Davidson Grandrounds2010 Final

Evidence-Based Geriatric Pharmacotherapy: 2010

H. Edward Davidson, PharmD, MPHEastern Virginia Medical School

Insight Therapeutics, LLC

Vaccines

Varicella Zoster Infection

Primary Infection

(Chickenpox)

Latency Reactivation(Shingles)

Varicella ZosterDorsal

Ganglion

Varicella Zoster In US(Pre-Vaccine Era)

Primary Infection in the U.S.

4 million cases annually

95% of persons infected by age 15

145 deaths annually; adult rate

higher

12,000 hospitalizations

annually

Varicella Zoster In US(Post-Vaccine Era)

Primary Infection in the U.S.

~ 800,000 cases annually

81% of persons vaccinated

~ 1500 hospitalizations

annually

66 deaths annually

Risk Factors for “Shingles”

Stressful events– trauma, surgical procedures, X-ray, other

physical, emotional stress

Immune system alteration– HIV, malignancy– drugs - cytotoxic, corticosteroids

Age– age-related decline in cell mediated immunity

Reducing Incidence of “Shingles”

Exposure to children with primary varicella infection (“Chickenpox”)– Pediatricians have a reduced rate of zoster – Household exposure enhances cell mediated

immunity

Varicella vaccination of adults– Several small studies and one large study

(38, 500 patients) have shown reduced incidence of zoster

– Vaccine (Zostavax) approved by FDA in 2006

Number of Herpes Zoster Cases Observed in MSGP4

0

20

40

60

80

100

120

140

160

180

2000-

4

5-9

10-1

4

15-1

9

20-2

4

25-2

9

30-3

4

35-3

9

40-4

4

45-4

9

50-5

4

55-5

9

60-6

4

65-6

9

70-7

4

75-7

9

Age

Zo

ster

cas

es

Data – Children < 16 years

Data – No Children

Model – Children < 16 years

Model – No Children

Brisson, M et al. Vaccine. 2002MSGP4 = National Survey of Morbidity in General Practice 4

Prediction of Post-Vaccination Incidence of Herpes-Zoster

0

100

200

300

400

500

600

700

800

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70

No Vaccination

Best Fit, 20yrs immunity

95% CI, 7-41yrs immunity

Zo

ster

inci

den

ce r

ate

(per

100

,000

per

yea

r)

Year after start of vaccination

Brisson, M et al. Vaccine. 2002

Herpes Zoster Related Hospitalizations and Expenditures Before and After

Introduction of the Varicella Vaccine in the

United States

Patel MS et al. Infect Control Hosp Epidemiol 2008;29:1157-63

Herpes-Zoster Related Hospitalizations

Retrospective analysis of a deidentified dataset, Nationwide Inpatient Sample (NIS) (AHRQ)

Nationally representative sample Study period 1993 – 2004 Herpes zoster-related hospital discharges

(HZHDs) and varicella-related hospital discharges (VRHDs) identified (ICD-9)

Resource utilization and clinical data analyzed

HZHDs and VRHDs by Year

Universal Universal Vaccination in U.S.Vaccination in U.S.

HZHDs by Year and Age


Cost of HZHD and VRHD by Year


Barriers to Use of Herpes Zoster Vaccine

Hurley LP et al. Ann Intern Med 2010;152;555-60. Mail + internet-based survey of general internists

and family medicine physicians, July-Sept 2008 Funded by CDC Measured survey responses on:

– Current vaccination practices– Knowledge and practice regarding reimbursement– Barriers to vaccination

Perceived Barriers to Administering HZ Vaccine in the Office

56191312Difficulty in obtaining vaccine

35302312More pressing medical issues

42222016Need to store in freezer

34182523Patient pick-up at pharmacy

19172143Up-front costs for practice

13102552Reimbursement issues

7103053Cost for patient

Not at allMinorSomewhatMajor

Responses, %

Barrier

Provider strength of recommendation for herpes zoster vaccine compared with other vaccines

Hurley L P et al. Ann Intern Med 2010;152:555-560

©2010 by American College of Physicians

Take away …

Less than 7% of target population (> 59 yrs, no recent hx) for HZ vaccine have received it1

Epidemiologic evidences suggest a “rash” of new cases in the elderly are coming

Barriers exist to HZ vaccine administration– Storage – refrigerator stable formulation licensed in

EU– Cost – covered by Medicare (under Part D); need to

streamline reimbursement process– Lack of awareness of epidemiology trend

1. Schiller JS, Euler GL. CDC, 2010.

Psychopharmacology

Snitz BE, O'Meara ES, Carlson MC, et al. Ginkgo biloba for preventing cognitive decline in older adults: a randomized trial. JAMA 2009;302:2663–2670.

DeKosky ST, Williamson JD, Fitzpatrick AL, et al. Ginkgo biloba for prevention of dementia. JAMA 2008; 300: 2253–2262.

Overview of GEMS

Primary outcome: Determine whether occurrence of dementia (any type) and Alzheimer’s disease specifically is lower for older people with normal memory treated with Ginkgo biloba compared with a placebo

Design:

– Randomized, double-blind, multi-center clinical trial

– 3,069 persons ≥ 75 years old with normal memory or very mild cognitive impairment (MCI = 10%)

Secondary Outcomes

All-cause mortality Combined CHD – nonfatal MI, CHD death,

coronary revascularization, hospitalized angina Combined CVD – combined CHD, stroke, lower

extremity revascularization, treated angina, fatal/ hospitalized/treated CHF, hospitalized or outpatient PAD

General cognitive function (change over time) Physical function

Sites in GEMS

5 clinical sites in the United States, all Academic Medical Centers:– Johns Hopkins (Hagerstown, MD)– University of California, Davis (Sacramento,

CA)– University of Pittsburgh, (Pittsburgh, PA)– Wake Forest University

o Winston-Salem, NCo Greensboro, NC

Randomized Design of GEMS

Persons with Normal Memory Function

or

Mild Cognitive Impairment (MCI)

Consent / Randomize

(3,069)

Ginkgo biloba

or

Placebo

Test every 6 months for:

2. New onset dementia of any type and Alzheimer’s disease specifically, and

3. Other outcomes until death or end of study (up to 6.5 years).

GEMS Results:Baseline Characteristics

Characteristic Placebo Ginkgo pa

N (%)/ Mean (SD) 1524 (50) 1545 (50) Age 79.1 (3.3) 79.1 (3.3) 0.88 Gender Females Males

716 (47) 808 (53)

702 (45) 843 (55)

0.39

Race Caucasian Non-Caucasian

1448 (95) 76 (5)

1482 (96) 63 (4)

0.23

Education High School or Less Some College College Graduate Post-Graduate

534 (35) 395 (26) 229 (15) 366 (24)

570 (37) 380 (25) 250 (16) 344 (22)

0.40

Medical History MI Heart Failure Stroke Hypertension Diabetes Cancer (past 5 yrs)

152 (10) 33 (2) 45 (3) 832 (55) 138 (9) 281 (18)

148 (10) 28 (2) 43 (3) 833 (54) 139 (9) 283 (18)

0.50 0.62 0.37 0.71 0.18 0.61

GEMS Results: Baseline Characteristics

Characteristic Placebo Ginkgo pa N (%)/ Mean (SD) 1524 (50) 1545 (50)

Cognitive Tests 3MSE (mean) CDR 0 0.5 ADAS-Cog

93.3 (4.7) 922 (61) 600 (39) 6.4 (2.7)

93.3 (4.7) 910 (59) 631 (41) 6.5 (2.8)

0.76 0.69

0.17 Difficulty with ADLs (1 or more) 269 (18) 273 (18) 0.99 Gait Speed (sec to walk 15 ft) 5.1 (1.5) 5.1 (1.2) 0.20 Mean Blood Pressure Systolic (mm/Hg) Diastolic (mm/Hg)

133(18.4) 69.0 (9.9)

133(18.1) 68.8 (9.9)

0.36 0.71

BMI Underweight (>18.5) Normal (18.5-25) Overweight (25-30) Obese (30+)

14 (1) 478 (31) 687 (45) 341 (22)

12 (1) 482 (31) 724 (47) 319 (21)

0.62

Smoking Status Never Former Current

622 (42) 805 (53) 65 (4)

602 (40) 846 (56) 71 (5)

0.51

Mild Cognitive Impairment at Baseline

226 (14.8)

256 (16.6)

.18

GEMS Results: Cumulative Dementia Rates by Treatment

GEMS ResultsHazard Ratios for Cox Regression Analyses All Dementia and Subtypes of Dementia comparing Ginkgo to placebo

Outcome All Participants

(N=3069)

# of

Events HR (95% CI)

P

value

All Dementia 523 1.12 (0.94, 1.33) 0.21

Alzheimer’s* without

vascular dementia** 353 1.18 (0.97, 1.46) 0.11

Alzheimer’s with

vascular dementia 124 1.09 (0.77, 1.55) 0.63

Total Alzheimer’s

Dementia 477 1.16 (0.97, 1.39) 0.11

Vascular dementia

without Alzheimer’s 24 0.41 (0.17, 0.98) 0.05

GEMS ResultsAdverse Events

Type of SAE Placebo

N (%)

Ginkgo

N (%)

Hazard Ratio

(95% C.I)

P

value

Deaths 188 (12.3) 197 (12.8) 1.04 (0.85-1.26) 0.72

Bleeding - total

GI

All Other

140 (9.2)

77 (5.1)

71 (4.7)

138 (8.9)

83 (5.4)

64 (4.1)

0.97 (0.77-1.23)

1.06 (0.78-1.45)

0.89 (0.64-1.25)

0.81

0.70

0.52

Myocardial Infarctions 76 (5.0) 90 (5.8) 1.18 (0.87-1.59) 0.30

Strokes

Ischemic

Hemorrhagic

Unknown

62 (4.1)

8 (0.5)

2 (0.1)

62 (4.0)

16 (1.0)

3 (0.2)

0.99 (0.70-1.41)

1.97 (0.84-4.61)

-

0.96

0.12

-

Overall Conclusion

Ginkgo biloba at 120 mg twice a day is not effective in reducing the overall incidence

of dementia or Alzheimer’s disease in older adults. Neither is Ginkgo biloba effective in preventing dementia in persons with

mild cognitive impairment.

GEMS Memory Study

A Case Study of Herbal RemedyPolypharmacy

77 yo wm referred to geriatric assessment clinic in CA spring 2009

Progressive problems with word finding, disorientation, agitation, and irritability

Sister with dementia History of smoking (quit 30 yrs ago), ethanol

abuse, illicit drug use Problem list (PCP); Alzheimer’s dementia

(MMSE 15/30, could not draw clock), CAD with history of MI, bradycardia, hypertension, dyslipidemia, gait and balance problems, hx falls, incontinence, depression

Prescription Medications

Pravastatin Lisinopril Aspirin Niacin Triamterene/hydrochlorothiazide Sertraline Donepezil Memantine

Dietary and Herbal Supplements

B-100 complex Coenzyme Q-10 Omega-3 fatty acids Core complex (quercetin) CardioHealth B-12 Folic Acid Vitamin C Vitamin E Beta carotene Valerian root complex

Vitamin D3 Calcium complex Triple berry complex Schizandra plus Mega garlic plus Garden 7 phytonutrients Rose OX Joint support Generic multivitamin Cell activator NiteWorks (amino acids)

Strategies to Address this Issue

Include discussion of supplements/herbal remedies with each medication reconciliation– Natural Medicines Comprehensive Database

(available from Prescriber’s Letter, www.naturaldatabase.com)

– On-line version also available

Research is limited on these products May be a waste of limited resources

http://www.naturaldatabase.com/

Preferred Medications in the Elderly

Historically, medication use in the elderly has evolved around avoiding “potentially inappropriate medications” (e.g., Beers criteria)

Medicare Part D and PDPs have developed formularies based primarily on cost/rebates

Need for “geriatrics-focused expert review”

“Positive” Beers Criteria

First article published August 2009– Consult Pharm 2009;24:601-10.– http://

www.ascp.com/resources/clinical/upload/BeersCriteria.pdf

Focus on CNS medications Consensus panel of geriatricians, other

providers Literature review using AHRQ criteria for

comparative effectiveness Delphi consensus process on final selection

http://www.ascp.com/resources/clinical/upload/BeersCriteria.pdf

http://www.ascp.com/resources/clinical/upload/BeersCriteria.pdf

Definition: IOM

Comparative effectiveness research (CER) is the Comparative effectiveness research (CER) is the generation and synthesis of evidence that generation and synthesis of evidence that compares the benefits and harms of alternative compares the benefits and harms of alternative methods to prevent, diagnose, treat and monitor a methods to prevent, diagnose, treat and monitor a clinical condition or to improve the delivery of clinical condition or to improve the delivery of care. The purpose of CER is to assist consumers, care. The purpose of CER is to assist consumers, clinicians, purchasers and policy makers to make clinicians, purchasers and policy makers to make informed decisions that will improve health care at informed decisions that will improve health care at both the individual and population levels.both the individual and population levels.

National Priorities for Comparative Effectiveness ResearchNational Priorities for Comparative Effectiveness ResearchInstitute of Medicine Report BriefInstitute of Medicine Report Brief

June 2009June 2009

AHRQ’s Role in AHRQ’s Role in Comparative EffectivenessComparative Effectiveness

Using Information to Drive Improvement: Using Information to Drive Improvement: Scientific Infrastructure to Support ReformScientific Infrastructure to Support Reform

Lead federal fundingLead federal funding

Engage private sectorEngage private sectorAggregate best Aggregate best evidence to inform evidence to inform complex learning complex learning and implementation and implementation challengeschallenges

Increase knowledge base Increase knowledge base to spur high-value careto spur high-value care

21st Century Health Care

Comparative Effectiveness Comparative Effectiveness and the Recovery Act and the Recovery Act

The American Recovery and The American Recovery and Reinvestment Act of 2009 includes Reinvestment Act of 2009 includes $1.1 billion for comparative $1.1 billion for comparative effectiveness research:effectiveness research:

– AHRQ: $300 millionAHRQ: $300 million

– NIH: $400 million (appropriated to NIH: $400 million (appropriated to AHRQ and transferred to NIH)AHRQ and transferred to NIH)

– Office of the Secretary: $400 million Office of the Secretary: $400 million (allocated at the Secretary’s discretion)(allocated at the Secretary’s discretion)

Federal Coordinating Council appointed to coordinate comparative Federal Coordinating Council appointed to coordinate comparative effectiveness research across the federal governmenteffectiveness research across the federal government

Preferred CNS Medicationsfor the Elderly

Entacapone (add-on only)RopiniroleCarbidopa/Levodopa

Parkinson’s Disease

CitalopramDuloxetineEscitalopramBupropionMirtazapine

Depression

DonepezilGalantamine (ER only)Memantine (add-on only)

Dementia

MedicationTherapeutic Area

Take Away …

Comparative effectiveness is coming Research funded by American Recovery and

Reinvestment Act of 2009 will begin soon This is an example of how criteria might be

applied and the results NICE (National Institute for Clinical Evidence),

the European Union equivalent to proposed comparative effectiveness, provides an example of what we might expect in the future

http://www.nice.org.uk/

Chronic Kidney Disease

800

1000

1200

1400

1600

1800

2000

2200

Cre

atin

ine

Exc

reti

on

, m

g/d

ay

0.0

0.2

0.4

0.6

0.8

1.0

1.2

Ser

um

C

reat

inin

e C

on

c.,

mg

%

Average Age, years20 40 60 80

Creatinine Excretion and Serum Creatinine by Age

10 73 122 152 94 68 29

Equations for Estimating GFR

Abbreviated MDRD Study EquationAbbreviated MDRD Study Equation

GFR (mL/min/1.73 m2) = 186.3 × SCr -1.154 × Age-0.203

× 0.742 (if female) × 1.210 (if African American)

MDRD = Modification of Diet in Renal Disease; CrCl = creatinine clearance; SCr=serum creatinine in mg/dL

Cockcroft-Gault EquationCockcroft-Gault Equation

CrCl = (mL/min)

(140 – Age) × Weight in kg

72 × SCr× 0.85 if female

Levey AS, et al. Ann Intern Med. 2003;139:137-47.Levey AS, et al. Ann Intern Med. 2003;139:137-47.

0

20

40

60

80

65-69 70-74 75-79 80-84 85-89 90-94 95+

<30 (Men) <30 (Women) 30-59 (Men) 30-59 (Women)

Age (years)

Per

cen

t o

f P

atie

nts

Garg AX, et al. Kid Int 2004;65:649-53.Garg AX, et al. Kid Int 2004;65:649-53.

Prevalence of Low GFR in Nursing Home Elderly – Cockcroft-Gault

0

20

40

60

65-69 70-74 75-79 80-84 85-89 90-94 95+

<30 (Men) <30 (Women) 30-59 (Men) 30-59 (Women)

Age (years)

Per

cen

t o

f P

atie

nts

Garg AX, et al. Kid Inter 2004;65:649-53.Garg AX, et al. Kid Inter 2004;65:649-53.

Prevalence of Low GFR in Nursing Home Elderly – MDRD

Cockcroft-Gault (CG) or MDRD?

Recent Study in JAGS 2009;57:1638-43 Measured CrCl based on 24-hour urine

collection Comparison to measured value:

– CG slightly underestimates CrCl– MDRD strongly overestimates CrCl

KDOQI guidelines recommend MDRD for diagnosing and staging of CKD

CG should be used for dosing medications

KDOQI = Kidney Disease Outcomes Quality InitiativeKDOQI = Kidney Disease Outcomes Quality Initiative

Drugs That Need Special Attention in CKD

Warfarin– Warfarin metabolism not significantly altered– Hemorrhage more likely - probably due to platelet

dysfunction/drug-interactions

Low-molecular-weight heparins– Cleared primarily by the kidneys– Risk of hemorrhage more likely with CKD– Dose reduction required for most (usual cut-off 30 ml/min)

Direct thrombin inhibitors– Reduce dose for most – Hirudin, lepirudin– Fondaparinux – avoid when CrCl less than 30 ml/min

Gabardi S, Abramson S. Med Clin N Am 2005;89:649-87.Gabardi S, Abramson S. Med Clin N Am 2005;89:649-87.

Drugs That Need Special Attention in CKD (2)

ACE inhibitors– As a class, generally cleared by the kidney (exception

is fosinopril – hepatobiliary excretion)– Reduce dose, however use not contraindicated – ACEs beneficial in many with CKD (diabetes, CHF)– NSAIDs should be avoided with ACEs in CKD

ARBs– Metabolized by liver – no adjustment needed– Similar risk for ARF to ACE – monitor appropriately– Combination of ACE + ARB seems to be safe in CKD



Antihypertensive agents– Alpha-blockers – increased risk of orthostasis/hypotension– Beta-blockers – increased risk of bradycardia: reduce dose of

acebutolol, atenolol, nadolol, and sotalol

Diuretics– Spironolactone + ACE in HF (↑ K+); careful in advanced CKD

(SCr ≥2.5; GFR <15 mL/min)– Thiazides have little effect if used alone in CKD – trouble

reaching the nephron– Loops have similar problems, but dose increases or the addition

of a thiazide may overcome resistance– Ototoxicity is more common in CKD due to impaired clearance

and higher doses of loops used



NSAIDs; problems in CKD include hyperkalemia, hyponatremia, fluid retention, acute renal failure

Narcotics– Meperidine metabolism altered in CKD, resulting in

accumulation of normeperidine (metabolite); may cause seizures

– Morphine metabolites (morphine-3 and morphine-6-glucuronide) can accumulate in CKD causing prolonged sedation and respiratory depression

– Oxycodone concentrations about 50% higher in CKD



Oral Hypoglycemics– Acetohexamide, chlorpropamide, glyburide, and tolazamide; all

have active metabolites that may accumulate causing prolonged hypoglycemia

– Metformin: increased risk of lactic acidosis in CKD

Antimicrobials– Aminoglycosides/vancomycin: use with caution and if using,

monitor serum concentrations closely– Cephalosporins/penicillins; most are renally eliminated: in most

cases, dose is reduced in lieu of interval; Efficacy in UTI may be reduced

– Fluoroquinolones; most are renally eliminated. Better in UTI than cephs/pens in CKD


Transitions of Care

Transition of Care vs Transitional CareTransition of Care vs Transitional Care

The movement of patients from one practitioner or setting to another

Multiple levels– Within Settings

o Primary care Specialty care

– Between Settingso Hospital Home

– Across health stateso Curative care Palliative

care/Hospice

A set of actions ensuring the coordination and continuity of care as patients transfer between locations or levels of care

Includes:– Logistical arrangements– Education of the patient

and family– Coordination among the

health professionals involved in the transition

Coleman E, et al. J Am Geriatr Soc 2003;51:556-7.

Ineffective Transitions Ineffective Transitions Lead to Poor OutcomesLead to Poor Outcomes

Wrong treatment Delay in diagnosis Severe adverse events Patient complaints Increased healthcare costs Increased length of stay

Australian Council for Safety and Quality in Health Care. Clinical hand-over and Patient Safety literature Review Report. March 2005. Available www.safetyandquality.org/internet/safety/publishing.nsf/Content/ AA1369AD4AC5FC2ACA2571BF0081CD95/$File/clinhovrlitrev.pdf

Care Transitions 30 DaysCare Transitions 30 DaysFollowing Acute CareFollowing Acute Care

Hospital

Home64%

77%13%

11%

Nursing Facility

Hospital or TCU

16% 10%

74%

TCU = Transitional Care UnitColeman EA et al. Health Svcs Research 2004;37:1423-40

Predictors of Complicated Predictors of Complicated Care TransitionsCare Transitions

Heart disease Diabetes # of prior hospitalizations Visual impairment Medicaid recipient Prior stroke

Coleman EA et al. Health Svcs Research 2004;37:1423-40.

Incr

easi

ng

Ris

k

Medication Discrepancies: Hospital to SNFs Transitions

Tija et al. J Gen Intern Medicine 2009. Cross-sectional study of patients admitted to

SNF for subacute care (N=199, 2319 meds) Results:

– 21.3% of medication orders had a discrepancy– At least one discrepancy in 71.4% of patients– CV agents, opioid analgesics, neuropsychiatric

agents, hypoglycemics, antibiotics, and anticoagulants accounted for > 50% of all discrepancies

SNF=Skilled nursing facility

Models of CareModels of Care

Guided Care– http://www.guidedcare.org/

The Transitional Care Model (TCM)– http://www.transitionalcare.info/

The Care Transitions Intervention (CTI)– http://www.caretransitions.org/

Project RED– http://www.bu.edu/fammed/projectred/

Project REDProject RED

http://www.bu.edu/fammed/projectred/index.html

http://relationalagents.com/red_demo_4545.wmv



CTM-3

The hospital staff took my preferences and those of my family or caregiver into account in deciding what my health care needs would be when I left the hospital.

When I left the hospital, I had a good understanding of the things I was responsible for in managing my health.

When I left the hospital, I clearly understood the purpose for taking each of my medications.

http://www.caretransitions.org/documents/CTM3Specs0807.pdf

Snow V et al. J Gen Intern Med 2009;24:971-6.

““Ideal Transition Record”Ideal Transition Record”(ACP, SGIM, SHM, AGS, ACEP, (ACP, SGIM, SHM, AGS, ACEP,

and SAEM)and SAEM)1. Primary, secondary diagnoses and problems list2. Medication list (reconciliation) including OTC/other 3. Treatment and diagnostic plan 4. Clearly identifiable medical home/coordinating and

transferring MD/institution and contact information5. Prognosis and outcome goals 6. Test results (available and pending)7. Patient cognitive status8. Advance directives, power of attorney, consent9. Planned interventions, med equipment, wound care10. Emergency plan, contact information 11. Assessment of caregiver status

Medication List ToolkitMedication List Toolkit

www.patientsafety.org/page/109587/

H.R. 3590 and H.R. 4872

Community-based Care Transitions Program Demonstration project to evaluate integrated

care around hospitalization Independence at home demonstration program State option to provide health homes to

Medicaid enrollees with chronic conditions Community Health Teams to support the

Patient-Centered Medical Home CMS Innovation Center to test models of care

Working to Address the Issueswww.ntocc.org

Recent Practice Guidelines

American Geriatrics Society - Pharmacological Management of Persistent Pain in Older Persons

Infectious Disease Society of America/ Society for Healthcare Epidemiology of America – Clostridium difficile infection in adults: 2010 update

American Medical Directors Association – Transitions of Care in the Long-Term Care Continuum

Questions?

Davidson Grandrounds2010 Final

Health & Medicine

Transcript of Davidson Grandrounds2010 Final