, high-mortality

condition. This also makes colon cancer a high priority for CER. Options for Addressing the Issue Based on recent


SYSTEMATIC REVIEWS • Imaging Techniques for the Surveillance, Diagnosis, and Staging of Hepatocellular Carcinoma

(HCC) (EPC Project In Process)11 • Local Therapies for Unresectable Primary Hepatocellular Carcinoma: Comparative

Effectiveness Review (Draft 2012)14 • Belinson S, Chopra R, Yang Y, Shankaran V, Aronson N. Local Hepatic Therapies for

Metastases to the Liver From Unresectable Colorectal Cancer. Comparative Effectiveness Review No. 93. AHRQ Publication No. 13-EHC014-EF. Rockville, MD: Agency for Healthcare Research and Quality. December 2012.8

SCREENING/EARLY DIAGNOSIS • Primary liver cancer (HCC)11

o Among patients with hepatitis B or C, screening is typically done using ultrasonography (u/s), computerized tomography (CT, aka CAT scan), and magnetic resonance imaging (MRI)

o Otherwise, primary liver cancer is most often found incidentally on imaging studies done for other reasons

• Secondary liver cancer (liver metastases) o Liver metastases not typically screened for, though primary cancers that lead to liver

metastases often have established screening tests (eg, colon cancer and screening with a colonoscopy)

TREATMENT • Primary liver cancer (HCC): In cases where HCC is detected early enough and the patient’s

liver function is sufficient to allow a procedure, a variety of procedural treatments may be possible.

o Medical treatment (most commonly a drug called sorafenib) is sometimes an option, but HCC tends to be resistant to standard drug therapy14-15

o Surgery: If a tumor meets certain criteria for size and location, surgical removal may be an option, and may prolong survival or even be curative.

o Liver transplantation: This is the treatment of choice for some patients with poor liver function who cannot tolerate surgery.

o Treatment with one of the below therapies may be used as a bridge to transplant. o Ablation: Destruction of liver cancer tissue through chemical injury or heating. o Embolization: Blockage of blood vessels that supply the liver cancer. o Radiotherapy: Directed radiation to destroy liver cancer tissue.

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• Secondary liver cancer (liver metastasis): In cases where metastases are confined to the liver, local treatment may be possible, along with treatment of the primary cancer and chemotherapy (focus here is on colon cancer, as this is the most common cause for liver metastases).8

o Surgery: If a metastatic tumor in the liver meets certain criteria for size and location, surgical removal may be an option, and may prolong survival or even be curative. Pretreatment with chemotherapy may also shrink metastatic tumors so that they can be treated surgically.

o Ablation: Destruction of liver cancer tissue through chemical injury or heating. o Embolization: Blockage of blood vessels that supply the liver cancer. o Radiotherapy: Directed radiation to destroy liver cancer tissue.

What could new


New research could contribute to achieving better patient-centered outcomes by evaluating:8,14 • Comparative effectiveness (regarding survival and quality of life) of the various liver-directed

therapies in patients with primary or secondary liver cancer who are not otherwise candidates for surgical resection (or liver transplantation for primary liver cancer) Comparative harms (regarding side effects) of the various liver-directed therapies in patients with primary or secondary liver cancer who are not otherwise candidates for surgical resection (or transplantation)

• Effect of specific patient and tumor characteristics, such as age, sex, disease etiology, and liver function on comparative effectiveness of various liver-directed therapies in patients with primary or secondary liver cancer who are not otherwise candidates for surgical resection (or transplantation)

• Role of the various liver-directed therapies in patients who are candidates for liver-directed therapy as an adjunct to chemotherapy for metastases to the liver that cannot be operated on


Recent innovations: • Many available procedural therapies for primary or secondary liver cancer represent recent

innovations, and procedural techniques continue to evolve. • New comparative-effectiveness research (CER) will likely be needed to establish which of the

options is preferred in specific clinical situations and in specific patient subgroups. How widely does

care now vary? VARIABILITY IN CARE • While the indications for surgery for primary or secondary liver cancer are reasonably well-

understood, there is likely more variability in the use of other newer procedural therapies due to variation in local expertise and access to advanced care. o Care may be provided by different specialties (surgeons, medical oncologists,

interventional radiologists, radiation therapies) o Local practices, financial incentives/disincentives may contribute to variability in care


RECENT PUBLICATIONS • MEDLINE search 1/1/08-4/16/13:

o Total: 6,442 citations o Labeled as randomized controlled trial (RCT): 224 o Labeled as meta-analysis or systematic review: 386

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ONGOING TRIALS • Clinicaltrials.gov: search term ‘liver cancer’

o Ongoing trials: 645 o Completed trials: 414

• Clinicaltrials.gov: search term ‘hepatocellular carcinoma’ o Ongoing trials: 397 o Completed trials: 226

• NIH reporter: Hepatic carcinoma o Projects: 662 o Publications: 143


KEY UNCERTAINTIES IN CLINICAL DECISION-MAKING • Optimal strategy for screening/early diagnosis • Comparative effectiveness of treatment options (surgery, medical therapy, ablation, or

observation) on disease-free survival and overall survival, tumor recurrence, and quality of life in patients with: o Primary liver cancer o Secondary liver cancer

• Optimal treatment for primary and secondary liver cancer that cannot be operated on LIKELIHOOD THAT CER WOULD BE ABLE TO REDUCE THESE UNCERTAINTIES • Appropriately designed studies would have a high likelihood of answering the above

questions and reducing key areas of uncertainty • Randomized trials of easily measured outcomes (like disease-free survival and overall

survival) usually sponsored by National Cancer Institute or manufacturer (especially chemotherapeutic drugs)

o Treatments based on surgical procedures (eg, cutting off tumor blood supply with embolization) are less likely to be subjected to RCTs, because either no regulatory requirements (surgical procedures) or fewer restrictive regulatory requirements (devices) compared to drugs

• CER by PCORI focused on patient-centered outcomes, particularly quality of life, preferences for different treatments, as well as other factors, more feasible than large-scale RCTs with mortality as primary outcome



FACILITATORS • Acceptance of evidence-based treatment results generally better in cancer treatment than

other areas of medicine • Evidence of improved survival and other outcomes likely to be well accepted by both

patients and health care providers BARRIERS • Treatment options may be expensive and uncovered or only partially covered by third-party

payers • Access to different treatments may be affected by availability of appropriately trained and

experienced clinicians

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REFERENCES:

1. Liver cancer. Memorial Sloan Kettering Cancer Center. www.mskcc.org/cancer-care/adult/liver/about-liver. Accessed April 16, 2013.

2. Liver cancer. National Cancer Institute. www.cancer.gov/cancertopics/types/liver/. Accessed April 16, 2013. 3. Liver metastases (secondary liver cancer). Memorial Sloan Kettering Cancer Center. www.mskcc.org/cancer-

care/adult/liver-metastases-secondary-liver/about-liver-metastases. Accessed April 16, 2013. 4. Centers for Disease Control and Prevention (CDC). Hepatocellular carcinoma - United States, 2001-2006. MMWR

Morb Mortal Wkly Rep. 2010;59(17):517-520. 5. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69-

90. 6. Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database:

Incidence - SEER 18 Regs Research Data + Hurricane Katrina Impacted Louisiana Cases, Nov 2011 Sub, Vintage 2009 Pops (2000-2009). National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2012, based on the November 2011 submission.

7. SEER Stat Fact Sheets: Colon and Rectum. http://seer.cancer.gov/statfacts/html/colorect.html. Accessed April 16, 2013.

8. Belinson S, Chopra R, Yang Y, Shankaran V, Aronson N. Local Hepatic Therapies for Metastases to the Liver From Unresectable Colorectal Cancer. Comparative Effectiveness Review No. 93. (Prepared by Blue Cross and Blue Cross Blue Shield Association Technology Evaluation Center under Contract No. 290-2007-10058-I.) AHRQ

• Different financial incentives/disincentives for treatment options, competition between different types of practitioners


EVIDENCE OF BENEFIT • Evidence of benefit, particularly for survival, likely to be rapidly implemented EVIDENCE OF NO BENEFIT OR HARM • Evidence of no benefit may or may not be rapidly implemented (ie, treatment with no

benefit compared to other available treatments may continue to be used) based on issues of access, provider incentives, and other factors.

• Evidence of harm may or may not be rapidly implemented depending on types of harm (decreased survival likely to be implemented, increased risk of side effects or negative impact on quality of life possibly less likely to be implemented depending on other factors)


• Primary Liver Cancer (HCC) o Incidence attributable to chronic hepatitis likely to continue to rise even if vaccine for

hepatitis C is discovered, given high prevalence in other parts of world and difficulty in establishing vaccination program

o Incidence related to other causes, particularly nonalcoholic fatty liver disease, also likely to continue to increase

• Secondary Liver Cancer (liver metastases)

o Given that colon cancer is the third most common cancer in the United States, high rate of metastases, and variability in cancer outcomes even for same treatment in same cancer type, CER results unlikely to become obsolete CER results may be modified if genetic or other biomarkers predictive of treatment

response become available

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http://www.mskcc.org/cancer-care/adult/liver/about-liver

http://www.cancer.gov/cancertopics/types/liver/

http://www.mskcc.org/cancer-care/adult/liver-metastases-secondary-liver/about-liver-metastases

http://www.mskcc.org/cancer-care/adult/liver-metastases-secondary-liver/about-liver-metastases

http://seer.cancer.gov/statfacts/html/colorect.html

Publication No. 13-EHC014-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2012. www.effectivehealthcare.ahrq.gov/reports/final.cfm. Published December 2012.

9. Qiao CX, Zhai XF, Ling CQ, Lang QB, Dong HJ, Liu Q, Li MD. Health-related quality of life evaluated by tumor node metastasis staging system in patients with hepatocellular carcinoma. World J Gastroenterol. 2012;18(21):2689-2694.

10. Stafford RS, Cyr PL. The impact of cancer on the physical function of the elderly and their utilization of health care. Cancer. 1997;80(10):1973-1980.

11. Imaging Techniques for the Surveillance, Diagnosis, and Staging of Hepatocellular Carcinoma (HCC) (EPC Project In Process) (www.effectivehealthcare.ahrq.gov/search-for-guides-reviews-and-reports/?pageaction=displaytopic&topicid=479&search=liver%20cancer). Accessed April 16, 2013.

12. Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol. 2009;27(9):1485-1491.

13. O'Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst. 2004;96(19):1420.

14. Local Therapies for Unresectable Primary Hepatocellular Carcinoma: Comparative Effectiveness Review (Draft 2012) (http://www.effectivehealthcare.ahrq.gov/ehc/products/360/1012/HCC_protocol-amendment_20121212.pdf). Accessed April 16, 2013.

15. Clavien PA, Lesurtel M, Bossuyt PM, et al. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol. 2012;13:e11-22.


Nominated by Institute of Medicine 1) Compare the effectiveness of surgical resection, observation, or ablative techniques on disease-free and overall

survival, tumor recurrence, quality of life, and toxicity in patients with liver metastases. Nominated by ‘Web’

1) Treatments for Unresectable Liver Cancer - This is a Center for Medical Technology Policy (CMTP)-identified CER priority

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http://www.effectivehealthcare.ahrq.gov/search-for-guides-reviews-and-reports/?pageaction=displaytopic&topicid=479&search=liver%20cancer

http://www.effectivehealthcare.ahrq.gov/search-for-guides-reviews-and-reports/?pageaction=displaytopic&topicid=479&search=liver%20cancer

http://www.effectivehealthcare.ahrq.gov/ehc/products/360/1012/HCC_protocol-amendment_20121212.pdf

http://www.effectivehealthcare.ahrq.gov/ehc/products/360/1012/HCC_protocol-amendment_20121212.pdf

http://www.uptodate.com/contents/liver-transplantation-for-hepatocellular-carcinoma/abstract/6

http://www.uptodate.com/contents/liver-transplantation-for-hepatocellular-carcinoma/abstract/6

Topic 15: “Macular Degeneration” Comparative effectiveness of treatment for patients with age-related macular degeneration (AMD).

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of topic DESCRIPTION OF CONDITION 1,2 • Macular degeneration is a degenerative disease of the central portion of the retina (macula). • Age-related macular degeneration (AMD) is the most common form. • Two types of AMD:

o Dry (atrophic) is chronic. o Wet (neurovascular or exudative) is an abrupt onset that can rapidly progress to

blindness if untreated. • Dry AMD is a risk factor or precursor state for wet AMD, with early dry phase converting to

more severe wet form in 10-20% of patients. • Early stage of dry AMD is asymptomatic.


SYMPTOMS1 • With AMD, there is progressive visual loss, primarily of the central (rather than peripheral)

vision • Central vision is needed for reading and driving. • Central vision loss is associated with increased falls and hip fractures.



PREVALENCE1,2

• 10-15 million people in the United States are living with AMD, two million of whom have advanced disease.

• Prevalence is increasing (by 2020, three times as many people will have AMD than in 1995). • Prevalence increases with age, with 2% of people at age 40 to 25% at age 80. • Risk factors include age, smoking, family history, cardiovascular disease, lightly pigmented

skin, and female sex. INCIDENCE • 15-year cumulative incidence is 14% for early AMD and 3% for late AMD.


QUALITY OF LIFE (QOL)2,3 • AMD is the leading cause of blindness in the United States. • AMD is associated with impairment in driving, ambulation, reading, recognizing faces, and all

activities of daily living. PRODUCTIVITY • Condition can result in loss of independent living. FUNCTIONAL CAPACITY • Leads to vision impairment or blindness. USE OF HEALTH CARE SERVICES4 • Among Medicare beneficiaries diagnosed with wet AMD between 2004 and 2008, the mean

cost per case for the year after diagnosis was $12,422 ($4,884 higher than the year before diagnosis).

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How strongly does


There is a high overall societal burden caused by AMD-associated blindness, decreased QOL, and caregiver burden. Comparative-effectiveness research (CER) on alternative approaches for the prevention of progression of AMD could decrease societal burden through preservation of a patient’s sight.



TREATMENT OPTIONS • There are no proven effective treatments for dry AMD, which is asymptomatic in the early

stages. • For wet AMD, treatment options include:

o Laser photocoagulation prevents further vision loss by destroying the new vessels that develop in AMD. Introduced in the 1980s and less commonly used now, in part because it is generally not indicated for disease at the center of the macula.

o Photodynamic therapy uses a combination of laser and injected medicine. Requires evaluation by a retina specialist to determine eligibility.

o Macular translocation surgery involves moving the macula to a different part of the retina to restore central vision. Still largely experimental.

o Intravitreal injections with vascular endothelial growth factor (VEGF) inhibitors (prevent or inhibit VEGF; which are proteins that stimulate the creation of new blood vessels) such as ranibizumab, pegaptanib, bevacizumab, or aflibercept. In the past six years, VEGF inhibitors have largely replaced laser photocoagulation and photodynamic therapy.5

Ranibizumab has been shown in a randomized sham-controlled study to be effective in the treatment of AMD. Bevacizumab has been used off-label to treat AMD, despite the absence of similar supporting data. A recent comparison of AMD treatments trials (CATT study) showed that ranibizumab and bevacizumab did not differ in effects on visual acuity for wet AMD when administered according to the same schedule,6 and suggests that modification of monthly dosing regimens is feasible.7 Uncertainties include: Dosing regimen Cost Safety concerns, including possible increased risk of systemic vascular events

o Diet and supplements such as omega-3 fatty acids and/or high doses of antioxidants and minerals such as vitamins C and E, beta-carotene, and zinc. A meta-analysis suggests that foods rich in omega-3 fatty acids may be associated with a lower risk of AMD, there is insufficient evidence (few prospective studies and no randomized controlled trials [RCTs]), to support their consumption for AMD prevention.8

o Visual rehabilitation using visual aids can be effective in managing vision loss.9

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What could new


• New research on comparative effectiveness, safety, and cost of management options could inform providers and patients. Research on prevention of AMD as well as management of vision loss might also improve patient-centered outcomes.

• A technology assessment published in 2009 by the Canadian National Institutes for Health Research evaluated cost-effectiveness associated with different dosing regimens of VEGF inhibitors10; additional research in this area could help inform dosing decisions.


The most recent innovation has been the approval of VEGF inhibitors for the treatment of AMD. Current uncertainties regarding comparative effectiveness, safety, and cost of different VEGF inhibitors, as well as unanswered questions about optimal dosing regimens, may make this topic compelling for new CER. Advances in retinal imaging represent another innovation that could lead to improved screening and management.


Management of AMD in the United States is generally provided by ophthalmologists with appropriate expertise. There is evidence that black patients are less likely than white patients to receive VEGF inhibitor therapy,11


Medline search from 1/1/2008 to 12/31/2013: • Total: 2,341 citations o Labeled as RCTs: 333 citations o Systematic Reviews: 159 citations

Search on ‘clinicaltrials.gov”:

• Ongoing trials: 420* • Completed trials: 398

*The AREDS2 trial is an ongoing RCT designed to evaluate whether the vitamin supplements lutein, zeaxanthin, or omega-3 fatty acids affect the course of dry AMD.


• New CER that provides compelling information about screening or prevention measures could inform clinical decision making by patients and providers.

• More information about different responses to treatment by patient subgroups may also guide clinical decision making.

• Primary care providers might encourage routine eye exams to more patients (eg, patients older than 50, relatives of affected individuals) if new findings supported that approach.

• If patients knew that they should be screened based on age or risk factors, they might be willing to get their eyes examined more often.

• If people knew, they could prevent AMD by engaging in lifestyle changes (like changing their diet or taking vitamins)


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What are the


FACILITATORS • Most care is provided by ophthalmologists, so rapid dissemination of new findings to the

target audience is feasible with a targeted audience of one type of health care provider. • Active patient advocacy groups (AMD Alliance, Macular Degeneration Foundation, and

Macular Degeneration International) could assist with dissemination to patients BARRIERS • New findings would likely need to be strongly compelling to result in changes in decision

making by ophthalmologists. How likely is it that


• There are certainly knowledge gaps, but there may not be a strong sense among ophthalmologists with expertise in AMD that current treatment practice needs to change (unless there is compelling research showing new and improved screening and treatments).

• Also, if new research findings support that lifestyle changes or taking vitamins or omega-3 supplements would prevent or reduce worsening of AMD, then research findings might be implemented quickly by patients.


• This is a relatively active area of research, with 424 ongoing trials identified in clinicaltrials.gov and identified by the search terms “macular degeneration.”

• New information about the most effective prevention and treatment therapies, including optimal dose and timing of treatments, may remain current for several years.

REFERENCES

1. Lim LS, Seddon J, Holz FG, Wong TY. Age-related macular degeneration. Lancet. 2012; 379:1728-1738. 2. Technology Assessment: Quality of Life in Macular Degeneration (2006)

(http://www.cms.gov/Medicare/Coverage/DeterminationProcess/downloads/id30TA.pdf) 3. Bennion AE, Shaw RL, Gibson JM. What do we know about the experience of age related macular degeneration? A

systematic review and meta-synthesis of qualitative research. Social Science and Medicine. 2012; 75:976-985. 4. Qualls LG, Hammill BG, Wang F, Lad EM, Schulman KA, Cousins SW, Curtis LH. Costs of newly diagnosed

neovascular age-related macular degeneration among Medicare beneficiaries, 2004-2008. Retina. 2013 Apr;33(4):854-861.

5. Campbell RJ, Bronskill SE, Bell CM, Paterson JM, Whitehead M, Gill SS. Rapid expansion of intravitreal drug injection procedures, 2000 to 2008: a population-based analysis. Arch Ophthalmol. 2010 Mar;128(3):359-362.

6. CATT Research Group. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011 May 19;364(20):1897-908.

7. Davis J, Olsen TW, Stewart M, Sternberg P Jr. How the comparison of age-related macular degeneration treatments trial results will impact clinical care. Am J Ophthalmol. 2011 Oct;152(4):509-514.

8. Dietary omega-3 fatty acid and fish intake in the primary prevention of age-related macular degeneration: a systematic review and meta-analysis. (2008) (http://www.ncbi.nlm.nih.gov/pubmed/18541848)

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9. Decarlo DK, McGwin G Jr, Searcey K, Gao L, Snow M, Stevens L, Owsley C. Use of prescribed optical devices in age-

related macular degeneration. Optom Vis Sci. 2012 Sep;89(9):1336-1342. 10. www.cadth.ca/media/pdf/htis/L0026%20Pharmacological%20Management%20in%20AMD%20final.pdf 11. Curtis LH, Hammill BG, Qualls LG, DiMartino LD, Wang F, Schulman KA, Cousins SW. Treatment patterns for

neovascular age-related macular degeneration: analysis of 284 380 medicare beneficiaries. Am J Ophthalmol. 2012 Jun;153(6):1116-1124.e1.

APPENDIX: Topic Questions Nominated by ‘Web’ 1) What is the optimal treatment and dosing schedule as a patient with AMD? Does it vary based on age, gender,

ethnicity, etc.? Population: Typically, these are older white patients.

Importance: This is an important question because of the significant impact that age-related macular degeneration has on the United States’ population, and the implication for patients (number of visits, out-of-pocket costs) and for third-party payers.

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Topic 16: “Melanoma” Comparative effectiveness of using surgical treatment options to prevent recurrence of melanoma.

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of topic DESCRIPTION OF CONDITION • Melanoma is the most fatal form of skin cancer, with a rising incidence in the United States,

as well as in people of European descent worldwide. • Prognosis and treatment of melanoma both depend on the stage (or thickness) of the

melanoma at the time of diagnosis. o There is currently some controversy over the best surgical treatments for patients who

have evidence of melanoma in their lymph nodes. o Other types of skin cancer treatment include phototherapy (using laser treatment),

radiation therapy, biologic therapy (using medicines to help the immune system fight the cancer), and chemotherapy.

o Focus of the nomination and topic brief document is on the comparative effectiveness of surgical resection of the skin cancer based on lymph node involvement.


SYMPTOMS1 • Melanomas appear as irregularly shaped, dark (hyperpigmented) skin moles. • Melanoma does not cause any symptoms to the patient unless it has spread to other organs

(ie, becomes metastatic). • A mole should be examined for possible melanoma if it has a suspicious appearance based on

the “ABCDE” criteria—an uneven appearance, irregular border, color variation, bigger than 6mm in diameter, and evolving (or changing) appearance.

OUTCOMES1 • Outcomes that are commonly reported include spread to lymph nodes (local or distant),

spread to other organs, complications from surgery, and survival. • Important patient-centered outcomes that are not commonly reported in the medical

literature include disfiguration from surgery, fatigue and side effects from chemotherapy, and psychological distress from concerns about survival and recurrence of the cancer.

• Patients with melanoma that has spread to distant lymph nodes or organs have worse outcomes than those with disease limited to the skin.



INCIDENCE (NEW CASES)2 • Incidence of melanoma has been increasing over the past three decades, with 19.2 cases in

the United States per 100,000 people from 2004-2006. • Incidence and severity vary by patient characteristics including sex, age, race, and

socioeconomic status. • Males have a higher incidence and greater severity of the condition compared with women. • In 2008, the incidence of melanoma was 29.1 cases per 100,000 males compared with 19

cases per 100,000 females. • There is a greater incidence with older age, but men continue to have a higher incidence in

all age groups except those younger than age 44. • Though melanoma affects whites more than other races, it does affect other

races/ethnicities (Hispanic people had 3.9 cases and Native Americans had 3.7 cases per

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100,000 people between 2004 and 2008). • There is a higher incidence of melanoma among people of higher socioeconomic status,

although the incidence seems to be rising among people of all socioeconomic groups. PREVALENCE (PROPORTION OF POPULATION LIVING WITH THE CONDITION) • In the United States, melanoma is the fifth most common cancer in men and seventh most

common cancer in women. • It is estimated that about 9500 people died from melanoma in the United States in 2011.


QUALITY OF LIFE • A patient’s quality of life can be affected by the treatment regimen (surgery and

chemotherapy). • With regard to surgical treatments and lymph node dissections, patients can experience

complications including lymphedema (severe swelling of the extremity requiring ongoing care to manage), pain, decreased ability to care for oneself while recovering, activity restrictions, infection, and wound complications.

PRODUCTIVITY o Based on data from the Centers for Disease Control and Prevention as well as Prevention

National Vital Statistics Surveillance System from 2000-2006, the decrease in productivity related to all melanoma-related deaths in the United States during this time was estimated at $3.5 billion, with an average cost for lost productivity per death of $413,370.3

FUNCTIONAL CAPACITY o Patients undergoing treatment for melanoma have decreased functional capacity. o This can be an ongoing problem depending on the extent of surgical revision and if there is

ongoing lymphedema that requires chronic management and possibly limited range of movement.

MORTALITY o In general, a thin melanoma of ≤1.0mm is associated with a 96% melanoma-specific survival

at 20 years. o Thicker melanomas are associated with a higher incidence of spreading, particularly to local

lymph nodes. o For patients with small amounts of cancer spreading to lymph nodes, survival is based on

the number of lymph nodes involved, with overall five-year survival of 71% (one lymph node), 65% (two lymph nodes), and 61% (three lymph nodes).

o For patients with larger amounts of cancer spreading to local lymph nodes, the prognosis is worse, with overall five-year survival of 50% (one lymph node), 43% (two lymph nodes), and 40% (three lymph nodes).

o Prognosis of patients with distant metastases is generally worse but also is dependent on characteristics of the tumor, patient, and markers described briefly above.

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How strongly does


• Given the rising incidence of melanoma, it is important to find the optimal treatments for the different stages of disease and to determine the risks and benefits for the different treatment options.

• In particular, with regard to patients with melanoma that has spread to a lymph node, (but only in a small amount or to a few lymph nodes), it is unclear if surgically removing and testing many lymph nodes is needed—and if the benefits of doing this more invasive surgery with increased complication risks, such as the chronic swelling caused by lymphedema, is worthwhile compared with less extensive surgery.



Systematic reviews o Current guidelines recommend that patients with intermediate-thickness melanomas

undergo a lymph node dissection, and if that node shows signs of cancer, the patient should have an extensive, complete lymph node dissection.4

o No systematic review was identified pertaining to lymph node dissections for skin cancer. o One clinical review describes clinical trials and observational studies regarding the surgical

treatment of intermediate-thickness melanoma that has only begun to spread (micrometastasis). o The Multicenter Selective Lymphadenectomy Trial (MSLT 1) evaluated patients with

intermediate-thickness melanoma and found that a sentinel lymph node biopsy (SLNB), or biopsy of the first lymph node that is draining from the cancer site, was a good indicator of prognosis.

o This study found that survival was better among the patients who underwent SLNB along with wide excision of the tumor.

o There was also improved survival among patients who underwent complete lymph node dissection if the SLNB was positive compared with patients who underwent only wide excision of tumor with observation and treatment of nodal disease only when it became obvious that the cancer had spread.

o There are harms associated with the SLNB procedure: In a review of over 400 SLNB biopsies, the complication rate was found to be 4.26% with

complications including hematoma (collection of blood/bruising), lymphedema (severe swelling of involved extremity), seroma (pockets of clear fluid collecting around surgical site), wound infection, thick scars, and pain.5

o It is not clear that extensive lymph node dissection is needed for all positive sentinel lymph nodes.

o The potential harm of increased risk of recurrent disease without extensive lymph node dissection could be worse than surgical complications.


Further studies about prognosis for recurrence of melanoma for patients with positive sentinel lymph nodes are needed to determine if specific markers of disease can help to identify the patients who would benefit from more extensive surgical dissection vs. less invasive surgery.

Have recent innovations made

Recent innovations: • New markers of the disease have been identified in patients’ blood work.

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research on this topic especially compelling?

• Measures of the extent of disease with tissue samples, radiologic findings, and gene mutations have been found that are also associated with prognosis.

• These markers may be able to help determine the best treatment for individual patients. How widely does

care now vary? VARIABILITY IN CARE • There are no publications assessing variation in regional vs. extensive lymph node dissection

in the melanoma population in the United States. • Studies have evaluated the use of SLNB in patients with melanoma for surgical staging (ie,

diagnosis phase of the disease) and found practice variations in SLNB, with underutilization in the elderly and minority populations, in patients with head, neck, or trunk melanomas, and in some geographic regions of the United States.6


PACE OF RESEARCH Search on Medline:

• Total citations: 843 • Labeled as randomized controlled trial (RCT): 50 • Labeled as meta-analysis or systematic review: 67

Search on Clinicaltrials.gov:

• “Melanoma” AND “(nodal dissection OR lymph node excision OR lymph node dissection OR node dissection)”

o Total ongoing trials: 24 The MSLT II trial is evaluating patients with a positive SLNB and

randomizing them to either complete lymph node dissection or observation with ultrasound surveillance. Outcomes include disease-free survival as well as quality of life.

The European Organisation for Research and Treatment of Cancer melanoma group MINITUB (Minimal Tumor Burden) is a registry that is following patients with a positive SLNB but with minimal tumor size, thickness, and spread who did not undergo complete lymph node dissection.

o Completed trials: 14


KEY UNCERTAINTIES IN CLINICAL DECISION MAKING For patients with a positive SLNB, it is unclear if extensive lymph node dissection is needed for all of these patients or if ongoing surveillance, less extensive surgery, or potentially nonsurgical treatments would be suitable treatments associated with fewer complications.

LIKELIHOOD THAT CER WOULD BE ABLE TO REDUCE THESE UNCERTAINTIES • Some studies have found that the use of certain biomarkers and additional imaging studies7

may help determine the significance of a positive SLNB. • New clinical trials and comparative-effectiveness research (CER) are needed to

determine the best method of performing SLNB as well as the best treatment options—both surgical and nonsurgical—for patients with a positive SLNB.


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What are the


FACILITATORS • There is great interest in optimizing treatment for melanoma, which is rising in incidence. BARRIERS • Surgeons may be resistant to less aggressive surgical interventions unless there are data to

confirm that benefits outweigh risks.


• Given the rising incidence of melanoma and the high mortality associated with intermediate-thickness and advanced melanomas, any progress made to better understand the risk of recurrence and how to decrease that risk with minimal morbidity would likely be readily implemented by specialists treating this condition.


• One ongoing trial (MSLT II) is addressing this specific question. • Further trials addressing this topic would help support or dispute any trends seen in this one

trial.

REFERENCES

1. http://www.uptodate.com/contents/screening-and-early-detection-of-melanoma?source=search_result&search=melanoma&selectedTitle=5%7E150

2. Little EG, Eide MJ. Update on the current state of melanoma incidence. Dermatol Clin. 2012;Jul;30(3):355-361. doi: 10.1016/j.det.2012.04.001. Epub 2012 Jun 8.

3. Ekwueme DU, Guy GP Jr, Li C, Rim SH, Parelkar P, Chen SC. The health burden and economic costs of cutaneous melanoma mortality by race/ethnicity-United States, 2000 to 2006. J Am Acad Dermatol. 2011;Nov;65(5 Suppl 1):S133-143. doi: 10.1016/j.jaad.2011.04.036.

4. Wong SL, Balch CM, Hurley P, Agarwala SS, Akhurst TJ, Cochran A, Cormier JN, Gorman M, Kim TY, McMasters KM, Noyes RD, Schuchter LM, Valsecchi ME,Weaver DL, Lyman GH. Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology joint clinical practice guideline. J Clin Oncol. 2012;Aug 10;30(23):2912-2918. doi: 10.1200/JCO.2011.40.3519. Epub 2012 Jul 9.

5. Cigna E, Gradilone A, Ribuffo D, Gazzaniga P, Fino P, Sorvillo V, Scuderi N. Morbidity of selective lymph node biopsy for melanoma: meta-analysis of complications. Tumori. 2012;Jan-Feb;98(1):94-98. doi: 10.1700/1053.11506.

6. Cormier JN, Xing Y, Ding M, Lee JE, Mansfield PF, Gershenwald JE, Ross MI, Du XL. Population-based assessment of surgical treatment trends for patients with melanoma in the era of sentinel lymph node biopsy. J Clin Oncol. 2005;Sep 1;23(25):6054-6062.

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http://www.uptodate.com/contents/screening-and-early-detection-of-melanoma?source=search_result&search=melanoma&selectedTitle=5%7E150

http://www.uptodate.com/contents/screening-and-early-detection-of-melanoma?source=search_result&search=melanoma&selectedTitle=5%7E150

http://www.ncbi.nlm.nih.gov/pubmed?term=Little%20EG%5BAuthor%5D&cauthor=true&cauthor_uid=22800543

http://www.ncbi.nlm.nih.gov/pubmed?term=Eide%20MJ%5BAuthor%5D&cauthor=true&cauthor_uid=22800543


7. Stoffels I, Boy C, Pöppel T, Kuhn J, Klötgen K, Dissemond J, Schadendorf D, Klode J. Association between sentinel lymph node excision with or without preoperative SPECT/CT and metastatic node detection and disease-free survival in melanoma. JAMA. 2012;Sep 12;308(10):1007-1014. doi: 10.1001/2012.jama.11030.

APPENDIX: Topic Question Nominated by ‘Web’ • Use of Extensive or Limited Lymph Node Dissection to Prevent Recurrence of Melanoma (Friends of Cancer

Research, CER priority)

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Topic 17: “Migraine Headache” Comparative effectiveness of different treatment strategies for adults with frequent migraine headaches.

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Criteria Brief Description Introduction Overview/ definition of

topic

DESCRIPTION OF CONDITION1-2 • Migraine is a recurring disorder characterized by severe headache, generally associated with nausea,

vomiting, and other neurologic symptoms during attacks, with no symptoms between attacks • “Chronic migraine” is diagnosed if migraine headaches occur on 15 or more days per month for more

than three months o Chronic migraine is diagnosed only if painkiller medication overuse has been excluded o Still a controversial diagnosis, with no universally agreed definition


SYMPTOMS2

• Phases of migraine episode: 1. Premonitory or prodrome (hyper- or hypo-activity, depression, food cravings, repetitive

yawning) 2. Aura or perceptual disturbance (visual, sensory, verbal, or motor disturbances)—may or may not

be present 3. Headache is typically one-sided, throbbing, moderate to severe in intensity, lasting hours to

days, and aggravated by physical activity (nausea and vomiting, intolerance to light and noise) 4. Postdrome (extreme fatigue, loss of appetite, depression)

• Commonly mentioned precipitating factors include stress, menstruation, visual stimuli, weather changes, nitrates, fasting, and wine (aged or fermented food/drink)

DIAGNOSIS • No objective diagnostic tests • Diagnosis based on clinical features, medical history, and physical exam; diagnostic criteria defined

by the International Headache Society2 Burden on Society Recent

prevalence in populations and sub-populations

INCIDENCE • Each year, approximately 2.5% of patients with episodic migraine develop new-onset chronic

migraine3 PREVALENCE4-6

• Episodic migraine affects up to 12% of population (8% of children) o More frequent in women (17%) than in men (6%) o Prevalence is

higher in whites than in blacks inversely related to household income highest in middle life (30-49 years)

o Chronic migraine is less common (1.3% of women and 0.5% of men) o Prevalence highest among females, in mid-life, and in households with the lowest annual

income7 o Severe headache-related disability is more common among persons with chronic migraine

than episodic migraine, especially among women7 Effects on

patients’ QUALITY OF LIFE5,8 • Migraine causes impairment in activity and may require bed rest during attacks

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• Compared with patients with episodic migraine, those with chronic migraine have worse socioeconomic status, reduced health-related quality of life, increased headache-related burden (including impairment in occupational, social, and family functioning), and greater psychiatric and medical comorbidities3

PRODUCTIVITY5 • Missed school or work days • Reduced work or school productivity • National annual indirect burden of illness, excluding being at work but being less productive,

estimated to be $12 billion (mostly attributed to absenteeism)11 HEALTH CARE SERVICE UTILIZATION8 • More frequent health care usage among persons with migraine. • Estimated annual US migraine-related health care costs in 2010 were $3.2 billion for outpatient

visits, $700 million for emergency room visits, and $375 million for hospitalizations.10 • Headache among top 20 reasons for outpatient office visits (1.2% of office visits)

o Approximately 12.1 million office visits for headache annually • Estimated 6.2 million prescriptions for antimigraine drugs in 2009 • 80% of prescription for triptans (nearly half for sumatriptan) • Headache or head pain fifth is the leading cause of visits to emergency department • Chronic migraine was associated with higher medical resource use and total costs compared to

episodic migraine.9 How strongly

does this overall societal burden suggest that CER on alternative approaches to this problem should be given high priority?

• For episodic migraine, the burden in both direct costs and indirect costs is high because of the high prevalence in working-age persons.

• For chronic migraine, a small portion of this population is more severely affected. This suggests alternative approaches should be considered or more effective treatment identified.


systematic reviews, what is known about the relative benefits and harms of the

MANAGEMENT OPTIONS • The focus of management for chronic migraine is prevention • Evidence-based guidelines based on systematic reviews suggest that preventive therapy should be

considered for patients who have contraindications or intolerance to acute treatment therapies, headaches symptoms occurring more than two days per week, headaches that severely limit quality of life, or if uncommon migraine conditions or complications are present.4,13-17 • Clinical trial literature focuses on episodic migraine and tension-type headaches, the most

common headache disorders, with relatively less attention to chronic migraine

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available management options?

• Clinical trial literature focuses heavily on placebo-controlled drug studies, with little direct comparisons between active therapies; also little clinically useful research on psychological and alternative medical therapies. Comparative studies—especially between drug and nondrug treatments—are few and inconclusive.

DRUG TREATMENTS • Antiepileptic drugs (AEDs)

o Benefits: Divalproex sodium, sodium valproate, and topiramate have been shown to be effective for preventing episodic migraine. Other AEDs ( eg, lamotrigine) have been shown to be ineffective; there is insufficient evidence regarding other AEDs.

o Harms: Weight gain or loss, paresthesias (abnormal sensation of tingling, numbness, or burning), drowsiness, need for monitoring for liver disease and pancreatitis, and potential birth-defect risks.

o Comparisons: Topiramate as effective as valproate, propranolol, or amitriptyline • Antidepressants

o Benefits: Amitriptyline and venlafaxine have been shown to likely be effective but there remains conflicting evidence for other antidepressants.

o Harms: Nausea, vomiting, drowsiness, sedation, urinary retention, constipation, dry mouth, dizziness, liver enzyme elevation, arrhythmia

o Comparisons: Venlafaxine possibly as effective as amitriptyline. Amitriptyline probably as effective as topiramate.

• Beta-Blockers o Benefits: Metoprolol, propranolol, and timolol have been shown to be effective; atenolol

and nadalol also probably effective o Harms: Sleep disturbance, weight gain, fatigue, dry mouth

• Triptans—short-term use for prevention of menstrual-associated migraines o Benefits: Some effective (frovatriptan) or probably effective (zolmitriptan, naratriptan) o Harms: Weakness, headache, dizziness, nausea

• Other drugs: o Some ACE inhibitors (lisinopril), angiotensin-receptor blockers (candesartan), alpha-agonists

(clonidine, guanfacine), and antihistamines (cyproheptadine) are possibly effective NONDRUG TREATMENTS • Behavioral therapies:

o Benefits: Relaxation training, thermal biofeedback combined with relaxation training, electromyographic (EMG) biofeedback, and cognitive-behavioral therapy are all modestly effective in preventing migraine headaches when compared to a control.

• Botulinum toxin A: o Benefits: Botulinum toxin A compared with placebo was associated with a small-to-modest

benefit for chronic daily headaches and chronic migraines, but was not associated with fewer episodic migraine or chronic tension-type headaches per month.

o Harms: Drooping of upper eyelid, skin tightness, paresthesias (abnormal sensation of tingling, numbness, or burning), neck stiffness, muscle weakness, and neck pain

• Spinal manipulation: o Current evidence is limited, inconsistent, and does not support the use of spinal

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manipulation for the prevention of migraine headaches • Other physical treatments:

o There are insufficient data to draw conclusions about the possible benefits and harms of other physical treatments ( eg, transcutaneous electrical nerve stimulation [TENS], mobilization, physical therapy, massage, and hyperbaric oxygen)


KEY UNCERTAINTIES IN CLINICAL DECISION-MAKING • Which drugs (migraine-specific or nonmigraine-specific) are most effective in reducing the frequency

of chronic migraine headaches or improving quality of life? • Which nondrug therapies are most effective in reducing the frequency of chronic migraine

headaches or improving quality of life? • Are drug or nondrug treatments more effective in reducing the frequency of chronic migraine

headaches or improving quality of life? LIKELIHOOD THAT CER WOULD BE ABLE TO REDUCE THESE UNCERTAINTIES A multitude of treatments are currently used to treat migraines, but there are limited comparative data to recommend one therapy over another. The vast majority of existing research is on episodic migraine, rather than chronic migraine, the definition of which has only been somewhat standardized since 2006. New research in this area has the potential to significantly improve patient health and quality of life.


The quality of evidence for many preventive drugs is either inadequate or is conflicting, leaving room for studies of novel treatments, particularly angiotensin-receptor blockers, angiotensin-converting-enzyme inhibitors, alpha-agonists, antiepileptics, calcium channel blockers and botulinum toxin A, as well as various nondrug treatments, such as biofeedback, relaxation therapy, and cognitive-behavioral therapy.


• Evidence suggests only a small fraction of those with episodic migraine who might benefit from preventive therapy are receiving it.

• 80% of patients meeting criteria for chronic migraine were not properly recognized as such.18


RECENT PUBLICATIONS • MEDLINE search from 1/1/2008 – 4/4/2013: total 1,462 citations

o Labeled as randomized controlled trial (RCT): 249 o Labeled as meta-analysis or systematic review: 146



How likely is it that new CER on this topic would provide better

• Due to the wide variety of treatments currently in use for prevention of chronic migraine headaches, new comparative-effectiveness research (CER) that could identify the most effective treatments would provide helpful guidance for clinical decision making.

• It is important to note that AHRQ is currently sponsoring a Comparative Effectiveness Review designed to address preventive treatment for migraine—including chronic migraine—in children and

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information to guide clinical decision making?

adults.19



FACILITATORS • Migraine headaches are difficult and frustrating for both clinicians and patients, and evidence

regarding the most effective preventive treatments is highly desired by both • Current medications used to prevent migraine are already FDA-approved for this or other

conditions (such as depression, hypertension and seizure disorder) and would be easily accessible

BARRIERS

• Many nondrug treatments ( eg, biofeedback, relaxation therapy, and cognitive-behavioral therapy) may not be accessible in all areas

• Patients with migraine often have other comorbidities and require medications that may interact with preventive treatments for migraines, making selection of appropriate treatment more difficult

• It is likely that access to botulinum treatment, if effective, would be limited by providers trained in this technique and possibly by insurance coverage


• It is very likely that new data showing increased effectiveness of one or more drugs in preventing chronic migraine headaches would be implemented very quickly provided there was appropriate and timely dissemination of the data, as well as insurance coverage for use in chronic migraine.

• Current evidence for nondrug treatments is sparse and lacks clinically meaningful comparisons. If CER were to show effectiveness, implementation of nondrug treatments may be hampered by availability of properly trained providers and health insurance coverage.


• Further basic research may be able to better characterize the cause(s) of chronic migraine, which could lead to a greater ability to identify or create more targeted therapies.

• Given such new basic science discoveries: o CER exploring the comparative safety and effectiveness of novel targeted therapies for

chronic migraine is likely to remain current for several years.

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REFERENCES:

1. Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL. Jamesone JL (eds). Harrison’s Principles of Internal

Medicine, 15th ed. New York:McGraw-Hill: 2001 2. Headache Classification Subcommittee of the International Headache Society. The International Classification of

Headache Disorders: 2nd edition. Cephalalgia 2004;24 Suppl 1:1-160. http://ihs-classification.org/en/. Accessed April 16, 2013.

3. Manack AN, Buse DC, Lipton RB. Chronic migraine: epidemiology and disease burden. Curr Pain Headache Rep. 2011;15(1):70-78.

4. Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF; AMPP Advisory Group. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68(5):343-349.

5. Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache. 2001;41(7):646-567.

6. Howard Jacobs, MD; Jack Gladstein, MD. Pediatric headache: a clinical review. Headache. 2012;52(2):333-339. 7. Buse DC, Manack AN, Fanning KM, Serrano D, Reed ML, Turkel CC, Lipton RB. Chronic migraine prevalence,

disability, and sociodemographic factors: results from the American Migraine Prevalence and Prevention Study. Headache. 2012 Jun 22. doi: 10.1111/j.1526-4610.2012.02223.x. [Epub ahead of print].

8. Smitherman TA, Burch R, Sheikh H, Loder E. The prevalence, impact, and treatment of migraine and severe headaches in the United States: a review of statistics from national surveillance studies. Headache. 2013;53(3):427-436.

9. Stokes M, Becker WJ, Lipton RB, et al. Cost of health care among patients with chronic and episodic migraine in Canada and the USA: results from the International Burden of Migraine Study (IBMS). Headache. 2011;51(7):1058-1077.

10. Insinga RP, Ng-Mak DS, Hanson ME. Costs associated with outpatient, emergency room and inpatient care for migraine in the USA. Cephalalgia. 2011;31(15):1570-1575.

11. Hawkins K, Wang S, Rupnow MF. Indirect cost burden of migraine in the United States. J Occup Environ Med. 2007;49(4):368-374.

12. Gilmore B. Michael M. Treatment of acute migraine headache. American Family Physician. 2011;83(3) 271-80. 13. Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based

review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;55(6):754-762.

14. Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E; Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1337-1345.

15. Jackson JL, Kuriyama A, Hayashino Y. Botulinum toxin A for prophylactic treatment of migraine and tension headaches in adults: a meta-analysis. JAMA. 2012;307(16):1736-1745.

16. Posadzki P, Ernst E. Spinal manipulations for the treatment of migraine: a systematic review of randomized clinical trials. Cephalalgia. 2011;31(8):964-970.

17. Duke University, Center for Clinical Health Policy Research. Behavioral and Physical Treatments for Migraine Headache. Technical Review 2.2. February 1999. (Prepared for the Agency for Health Care Policy and Research under Contract No. 290-94-2025. Available from the National Technical Information Service; NTIS Accession No. PB99-127946).

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http://ihs-classification.org/en/

http://www.ncbi.nlm.nih.gov/pubmed?term=Lipton%20RB%5BAuthor%5D&cauthor=true&cauthor_uid=17261680

http://www.ncbi.nlm.nih.gov/pubmed?term=Bigal%20ME%5BAuthor%5D&cauthor=true&cauthor_uid=17261680

http://www.ncbi.nlm.nih.gov/pubmed?term=Diamond%20M%5BAuthor%5D&cauthor=true&cauthor_uid=17261680

http://www.ncbi.nlm.nih.gov/pubmed?term=Freitag%20F%5BAuthor%5D&cauthor=true&cauthor_uid=17261680

http://www.ncbi.nlm.nih.gov/pubmed?term=Reed%20ML%5BAuthor%5D&cauthor=true&cauthor_uid=17261680

http://www.ncbi.nlm.nih.gov/pubmed?term=Stewart%20WF%5BAuthor%5D&cauthor=true&cauthor_uid=17261680

http://www.ncbi.nlm.nih.gov/pubmed?term=AMPP%20Advisory%20Group%5BCorporate%20Author%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=migraine+prevalence%2C+disease+burden%2C+and+the+need+for+preventive+therapy

http://www.ncbi.nlm.nih.gov/pubmed?term=Lipton%20RB%5BAuthor%5D&cauthor=true&cauthor_uid=11554952

http://www.ncbi.nlm.nih.gov/pubmed?term=Stewart%20WF%5BAuthor%5D&cauthor=true&cauthor_uid=11554952

http://www.ncbi.nlm.nih.gov/pubmed?term=Diamond%20S%5BAuthor%5D&cauthor=true&cauthor_uid=11554952

http://www.ncbi.nlm.nih.gov/pubmed?term=Diamond%20ML%5BAuthor%5D&cauthor=true&cauthor_uid=11554952

http://www.ncbi.nlm.nih.gov/pubmed?term=Reed%20M%5BAuthor%5D&cauthor=true&cauthor_uid=11554952

http://www.ncbi.nlm.nih.gov/pubmed/?term=prevalence+and+burden+of+migraine+in+the+united+states%3A+Data+from+the+american+migraine+study+II

http://www.ncbi.nlm.nih.gov/pubmed/?term=Pediatric+Headache%3A+A+Clinical+Reviewhead_2086+333..339

http://www.ncbi.nlm.nih.gov/pubmed?term=Smitherman%20TA%5BAuthor%5D&cauthor=true&cauthor_uid=23470015

http://www.ncbi.nlm.nih.gov/pubmed?term=Burch%20R%5BAuthor%5D&cauthor=true&cauthor_uid=23470015

http://www.ncbi.nlm.nih.gov/pubmed?term=Sheikh%20H%5BAuthor%5D&cauthor=true&cauthor_uid=23470015

http://www.ncbi.nlm.nih.gov/pubmed?term=Loder%20E%5BAuthor%5D&cauthor=true&cauthor_uid=23470015


http://www.ncbi.nlm.nih.gov/pubmed?term=Insinga%20RP%5BAuthor%5D&cauthor=true&cauthor_uid=22013140

http://www.ncbi.nlm.nih.gov/pubmed?term=Ng-Mak%20DS%5BAuthor%5D&cauthor=true&cauthor_uid=22013140

http://www.ncbi.nlm.nih.gov/pubmed?term=Hanson%20ME%5BAuthor%5D&cauthor=true&cauthor_uid=22013140


http://www.ncbi.nlm.nih.gov/pubmed?term=Hawkins%20K%5BAuthor%5D&cauthor=true&cauthor_uid=17426520

http://www.ncbi.nlm.nih.gov/pubmed?term=Wang%20S%5BAuthor%5D&cauthor=true&cauthor_uid=17426520

http://www.ncbi.nlm.nih.gov/pubmed?term=Rupnow%20MF%5BAuthor%5D&cauthor=true&cauthor_uid=17426520


http://www.ncbi.nlm.nih.gov/pubmed?term=Silberstein%20SD%5BAuthor%5D&cauthor=true&cauthor_uid=10993991


http://www.ncbi.nlm.nih.gov/pubmed?term=Silberstein%20SD%5BAuthor%5D&cauthor=true&cauthor_uid=22529202

http://www.ncbi.nlm.nih.gov/pubmed?term=Holland%20S%5BAuthor%5D&cauthor=true&cauthor_uid=22529202

http://www.ncbi.nlm.nih.gov/pubmed?term=Freitag%20F%5BAuthor%5D&cauthor=true&cauthor_uid=22529202

http://www.ncbi.nlm.nih.gov/pubmed?term=Dodick%20DW%5BAuthor%5D&cauthor=true&cauthor_uid=22529202

http://www.ncbi.nlm.nih.gov/pubmed?term=Argoff%20C%5BAuthor%5D&cauthor=true&cauthor_uid=22529202

http://www.ncbi.nlm.nih.gov/pubmed?term=Ashman%20E%5BAuthor%5D&cauthor=true&cauthor_uid=22529202

http://www.ncbi.nlm.nih.gov/pubmed?term=Quality%20Standards%20Subcommittee%20of%20the%20American%20Academy%20of%20Neurology%20and%20the%20American%20Headache%20Society%5BCorporate%20Author%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=Quality%20Standards%20Subcommittee%20of%20the%20American%20Academy%20of%20Neurology%20and%20the%20American%20Headache%20Society%5BCorporate%20Author%5D


http://www.ncbi.nlm.nih.gov/pubmed?term=Jackson%20JL%5BAuthor%5D&cauthor=true&cauthor_uid=22535858

http://www.ncbi.nlm.nih.gov/pubmed?term=Kuriyama%20A%5BAuthor%5D&cauthor=true&cauthor_uid=22535858

http://www.ncbi.nlm.nih.gov/pubmed?term=Hayashino%20Y%5BAuthor%5D&cauthor=true&cauthor_uid=22535858



18. Bigal ME, Serrano D, Reed M, Lipton RB. Chronic migraine in the population: burden, diagnosis, and satisfaction with treatment. Neurology. 2008;71(8):559-566.

19. Research Protocol: Comparative Effectiveness of Preventive Pharmacological Treatments for Migraine. November 3, 2011. http://effectivehealthcare.ahrq.gov/index.cfm. Published November 3, 2011. Accessed April 16, 2013.


Nominated by Institute of Medicine (IOM): 1) Compare the effectiveness of different treatment strategies on the frequency and lost productivity in people with chronic, frequent migraine headaches. Nominated by ‘Web’: 1) Where is the best information about the treatment of constant migraine headache? Population: All patients

Importance: It seems that the treatments are diverse and not a single source of information to standardize the efforts.

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http://effectivehealthcare.ahrq.gov/index.cfm

Topic 18: “Multiple Sclerosis” Comparative effectiveness of treatment programs for recurring/remitting multiple sclerosis (MS).

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of topic DESCRIPTION OF CONDITION • Multiple sclerosis (MS) is a neurologic condition typically affecting young adults and is

characterized by an autoimmune disorder that causes damage (by demyelination) of nerves within the central nervous system (CNS). Patients have one of four types of MS: o relapsing-remitting (most common) o secondary progressive o primary progressive o progressive relapsing

• Patients have distinct episodes of CNS dysfunction (or relapses) that, at least partially, resolve over time.

• Most patients with relapsing-remitting MS will eventually enter a secondary progressive phase in which recovery between relapses becomes less often and for shorter periods of time.

• MS is a leading cause of disability in young adults; treatments for this condition are costly, including expensive medications and ongoing rehabilitation.

Relevance to patient-entered outcomes

SYMPTOMS1,2

• Patients have episodes of CNS dysfunction, lasting at least 24 hours, which at least partially resolve over time.

• CNS dysfunction most commonly first appears as sensory disturbances or visual loss, often due to optic neuritis (inflammation of the optic nerve), but also as motor weakness, diplopia (double vision), gait disturbances, or other neurologic symptoms.

• MS is associated with increased mortality, higher rates of cognitive decline, depression, and global fatigue.

OUTCOMES • Radiologic findings are used to diagnose MS (multiple characteristic T2 lesions seen with

magnetic resonance imaging (MRI) in areas of the CNS that vary over time). • The extent of disability resulting from MS varies depending on the type of MS.



INCIDENCE (NEW CASES)3 • More than 200 cases of MS are diagnosed weekly in the United States.3 • Incidence generally occurs between 20 and 50 years of age, peaking at about 30 years of

age.4 • Incidence is increasing, particularly among women. PREVALENCE (PROPORTION OF POPULATION LIVING WITH THE CONDITION)3 • Highest prevalence occurs among white people of Nordic origin, in areas with moderate

climates, and among higher income people. • Approximately 400,000 adults have MS in the United States, while there are 2.5 million adults

with this condition worldwide, with varying prevalence by country.3 • Prevalence peaks at about 50 years of age.4 • Women are affected by MS twice as often as men. • Prevalence of MS is increasing as incidence increases (along with more effective treatments

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extending survival of patients with MS). Effects on patients’


QUALITY OF LIFE (QOL) • Patients’ QOL is affected by disability (such as impaired mobility, chronic pain, cognitive

impairment, depression, and spasticity as well as bowel and bladder dysfunction and other neurologic impairments).5

• Based on a 2006 cost assessment and a quality-adjusted life-years valued at $60,000, the reduction in QOL due to MS was estimated to add $15,315 to annual costs per patient.6

PRODUCTIVITY • Based on a 2009 insurance claims database study, employees with MS had 29.8 disability

days per year compared to 4.5 days for employees without MS. • Employees with MS compared with employees without MS also had significantly higher

annual disability costs ($3868 vs. $414). • Absenteeism costs ($1901 vs. $1003), and total indirect costs ($5769 vs. $1417) are also

increased.7 FUNCTIONAL CAPACITY • The extent of disability varies depending on the type of MS and risk factors. • Natural history studies have also found varying degrees of progressive disability. • Using the Expanded Disability Status Scale as the reference, one study reported that median

time to development of significant disability (needing a cane to walk) was 28 years from disease onset.3

MORTALITY • MS is associated with higher mortality with a mean age of death of 58 years.1 • One study from Wales found that patients with MS are almost three times more likely to die

prematurely than the general population.9 COSTS • Total direct medical cost for all patients with MS in the United States is estimated to be more

than $10 billion per year.10 How strongly does


MS has a significant impact on the functional status of young adults. Given the burden that this condition places on the QOL of patients, as well as the economic burden (both direct and indirect costs) of this condition, it is important to determine the most effective treatments for this condition.


systematic reviews, what is known about the relative benefits and harms of the available

SCREENING/EARLY DIAGNOSIS o There are currently no screening or early diagnostic tests in widespread use. o Disease monitoring typically consists of tracking patient symptoms, recurrent physical

examinations, MRI, spinal fluid analysis, and laboratory tests. TREATMENT FOR RELAPSING-REMITTING MS • Drug treatment:

o Acute attacks (or relapses) are often treated with oral or intravenous glucocorticoids

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management options?

(type of steroid hormone medication).11 o Disease-modifying therapy with a medication that regulates your immunity (since MS is

an autoimmune disorder) typically administered soon after diagnosis, with the goal of decreasing the rate of relapse and slowing the accumulation of brain lesions that are seen on MRI.

Six disease- modifying drugs have been approved: interferon-beta, glatiramer acetate, mitoxantrone, natalizumab, fingolimod, and, recently, dimethyl fumarate. 12 These agents have been shown to affect the rate of developing new brain lesions, but there is insufficient evidence to support their effect on functional outcomes.

• Physical therapy and rehabilitation: o Physical therapy, exercise, and behavioral interventions have been shown to improve:

balance in patients with mild to moderate levels of disability,13 symptoms of fatigue and depression,14 and muscle strength.15

o Exercise therapy compared with no exercise therapy showed improved muscle power, exercise tolerance, and mobility-related activities. There was also moderate evidence found for improving mood.16

o In a meta-analysis of 22 uncontrolled trials of exercise, more benefits were associated with supervised exercise training and with exercise programs that were less than three months long.17

Exercise training was also shown to be associated with a small improvement in walking mobility.17

o No best “dose” of therapy or superiority of one therapy over another could be identified.18

Inpatient rehabilitation showed short-term gains in disability despite no change in the level of impairment.

Outpatient -and home-based rehabilitation showed limited short-term improvements in symptoms, disability, and QOL with high-intensity programs.

Low-intensity programs over a longer period showed longer-term gains in QOL.18


• New research could contribute to achieving better patient-centered outcomes by identifying, developing, improving, and supporting outcome measures that reliably assess clinically meaningful disease progression, mobility, functional capacity, and QOL.

• New comparative-effectiveness research (CER)could provide data to help MS patients with decision making regarding their care (data regarding physical therapy and potential impact on disease clinical course, management of symptoms, and resulting disability, as well as QOL).

• New CER of treatment options could identify new and more effective treatments. • Patient-centered outcomes might be improved if new research that compares

comprehensive care with usual care demonstrates superiority of one of the approaches. Have recent

innovations made research on this topic especially

• There have been recent technical innovations that facilitate diagnosis and disease monitoring (eg, improved imaging techniques and laboratory tests to identify antibodies in the blood and spinal fluid), but there does not appear to be clearly improved methods for examining treatment options and how they impact patient-centered outcomes.

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compelling? • The recent increase in medication treatments for MS has increased the need for CER to help guide patient decision making regarding risks and benefits to the variety of medication and nonmedication treatments for managing MS.


There is significant variability in the content of the number of MS clinical guidelines sponsored by organizations in both the United States and Europe.19 Also, recommendations for the treatment of MS has been known to change relatively rapidly.


RECENT PUBLICATIONS • In the past two years, many systematic reviews have been published that evaluated the

comparative effectiveness and safety of disease-modifying agents and behavioral interventions, including exercise and physical therapy.

• Another oral drug treatment, dimethyl fumarate, received FDA approval for relapsing MS in March 2013. Research at various stages is currently underway for many other new drug treatments and use of existing drugs in combination.

ONGOING TRIALS • ‘ClinTrials.gov’ lists search for multiple sclerosis showed:

o Total ongoing trials: 411 o Completed trials: 451


KEY UNCERTAINTIES IN CLINICAL DECISION MAKING • What are the best outcome measures for monitoring disease progression and treatment

efficacy, using outcomes that are meaningful to patients? • What are the comparative efficacy, safety, and cost of the FDA-approved disease-modifying

agents and other agents undergoing clinical development, by disease characteristics (eg, relapsing-remitting MS) and by patient subgroups?

• How do these treatments impact patient-centered outcomes? • Do health care delivery innovations (such as comprehensive, coordinated care) improve

processes and outcomes? LIKELIHOOD THAT CER WOULD BE ABLE TO REDUCE THESE UNCERTAINTIES • There is high likelihood that CER would be able to reduce these uncertainties. These are

answerable research questions that would guide clinical decision making. Potential for New Information to Improve Care and Patient-Centered Outcomes What are the


FACILITATORS • Most stakeholders (eg, patients, providers, payers) are likely to be interested in new

information about MS and in implementing new findings that might lead to improvement in disease monitoring or treatment efficacy and safety.

• A neurologist is likely to participate in the care of most patients under treatment for MS in the United States. Disseminating new findings to this relatively small group of specialists should not be difficult.

BARRIERS • Rapid changes in published clinical guidelines are a potential barrier. • The expected availability of still more drug treatment options could be a barrier.

How likely is it that the results of new research on this topic would be

EVIDENCE OF BENEFIT • Improved patient-centered outcome measures are likely to be used in practice right away if

the evidence supporting them is compelling and if the outcomes are considered by both patients and providers to be meaningful and useful.

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implemented in practice right away?

EVIDENCE OF NO BENEFIT OR HARM • New evidence that does not demonstrate benefits—or demonstrates harm—would likely be

incorporated into clinical decision making. Would new

information from CER on this topic remain current for several years, or would it be rendered obsolete quickly by subsequent studies?

• A systematic review titled “Comparative clinical and cost effectiveness of drug therapies for relapsing-remitting multiple sclerosis” is listed in the Prospero registry as being underway, with an anticipated completion date of August 2013. The four review questions to be addressed in that review focus on comparative efficacy, safety, and cost-effectiveness for both individual disease-modifying agents and combination therapy for relapsing-remitting MS. However, as new drug treatments continue to be approved, any CER that compares current drug treatments may quickly become outdated.

• Information from CER on the topics of patient-centered outcome measures or coordinated vs. usual care for MS, however, is likely to remain current for several years because neither topic appears to be an area of currently active research.

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adults?source=search_result&search=multiple+sclerosis&selectedTitle=2%7E150 2. Giesser BS. Diagnosis of multiple sclerosis. Neurol Clin. 2011 May;29(2):381-388. 3. Tullman MJ. Overview of the epidemiology, diagnosis, and disease progression associated with multiple sclerosis.

Am J Manag Care. 2013 Feb;19(2 Suppl):s15-20. 4. Koch-Henriksen N, Sørensen PS. The changing demographic pattern of multiple sclerosis epidemiology. Lancet

Neurol. 2010 May;9(5):520-532. doi: 10.1016/S1474-4422(10)70064-8. 5. Zwibel HL, Smrtka J. Improving quality of life in multiple sclerosis: an unmet need. Am J Manag Care. 2011 May;17

Suppl 5:S139-145. 6. Kobelt G, Berg J, Atherly D, Hadjimichael O. Costs and quality of life in multiple sclerosis: a cross-sectional study in

the United States. Neurology. 2006;66(11):1696-1702. 7. Ivanova JI, Birnbaum HG, Samuels S, Davis M, Phillips AL, Meletiche D. The cost of disability and medically related

absenteeism among employees with multiple sclerosis in the US. Pharmacoeconomics. 2009;27(8):681-669. 8. Tremlett H, Paty D, Devonshire V. Disability progression in multiple sclerosis is slower than previously reported.

Neurology. 2006 Jan 24;66(2):172-177. 9. Hirst C, Swingler R, Compston DA, Ben-Shlomo Y, Robertson NP. Survival and cause of death in multiple sclerosis: a

prospective population-based study. J Neurol Neurosurg Psychiatry. 2008 Sep;79(9):1016-1021. doi: 10.1136/jnnp.2007.127332. Epub 2008 Feb 26.

10. Mathis SA. Managed Care Aspects of Managing Multiple Sclerosis. Am J Manag Care. 2013;19:S28-S34 11. Burton JM, O’Connor PW, Hohol M, et al. Oral versus intravenous steroids for treatment of relapses in multiple

sclerosis. Cochrane Database Syst Rev. 2012(12):CD006921. 12. Luessi F, Siffrin V, Zipp F. Neurodegeneration in multiple sclerosis: novel treatment strategies. Expert Rev

Neurother. 2012;12(9):1061-1076. 13. Paltamaa J, Sjögren T, Peurala SH, et al. Effects of physiotherapy interventions on balance in multiple sclerosis: a

systematic review and meta-analysis of randomized controlled trials. J Rehabil Med. 2012;44(10):811-823. 14. Heesen C, Köpke S, Kasper J, et al. Behavioral interventions in multiple sclerosis: a biopsychosocial perspective.

Expert Rev Neurother. 2012;12(9):1089-1100. 15. Kjølhede T, Vissing K, Dalgas U. Multiple sclerosis and progressive resistance training: a systematic review. Mult

Scler. 2012;18(9):1215-1228.

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16. Rietberg MB, Brooks D, Uitdehaag Bernard MJ, et al. Exercise therapy for multiple sclerosis. Cochrane Database of

Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 2004. http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD00398

17. Snook EM, Motl RW. Effect of exercise training on walking mobility in multiple sclerosis: a meta-analysis. Neurorehabil Neural Repair. 2009 Feb;23(2):108-116.

18. Khan F, Turner-Stokes L, Ng L, et al. Multidisciplinary rehabilitation for adults with multiple sclerosis. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 2008. http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD00603

19 Trisolini MG. Comparison of Multiple Sclerosis Guidelines Underscores Need for Collaboration. 2008. http://guidelines.gov/expert/expert-commentary.aspx?id=16443.

APPENDIX: Topic Questions

Nominated by Institute of Medicine (IOM) 1) Compare the effectiveness of comprehensive, coordinated care and usual care on objective measures of clinical status, patient-reported outcomes, and costs of care for people with multiple sclerosis. Nominated by ‘Web’ 1) The measurement of new lesions and relapses for determining the efficacy of a drug is flawed. The real measurement should include disease progression and mobility

Population: All MS patients Importance: Because the treatments available for MS are crazy expensive. A patient can have lesions without progression. The real goal should be preventing or limiting progression.

2) My health insurance company has a $3000 annual cap for physical therapy. I reached that cap in April 2012. I requested additional PT along with copies of my PT progress note and a letter from my neurologist stating that continued therapy is medically necessary. I also included a statement explaining that in 2005 I was denied additional therapy therefore sought out other avenues to improve flexibility and strength. Unfortunately, I sustained a complete spiral fracture of my right femur while my personal yoga instructor assisted me with stretching my left hip. Well, the insurance company denied my 2012 appeal stating the notes do not reflect significant improvement. My question is (the insurance company will not provide detail) how can an insurance reviewer define what is significant improvement for an individual whom they have never met? Also, some conditions benefit from therapy even without improvement because without therapy the condition will deteriorate

Population: Persons with chronic progressive disease of all backgrounds. Progressive diseases of the central nervous system will benefit, Importance: This is important because people are denied physical therapy because of arbitrary caps and restorative discrimination and therefore deteriorating not because the disease is progressing but because of disuse. This causes unnecessary pain, surgery and loss of participation in family and community life.

3) Which is (are) the best treatment(s) for recurring/remitting MS? Could MS be effectively treated less expensively?

Population: All individuals diagnosed with recurring/remitting MS. Significantly more women than men. Most patients are diagnosed while still relatively young, so effective treatment could improve their quality of life over a long period of time.

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Importance: The treatments, none of which cure the disease or stop the progression, are all very expensive. With so much money being spent per patient to achieve such modest results, choosing the right treatment is critical.

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Topic 19: “Obstructive Sleep Apnea”

Comparative effectiveness of medical and surgical treatment options for obstructive sleep apnea in adults.

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of topic DESCRIPTION OF CONDITION1 • Individuals with obstructive sleep apnea (OSA) have repeated episodes during sleep where

their upper airway collapses and becomes obstructed. This obstruction occurs more frequently among obese individuals, who experience airway narrowing due to fat accumulation.

• This results in reduced breathing (hypopnea) or complete stoppage of breathing (apnea). • When breathing stops, oxygen levels drop, causing patients to wake repeatedly through the

night. • Over time, poor sleep quality and chronic dropping of oxygen levels lead to many problems.


SYMPTOMS/OUTCOMES • Symptoms (many of these may be noticed by spouse more than patient)1,2

o Daytime sleepiness o Snoring o Frequent awakening during the night o Awakening with a choking or smothering sensation, dry mouth, sore throat, or chest

pain o Irritability o Difficulty concentrating or mental fogging o Memory problems o Morning headaches o Decreased sex drive o Depression o Body aches o History of high blood pressure, diabetes, heart disease, or kidney disease

• Other outcomes1 o Cardiovascular disease (heart disease and stroke) o Hypertension o Diabetes mellitus o Higher rates of motor vehicle accidents o Decreased quality of life o Inability to function at a normal level during day due to sleepiness o Higher mortality



INCIDENCE (NEW CASES)/PREVALENCE (PROPORTION OF POPULATION LIVING WITH THE CONDITION) • Prevalence of OSA increases with age, from about 10% at age 40 to 20% among those older

than age 60.1,3 • Rates of OSA are higher in men than in women and African Americans and Asians may be at

risk at younger ages compared with Caucasians.3-6 • Rates of OSA are rising, probably related to increasing rates of obesity; up to 25% of adults

are at high risk for OSA.5

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QUALITY OF LIFE • OSA negatively affects patient quality of life, in a large part because of daytime sleepiness.7 PRODUCTIVITY • Studies using work productivity scales show that OSA negatively affects work productivity,

even in otherwise healthy patients.8 FUNCTIONAL CAPACITY • OSA appears to negatively impact exercise capacity, although the contribution of OSA is

difficult to distinguish from that of obesity.9 MORTALITY • OSA, particularly in severe cases and among elderly patients, increases all-cause mortality.1


Due to its relationship with obesity, OSA is rising in prevalence. OSA is associated with numerous bothersome symptoms such as daytime sleepiness and poor sleep quality, which reduce patient quality of life. Further, OSA is associated with devastating complications, including higher rates of cardiovascular disease and mortality. For all of these reasons, comparative-effectiveness research (CER) to identify optimal treatment approaches should be assigned high priority.



Systematic reviews: • AHRQ comparative effectiveness review: Diagnosis and Treatment of Obstructive Sleep

Apnea in Adults (2011)1 • Two AHRQ future research needs prioritization projects: Future Research Needs for Diagnosis

of Obstructive Sleep Apnea (2012) and Future Research Needs for Treatment of Obstructive Sleep Apnea (2012)10,11

• Numerous additional systematic reviews are available SCREENING/EARLY DIAGNOSIS1,2 • Diagnostic testing for OSA should be performed on any patient with typical symptoms of

OSA, particularly snoring and daytime sleepiness. It is important for medical providers to ask patients about OSA symptoms, particularly patients who have typical risk factors, such as obesity.

• Diagnosis of OSA is based on testing to identify episodes of reduced breathing (hypopnea) or complete stoppage of breathing (apnea): o The apnea-hypopnea index (AHI) is the count of the hourly apnea and hypopnea events

during sleep. o The American Academy of Sleep Medicine defines OSA by an AHI of at least 15 events

per hour (with or without OSA symptoms) or at least five events per hour with OSA symptoms.

• There are two main strategies for diagnosing OSA: o Polysomnography (PSG)—Patients sleep in a special lab with comprehensive brain,

breathing, heart monitoring and observation by a technologist. Though this is felt to be the most accurate way to diagnose OSA, disadvantages include cost, patient inconvenience, and differences in standards between labs.

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o Portable monitoring—Smaller monitors that collect data similar to PSG can be used at home or in sleep units.

Patient questionnaires may also have a role in identifying patients in whom testing for OSA is indicated. TREATMENT1,2

• Continuous positive airway pressure (CPAP) is the standard first-line treatment for OSA. CPAP machines improve the airway obstruction that causes OSA by delivering compressed air into the airway (via a nasal or oral mask) to hold it open. o CPAP improves sleep patterns and quality of life when used as directed.1 o Optimal CPAP settings can be determined during PSG. Biphasic positive airway pressure

(BiPAP) masks may be tolerated better by some patient subgroups. o The biggest drawback with CPAP is that patients have trouble tolerating it, often

because they find the CPAP mask to be uncomfortable. CPAP only benefits those who use it correctly. Greater adherence is predicted by worse severity as measured by AHI or Epworth Sleepiness Scale.1

o The systematic review suggests CPAP is more effective than dental/mandibular devices.1 • Dental/mandibular devices are fitted by a dentist and worn overnight in the mouth to hold

the airway open and prevent collapse. The systematic review suggests moderate effectiveness, but lower than with CPAP.1 o PSG or portable monitoring is recommended to confirm effectiveness of a patient’s

device. o Device is generally used in cases where CPAP cannot be tolerated or the patient prefers

an oral device. • Surgery can be performed to open up/widen the airway. The most common procedure is

uvulopalatopharyngoplasty, in which the soft tissue at the back of the throat is removed, as well as the tonsils and adenoids, if present. o Surgery is generally only performed in cases where CPAP or oral devices have not

worked. o The systematic review concluded that there is insufficient evidence to evaluate

comparative effectiveness with CPAP or other interventions. • Weight loss—since obesity is a common underlying cause for OSA, weight loss can be

effective in reducing symptoms if successful; options include lifestyle interventions and bariatric surgery.

• Other treatments—less used treatments for OSA may include devices that hold the head/neck in a certain position, as well as pharmacotherapy.


New research could contribute to achieving better patient-centered outcomes: • Diagnosis-related research:10

o How do different available tests compare in their ability to diagnose OSA in adults with symptoms suggestive of disordered sleep?

o How do these tests compare in different subgroups of patients based on race, sex, body mass index, existing noninsulin-dependent diabetes mellitus, existing cardiovascular disease, existing hypertension, clinical symptoms, previous stroke, or airway characteristics?

o How does phased testing (screening tests or battery followed by full test) compare with

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full testing alone? o In adults being screened for OSA, what are the relationships between AHI or oxygen

desaturation index and patient characteristics with long-term clinical and functional outcomes?

• Treatment-related research:11 o What is the comparative effectiveness of different treatments for OSA in adults? o Does the comparative effect of treatments vary based on presenting patient

characteristics, severity of OSA, or other pretreatment factors? o Are any of these characteristics or factors predictive of treatment success? o Does the comparative effect of treatments vary based on the definitions of OSA used by

study investigators? o In patients with OSA who were prescribed nonsurgical treatments, what are the

associations between pretreatment patient-level characteristics and treatment adherence?

o What is the effect of interventions to improve adherence with device use (positive airway pressure, oral appliances, and positional therapy) on clinical and intermediate outcomes?


Recent innovations: Recently, some improvements in CPAP masks have been developed to improve patient adherence to therapy.


VARIABILITY IN CARE • Though the American Academy of Sleep Medicine uses a standardized definition for

diagnosis of OSA based on AHI,2 different research studies have used different AHI cutoffs.1 • Some differences exist in diagnostic equipment and protocols used by sleep labs as well as in

patterns of treatment utilization. What is the pace of


RECENT PUBLICATIONS • MEDLINE search 1/1/08-4/9/13—Total: 2,269

o Tagged as randomized controlled trial (RCT): 267 o Tagged as meta-analysis or systematic reviews: 158

ONGOING TRIALS • Clinicaltrials.gov—Total ongoing trials: 269, completed trials: 262 • NIH reporter—Projects: 166, publications: 232


KEY UNCERTAINTIES IN CLINICAL DECISION MAKING • Should there be age- and sex-specific criteria for defining OSA? • What is the optimal test to identify and diagnose OSA? Should this differ in different

subgroups (eg, age, obese vs. nonobese, patients with jaw abnormalities)? • What is the role for routine (or selected) preoperative screening for OSA? • When is it appropriate to skip PSG in diagnosing OSA? • What are the available objectively-measured predictors of OSA diagnosis (eg, AHI), and which

ones are the best? • What are consumer preferences for strategies to diagnose OSA? • What is the value of less common strategies for diagnosing OSA (eg, scoring nasal flow

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limitation in recognizing mild OSA, brain MRI, 4-phase rhinomanometry in identifying patients with high nasal resistance and OSA)?

• What is the impact of different available strategies for OSA treatment on major long-term clinical outcomes (including CPAP, dental devices, different surgeries, weight-loss strategies such as lifestyle modification or bariatric surgery, pharmaceutical strategies)?

• How do patient characteristics (demographics, comorbidities, OSA severity) affect the likelihood of long-term clinical outcomes?

• What is the optimal treatment for OSA in different patient subgroups (differing disease severity, patients who do not tolerate CPAP)?

• What is the role of weight-loss programs and bariatric surgery as an adjunctive treatment for OSA?

• What CPAP and/or BiPAP masks are optimal for different patient subgroups, and how do they affect adherence to therapy?

• What is the role of postoperative CPAP for patients with OSA or at high risk of OSA undergoing any surgery with sedation?

LIKELIHOOD THAT CER WOULD BE ABLE TO REDUCE THESE UNCERTAINTIES • Appropriately designed studies would have a high likelihood of answering these questions

and reducing key areas of uncertainty. Potential for New Information to Improve Care and Patient-Centered Outcomes What are the


FACILITATORS • OSA is a common clinical problem with rising prevalence, so there is high societal motivation

to improve care. • OSA is associated with many serious clinical complications; these complications may be

prevented or treated through appropriate therapy. BARRIERS • Diagnostic strategies may inconvenience patients (time, costs, and other factors). • Treatments are costly and often poorly tolerated by patients, which reduces effectiveness. • Many different treatment options are available; effects may differ by patient subgroups,

which may make designing good trials challenging. How likely is it that


EVIDENCE OF BENEFIT • It is likely that research would be implemented widely if there is evidence of better patient-

centered outcomes EVIDENCE OF NO BENEFIT OR HARM • It is likely that research demonstrating no evidence of benefit would also have an impact on

practice, particularly because many strategies for diagnosing and treating OSA are costly.

Would new information from CER on this topic remain current for several years, or would it be rendered obsolete quickly by

OSA is a very common problem, and it is increasing in prevalence. Information from well-designed randomized controlled trials on this CER topic would likely remain relevant for several years.

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subsequent studies?

REFERENCES 1. Balk EM, Moorthy D, Obadan NO, Patel K, Ip S,Chung M, Bannuru RR, Kitsios GD, Sen S, Iovin RC, Gaylor JM,

D’Ambrosio C, Lau J. Diagnosis and Treatment of Obstructive Sleep Apnea in Adults. Comparative Effectiveness Review No. 32. (Prepared by Tufts Evidence-based Practice Center under Contract No. 290-2007-10055-1). AHRQ Publication No. 11-EHC052-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2011. www.effectivehealthcare.ahrq.gov/reports/final.cfm. Published July 2011.

2. Epstein LJ, Kristo D, Strollo PJ Jr, Friedman N, Malhotra A, Patil SP, Ramar K, Rogers R, Schwab RJ, Weaver EM, Weinstein MD, Adult Obstructive Sleep Apnea Task Force of the American Academy of Sleep Medicine. Clinical guideline for the evaluation, management and long-term care of obstructive sleep apnea in adults. J Clin Sleep Med. 2009;5(3):263-276.

3. Young T, Finn L, Peppard PE et al. Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort. Sleep 2008;31:1071-1078.

4. Punjabi NM, Caffo BS, Goodwin JL, et al. Sleep-disordered breathing and mortality: a prospective cohort study. PLoS Medicine/Public Library of Science 2009;6:e1000132.

5. Hiestand DM, Britz P, Goldman M, et al. Prevalence of symptoms and risk of sleep apnea in the US population: Results from the national sleep foundation sleep in America 2005 poll. Chest 2006;130:780-786.

6. Villaneuva AT, Buchanan PR, Yee BJ, Grunstein RR. Ethnicity and obstructive sleep apnoea. Sleep Med Rev. 2005;9(6):419-436.

7. Bulcun E, Ekici A, Ekici M. Quality of life and metabolic disorders in patients with obstructive sleep apnea. Clin Invest Med. 2012;35(2):E105-113.

8. Nena E, Steiropoulos P, Constantinidis TC, Perantoni E, Tsara V. Work productivity in obstructive sleep apnea patients. J Occup Environ Med. 2010;52(6):622-625.

9. Przybyłowski T, Bielicki P, Kumor M, et al. Exercise capacity in patients with obstructive sleep apnea syndrome. J Physiol Pharmacol. 2007;58(suppl 5):563-574.

10. Balk EM, Chung M, Moorthy D, Chan JA, Patel K, Concannon TW, Ratichek SJ, Chang LKW. Future Research Needs for Diagnosis of Obstructive Sleep Apnea. Future Research Needs Paper No. 11. (Prepared by the Tufts Evidence-based Practice Center under Contract No. 290-2007-10055 I.) AHRQ Publication No. 12-EHC031-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2012. www.effectivehealthcare.gov/reports/final.cfm. Published February 2012.

11. Balk EM, Chung M, Chan JA, Moorthy D, Patel K, Concannon TW, Ratichek SJ, Chang LKW. Future Research Needs for Treatment of Obstructive Sleep Apnea. Future Research Needs Paper No. 12. (Prepared by the Tufts Evidence-based Practice Center under Contract No. 290-2007-10055 I.) AHRQ Publication No. 12-EHC033-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2012. www.effectivehealthcare.gov/reports/final.cfm. Published February 2012.

APPENDIX: Topic Questions Nominated by ‘Web’

1) A sleep study confirmed I have sleep apnea. I failed CPAP, oral appliances, and other noninvasive measures. Surgery is my next step. What information can you provide to help me decide what type of surgery has the best outcome and the lowest cost, based on my history, morphology, and age.

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http://www.effectivehealthcare.gov/reports/final.cfm

http://www.effectivehealthcare.gov/reports/final.cfm

Population: an infant/adolescent; a teenager, adult 25-65 or over 65, regardless of sex or ethnicity Importance: It is well known obstructive sleep apnea leads to decrease day time alertness, physical and mental functioning, mental illness, motor vehicle accidence, and if untreated, diabetes, obesity, heart disease and other diseases or disabilities in the longer term. AHRQ conducted a comparative effectiveness analysis between CPAP and other appliances. Soft-tissue surgery is performed routinely but published study showed it has limited effectiveness and is associated with significant postoperative morbidity and even mortality. Maxillo-mandibular advancement (MMA) surgery, while more costly, appears to be associated with a much higher efficacy rate than soft-tissue surgery. That all surgical studies had limited sample size is part of the issue. Most insurers, however, would only approve MMA after a trial and failure of soft-tissue surgery even though its efficacy is low, increasing cost and subjecting many patients with two surgeries in order to attain relief.

Nominated by Agency for Healthcare Research and Quality (AHRQ)

1) Age- and gender-specific criteria for defining the OSA syndrome (and abnormal breathing)? 2) Effect of routine (or selected) preoperative screening for sleep apnea? 3) Diagnostic approaches to OSA in obese and nonobese patients? 4) Can PSG be skipped in making the diagnosis of sleep apnea? 5) Head-to-head comparisons of portable monitors, questionnaires, and prediction rules? 6) What are the available, objectively-measured predictors of sleep apnea diagnosis? 7) What is consumer willingness to pay for screening and to identify consumer preferences for strategies to

diagnose sleep apnea? 8) Value of scoring nasal flow limitation in recognizing mild OSA? 9) Value of brain MRI in evaluating OSA patients? 10) Value of using 4-phase rhinomanometry in recognition of patients with high nasal resistance and OSA? 11) Diagnostic approach to OSA in micrognathia and retrognathia? 12) What is the impact of treatment of sleep-disordered breathing on major long-term clinical outcomes, including

mortality, cardiovascular disease, and diabetes? 13) What are long-term outcomes of mandibular advancement devices (MAD) treatment? 14) Comparative studies of different sleep apnea treatments based on patient characteristics

a. Analyses of CPAP stratified by disease severity b. Analyses of non-CPAP treatments stratified by disease severity

15) Comparison of alternative treatments for patients who do not tolerate CPAP? 16) What is the association between sleep apnea severity and long-term clinical outcomes? 17) Trials to evaluate weight-loss programs as an adjunctive treatment for sleep apnea? 18) What is the value of bariatric surgery for treatment of sleep apnea? 19) Role of surgery for treatment of OSA? 20) Comparison of surgery vs. CPAP? 21) Role of orthognathic surgery (corrective jaw surgery)? 22) Comparison of genio-tubercle advancement vs. dental devices? 23) Evaluation of postoperative CPAP for all patients with OSA or at high risk of OSA undergoing any surgery with

sedation a. Trials comparing CPAP vs. pharmaceutical interventions b. Trials comparing different CPAP masks c. Trials comparing CPAP vs. oropharyngeal exercises d. Trials comparing different degrees of mandibular advancement

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e. Studies of factors influencing therapist decisions concerning CPAP mask choice

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Topic 20: “Osteoarthritis” Comparative effectiveness of treatment strategies for stabilization of symptoms from osteoarthritis.

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of topic DESCRIPTION OF CONDITION • Osteoarthritis (OA) is characterized by damage to cartilage and bones of joints, causing

symptoms of pain and stiffness in the affected joints. OA is also referred to as degenerative joint disease or wear-and-tear arthritis.

• OA is a very common condition, particularly in people over age 45 and is a major cause of physical disability, decreased quality of life, and increased health care costs.


SYMPTOMS • Pain and stiffness of affected joints—the most commonly affected joints are knees, hips,

hands, spine, and feet • Usually begins in a single joint OUTCOMES • OA has an impact on many aspects of patients’ lives including:

o Quality of life o Daily functioning o Mental health (including depressive symptoms) o Fatigue o Limitations with work o Quality of sleep o Ability to engage in other health behaviors (like physical activity)

• Other conditions more common in patients with OA include: Impact of disease on quality of life:

• Impaired functioning (pain, limited mobility) • Depression, anxiety, sleep disorders1

Related to treatments used for OA symptoms: • Nonsteroidal antiinflammatory drugs (NSAIDs) like aspirin, ibuprofen, and the like,

used to treat OA-related pain • Long-term use of these medications can contribute to peptic ulcer disease, kidney

disease Relationship to OA is unclear. Other metabolic disorders (diabetes, hypertension, high

cholesterol) are more common in patients with OA.2 Burden on Society Recent incidence


INCIDENCE (NEW CASES) • OA increases with age, occurring most often in people over age 45.3. • OA of the hand has one new case per year per 1000 people (0.1%) aged 20-89; higher as age

increases.1 PREVALENCE (PROPORTION OF POPULATION LIVING WITH THE CONDITION) • 27 million US adults (>10% of population) aged 18 years and older have one or more type of

clinical OA.2 • Prevalence varies by definition of OA, location of OA, and populations studied:4

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19% of people aged 45 or older and 37% of people aged 60 or older had knee OA on x-ray.4

In populations with higher proportions of African American, rural, and obese residents, 28% of people aged 45 or older and 50% aged 75 or older had knee OA on x-ray;4 prevalence of hip OA was similar.

Of those showing OA on x-ray, a smaller proportion report having symptoms (7-17%)4 Key risk subgroups:

o Risk of progression and severity of symptoms is greater in African Americans than Caucasians.

o There is greater prevalence and associated limitations on activity in women, particularly after menopause.


QUALITY OF LIFE o OA leads to functional limitations, pain, disability, lost earnings, and is associated with other

comorbid conditions, all of which can affect quality of life. PRODUCTIVITY o 5.3% of US adults aged 18-64 report arthritis-attributable work limitations (AAWL). Among

adults with arthritis, approximately 30% reported AAWL.5 o In 2003, indirect costs of earning losses due to all rheumatic conditions (with OA being the

most common of these) for adults in the United States was over $47 billion.2 o OA is the third leading cause of “years of life lost to disability” (after depression and alcohol

overuse).2 FUNCTIONAL CAPACITY2 o Most common functional limitations affect walking, standing, bending, and stooping

movements; people with OA are more than three times as likely to have trouble with walking as people without OA.

o Among older adults, the risk of disability attributable to knee OA is as great as that due to cardiovascular disease and greater than any other medical condition.6

o Data from the National Health Interview Survey show that people with arthritis-related disability (including disability from OA) have more numerous, longer, and more bothersome disabilities than people with heart disease-related disability.7

MORTALITY o Increased age-specific mortality among patients with OA, particularly symptomatic hip and

knee OA,3 compared to those without OA is at least partly attributable to: Gastrointestinal conditions related to NSAID use Cardiovascular-related conditions related to obesity8

How strongly does this overall societal burden suggest that CER on alternative approaches to this problem should be

Given the high prevalence of OA and the impact on functional status, productivity, and quality of life, high priority should be given to optimizing treatments to slow progression of disease, reduce pain, and maintain functional status.

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given high priority?



Four recent systematic reviews explored OA management options.9-12

• limited evidence on the relative benefits and harms of different therapies within each category (drugs, physical therapy/exercise, weight loss, or surgery)

• little evidence directly comparing relative effectiveness in terms of patient-centered outcomes between different categories, or between different combinations of categories

SCREENING/EARLY DIAGNOSIS • Diagnosing OA can be complex due to a lack of specific physical or laboratory findings and

discrepancies between symptoms and the results of radiographic examinations. • OA is frequently diagnosed by an overall clinical impression based on the patient's age and

history, findings on physical examination, and X-ray or MRI findings. MANAGEMENT OPTIONS11 • Pain relievers and anti-inflammatory drugs:

o Most trials were primarily short-term, conducted in ideal settings (few real-world effectiveness studies)

o Potential benefits: Pain control and reducing swelling

o Potential harms: Gastrointestinal bleeding Peptic ulcer disease Hypertension Swelling Renal disease

• Weight loss: o Identifying effective weight-loss strategies is no easier in an OA population than any

other (ie, extremely difficult) • Exercise and physical therapy:

o Unclear which type of exercise or physical therapy is best: Reviews report that no single physical therapy intervention improves all key clinical

and patient outcomes. Studies tended to focus on a single exercise therapy, but typical practice uses

combined interventions. Unclear if effects of exercise therapies on quality of life differ by key patient

populations or if outcomes are sustained over time. o Potential benefits for preserving physical function

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o Few harms were reported except for increased pain or swelling during and after exercise, but these did not deter participation in exercise programs.

• Combination management: o Using medications with exercise and physical therapy interventions

• Joint Surgery: o When medication and exercise or physical therapy are not enough to decrease pain

and improve quality of life, joint surgery is another option. What could new


• There are currently few studies that compare multimodal treatments ( eg, combinations of physical therapies) with exercise alone.

o Few studies explored how effects differed by key subgroups o Few studies evaluated optimal duration and intensity on interventions

• Existing evidence does not allow for conclusions about the following: o Comparative effectiveness of strategies to help patients engage in key behaviors for

managing OA (physical activity, weight management), in real-world settings (community, primary care)

o Comparative effectiveness of strategies to increase patient adherence to nonmedication-based strategies

o Comparative effectiveness of methods to assist patients with informed decision making regarding OA treatments ( eg, medication use, joint injections, physical therapy, joint replacement surgery), with a focus on individuals with low health literacy and limited health care access

o Methods for identifying and engaging patients early in the OA disease process, particularly fostering healthy behaviors (physical activity, weight management) to slow disease progression

o Comparative benefits of different exercise and physical therapy interventions o Which exercise therapies work best for key subgroups (sex, severity of disease, age,

obesity) o Long-term benefits of exercise therapy interventions and strategies for helping patients

adhere to exercise recommendations o How outcomes of pharmacotherapies will work outside of ideal study settings (need for

more real-world research) Have recent


• There have been no recent high-impact innovations related to strategies for improving patient-centered outcomes.

• Yet, there is a compelling argument for fostering comparative effectiveness research in this area, given the following: o High burden of disease and large burden on patient-centered outcomes (pain, functional

ability) o Existence of strategies to effectively improve these outcomes o High level of nonadherence to these strategies (both at the patient and health care

levels) How widely does

care now vary? VARIABILITY IN CARE • Clinical practice often does not reflect guideline recommendations for care.13 • In particular, there is low use of conservative, nonmedication strategies like exercise and

weight loss.

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What is the pace of


RECENT PUBLICATIONS • MEDLINE search from 1/1/2008 – 4/9/2013: total 4,570 citations

o 901 labeled as randomized controlled trials/therapy (RCTs) o 406 labeled as meta-analyses or systematic reviews

ONGOING TRIALS • There are at least 628 ongoing studies listed in ‘clinicalTrials.gov’ • NIH Reporter (a database of NIH funded studies) lists:



KEY UNCERTAINTIES IN CLINICAL DECISION MAKING • What management strategy or combination of management strategies works best for key

subgroups of patients? • What are effective strategies to foster long-term adherence rates to management strategies? • What are the comparative benefits and harms of different management strategies? • What are the best methods for engaging patients in the decision making process regarding

management strategies? LIKELIHOOD THAT CER WOULD BE ABLE TO REDUCE THESE UNCERTAINTIES • Effective treatments and behavioral strategies exist, but methods for employing and

sustaining these in real-world clinical settings are lacking; comparative-effectiveness research (CER) can help patients and providers by giving practical guidance in these areas.

• There are few comparative effectiveness studies of exercise and physical therapy strategies; understanding the best interventions in this area could improve care and outcomes by establishing a set of “best practices” to be employed in health care and community settings.

• Beyond compliance with interventions, there is little evidence regarding which patients do best with what management strategies ( eg, joint injections, pharmacotherapies, physical therapy); CER in this area could help patients and providers to better select strategies according to patient characteristics.



FACILITATORS • OA is a prevalent disease with wide impact on patient quality of life, functioning, and

productivity. Therefore patients are often motivated to engage in treatments that may improve their symptoms.

• Many nonmedication therapies can be delivered by individuals other than a physician and can be delivered in multiple settings to increase patient access.

• There are already evidence-based interventions for patients with OA. These “off-the-shelf” programs can be adapted to different settings and patient groups and can be readily used in comparative effectiveness research and implementation strategies.

BARRIERS • OA is primarily treated in primary care settings (until patients need certain types of joint

injections or are considering surgery). In primary care settings there are often many

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competing demands and little time; therefore any strategies need to consider this limitation. • Long-term adherence to exercise and weight loss in OA is a challenge, just as it is among

other patient groups. How likely is it that


• Provider-based interventions are more likely to be implemented right away if they are easy to implement for both the provider and the patient.

• Several professional societies have developed recommendations for the care and management of OA, and the core components of these recommendations are in agreement. However, there is a need to give providers: o Reminders to implement these recommendations o Specific guidance on when each management strategy may be appropriate for patients.

These types of reminders, particularly if automated and integrated into practice settings, could be feasibly implemented.

• Patient-based research that compares the effectiveness of different therapies is likely to be implemented right away if there are improvements in outcomes that are easy to achieve and can be customized to the individual patient.


• CER priority areas that seek to identify best strategies for implementing existing recommendations for care and patient interventions (physical activity and weight management) are needed.

• Other CER priority areas include comparative effectiveness of specific therapies ( eg, type of exercise or physical therapy intervention) and identification of optimal strategies for different patient subgroups.

• These types of findings are not likely to become obsolete quickly.

REFERENCES: 1. Gore M, Tai KS, Sadosky A, Leslie D, Stacey BR. Clinical comorbidities, treatment patterns, and direct medical costs

of patients with osteoarthritis in usual care: a retrospective claims database analysis. J Med Econ. 2011;14(4):497-507.

2. Murphy L, Helmick CG. The impact of osteoarthritis in the United States: a population-health perspective. Am J Nurs. 2012 Mar;112(3 Suppl 1):S13-19.

3. Hochberg MC. Osteoarthritis year 2012 in review: clinical. Osteoarthritis Cartilage. 2012 Dec;20(12):1465-1469. 4. Suri P, Morgenroth DC, Hunter DJ. PM R. Epidemiology of osteoarthritis and associated comorbidities. 2012

May;4(5 Suppl):S10-9. 5. Theis KA, Murphy L, Hootman JM, Helmick CG, Yelin E. Prevalence and correlates of arthritis-attributable work

limitation in the US population among persons ages 18-64: 2002 National Health Interview Survey Data. Arthritis Rheum. 2007 Apr 15;57(3):355-363.

6. Guccione AA, Felson DT, Anderson JJ, et al. The effects of specific medical conditions on the functional limitations of elders in the Framingham Study. Am. J. Public Health. 1997;84:351-358

7. Verbrugge LM, Juarez L. Arthritis disability and heart disease disability. Arthritis Care Res. 2008;59(10):1445-1457. 8. Hochberg MC. Mortality in osteoarthritis. Clin Exp Rheumatol. 2008 Sep-Oct;26(5 Suppl 51):S120-124. 9. Shamliyan TA, Wang S-Y, Olson-Kellogg B, Kane RL. Physical Therapy Interventions for Knee Pain Secondary to

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APPENDIX: TOPIC QUESTION Nominated by Institute of Medicine (IOM)

1) Compare the effectiveness of different treatment strategies in the prevention of progression and disability from osteoarthritis.

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