P R O G R E S S I N C A R D I O V A S C U L A R D I S E A S E S 5 7 ( 2 0 1 4 ) 1 9 7 – 2 0 3

Ava i l ab l e on l i ne a t www.sc i enced i rec t . com

ScienceDirect

www.on l i nepcd .com

Risk Stratification in Very Old Adults: How to Best

Gauge Risk as the Basis of Management Choices forPatients Aged Over 80

Susan P. Bell⁎, 1, Avantika SarafDivision of Cardiovascular Medicine and the Center for Quality Aging, Department of Medicine, Vanderbilt University School of Medicine,Nashville, TN, USA

A R T I C L E I N F O

⁎ Address reprint requests to Susan P. Bell,West End Avenue South, Nashville, TN 3720

E-mail address: Susan.p.bell@vanderbilt.e1 Supported in part by K12HD043483-11, M

Heart Service Fund.

http://dx.doi.org/10.1016/j.pcad.2014.08.0010033-0620/© 2014 Elsevier Inc. All rights rese

A B S T R A C T

Keywords:

Cardiovascular disease (CVD) is the leading cause of mortality in older adults, however, inthe elderly accurate stratification of CVD risk to guide management decisions is challengingdue to the heterogeneity of the population. Conventional assessment of CVD andtherapeutic risk is based on extrapolation of guidelines developed from evidencedemonstrated in younger individuals and fails to weight the increased burden ofcomplications and multimorbidity. Using a comprehensive geriatric based assessment ofolder adults with CVD that includes an estimation of complexity of multimorbidity as wellas traditional risk assessment provides a patient centered approach that allows formanagement decisions congruent with patient preferences. This review examines thecomplexity of risk stratification in adults over 80, assessment methods to augment currenttools and the basis of management decisions to optimize patient and family centered goals.

© 2014 Elsevier Inc. All rights reserved.

MultimorbidityPolypharmacyCardiovascular diseaseRisk stratificationElderly

Currently, 13% of the United States population is over the ageof 65 years. However, as survival rates increase, adults aged 65and older will increase to comprise 19% of the population by2030, with nearly 19 million adults aged over 85.1 Cardiovas-cular (CV) disease (CVD) affects approximately 40 millionindividuals over the age of 65 and is the leading cause ofmorbidity and mortality in that population.2 For individualsover the age of 80 the prevalence rises to encompass 83% ofmen and 87% of women.2 Heterogeneity among very oldadults is vast and current risk stratification methods topredict an individual's health trajectory are challengingwhen compared to younger individuals. The majority ofcardiovascular practitioners stratify risk based on standard-ized scores that have been developed and validated in middle

MBBS, MSCI, Division of C3-8300.du (S.P. Bell).entored Clinical Scientist

rved.

aged adults; however, in the very elderly their value indiscrimination of who will benefit rather than be harmed bya specific management strategy or intervention is unreliable.Further, standardized guidelines that are frequently used andpromoted for common CV conditions do not accommodatefor the very old adult with significant multimorbidity,polypharmacy, and goals of care not focused on mortality.3,4

For the patient over 80 that has already reached theiranticipated life expectancy the relevance and utility ofpredicting 10 year mortality are shadowed by the importanceof quality of life and maintaining independence. This articlewill focus on the challenges of stratifying risk in very old adults,assessment methods to augment current practices, and man-agement decision processes for optimumpatient centered care.

ardiovascular Medicine, Center for Quality Aging, Suite 350, 2525

Development Award from NICHD and the Eisenstein Women's

Abbreviations and Acronyms

BP = blood pressure

CV = cardiovascular

CVD = cardiovascular disease

DM = diabetes mellitus

DYS = dyslipidemia

HTN = hypertension

MI = myocardial infarction

198 P R O G R E S S I N C A R D I O V A S C U L A R D I S E A S E S 5 7 ( 2 0 1 4 ) 1 9 7 – 2 0 3

Traditional riskstratification

Conventional assess-ment of CV and thera-peutic risk is frequentlybased on validated in-struments that are op-timal for differentiationin patients in their 50'sand 60'swithout signif-icant comorbidities.5–7

Although some do encompass well defined factors such ashypertension (HTN), diabetes mellitus (DM), increasing age (upto 79), cholesterol, and smoking, they lack the ability todistinguish attributed risk from the complexity of multiplecontributing disease processes. Furthermore, they do not allowfor the addition of sensitive predictors of outcomes in veryelderly patients such as pulse pressure, cognitive impairment,disability, functional status and frailty.

Current clinical practice guidelines

Despite the high prevalence of CVD in older adults, theircorresponding underrepresentation in randomized controlledtrials of disease modifying therapies is significant.8,9 Theresulting effect is that clinicians are required to extrapolatestandard practice guidelines based on trial data derived fromyounger adults.10 Patients over 80 are essentially absent frommost pivotal randomized clinical trials which can result ineither the omission of evidence based beneficial therapies orthe underestimation of risk of procedures without survivalbenefit for that patient cohort.11,12 Recent updates to AmericanCollege of Cardiology/American Heart Association (AHA/ACC)guidelines have expanded the content related to elderlypatients and highlighted the difficulty in evaluating andmanaging adults >75 due to specificity of symptoms andlimitations of diagnostics.10,13,14 The guidelines also recognizethepresence of discordant outcomeswhenstratified by age andthe higher risk of complications experienced by olderadults.10,13,14 Population based recommendations howeverremain non-specific for the very elderly suggesting thatdecisions should be undertaken after incorporating age-related issues, careful consideration of patient and familypreferences, functional capacity, quality-of-life and end-of-lifeissues, as well as alternative management strategies.4

Role of traditional risk factors in very elderly

Hypertension

Hypertension in the elderly individual is frequently combinedwith other significant physiological hemodynamic changessuch as low renal blood flow, lower intra vascular volume,reduced cardiac output (particularly during activity), in-creased pulse pressure and marked vascular stiffness and

resistance.15 The result is that many will require a combina-tion of medications to control their blood pressure (BP)and hence be exposed to significant adverse effects.The overwhelming evidence documents that treating signif-icant HTN at any age, including the very elderly, reduces CVand cerebrovascular events.16,17 Previous guidelines basedon expert opinion recommended a goal BP of less than 140/90 mmHg for older adults with an acceptable systolic BP of140–145 mmHg in individuals over 80 years of age if tolerated,and particular caution to the aggressive reduction of BP (tobelow 130/70 mmHg) in octogenarians with comorbidites dueto the increase in adverse events.18 Recent updates have nowsuggested an even higher goal of less than 150/90 mmHg;however, the changes remain controversial.19 Practitionersshould plan on starting each therapy at a low dose and slowlybut consistently increasing medication with frequent contactto monitor for adverse drug events.

Dyslipidemia (DYS)

Numerous trials have documented the beneficial effects ofstatin therapy on CVD and mortality.20–22 The age range,however, for the majority has not included adults over80 years and hence the benefits have not been extrapolatedto managing octogenarians. The single randomized con-trolled trial that recruited older adults specifically showed abenefit in statin therapy for secondary prevention but not forprimary prevention of DYS.23 The gap in managementstrategy lies in the continued treatment of DYS in theoctogenarian and nonagenarian that has been taking andtolerating medications for several years and/or has a signif-icantly low future life expectancy. Recent developments ofPooled Cohort Risk Equations may allow for more accuratemortality risk estimations.24 Currently, guidelines suggestcaution in using high intensity statin therapy in individualsover 75 years of age and that therapy decisions should bebalanced between benefits, life expectancy, comorbidities andtreatment priorities.25

Smoking

The prevalence of smoking decreases with age but remains asignificant risk factor contributing to 30% of attributable riskin strokes and 36% in first myocardial infarction (MI). Smokingalso aggravates angina symptoms and can precipitate silentMI seen in older adults. Although the relative risk for MI ordeath attributed to smoking in an individual over 70 is twicethat of an individual 55–60,26 older adults are 20% less likely tobe advised to quit smoking by health care providers. Veryelderly individuals may be resistant to changing long-termlifestyle habits and providers may minimize anticipated bene-fits, however the impact of smoking and the positive effects ofcessation continue to be demonstrated irrelevant of age.

Diabetes

Epidemiological evidence has demonstrated the associationbetween uncontrolled DM and an increased of CVD.27 For theolder adult, the burden of DM is linked to significant

199P R O G R E S S I N C A R D I O V A S C U L A R D I S E A S E S 5 7 ( 2 0 1 4 ) 1 9 7 – 2 0 3

morbidity, reduced functional status, and mortality second-ary to CVD events.28 Despite this, the goal of tight glycemiccontrol in reducing CVD in adults over 80 has not beenestablished due to the dearth of evidence from previousrandomized control trials and the occurrence of significantlyhigher occurrences of hypoglycemia andmortality.29 Currently,opinion suggests that for older adults who are functional,cognitively intact and have a significant future life expectancy,risk and management of DM should be consistent with goalsdeveloped for younger adults.28 Management and goals forolder adults with comorbid conditions or life expectancy<10 years should balance glycemic control with risk ofadverse events and for those with life expectancy <5 yearsglucose lowering management should be established on anindividual basis.28

Multimorbidity

The conceptual approach to disease-centered care with con-sideration of comorbid conditions has not been amain focus ofprior management strategies. Evidence based clinical practiceguidelines continue to focus on single disease entities andtherefore create barriers to their application in adults withnumerous interacting comorbid disease processes.30 As a morepatient-centered approach has evolved the concept ofmultimorbidity allows not only the consideration of how eachcomorbid condition interacts with the primary disease but thechanging and varying interaction of all conditions.31 Theprevalence of multimorbidity (the coexistence of 2 or morechronic conditions) rapidly increases with age such that itoccurs in over 70% of 75 or older.32 In Medicare beneficiarieswith heart failure the burden of multimorbidity is significantwith over 50%having 5 ormore coexisting chronic conditions.32

The health care burden of multimorbidity is marked withindividuals costing 3 times the national average per capitaspending of Medicare beneficiaries and the highest 30 dayreadmission rates. Evaluation ofmultimorbidity should includenot only the contributing effects of chronic and acute diagnosesbut also the prevalence of common and frequently under-recognized geriatric syndromessuchasdementia, falls, delirium,incontinence, weight loss, depressive symptoms and functionalstatus decline.

Polypharmacy

Older adults with multimorbidity are frequently seen bymany general and specialist providers and as a result receivemultiple therapies. Often the standard of care for individualchronic illnesses leads to polypharmacy and potential drug–drug interactions for individuals with multiple chronicillnesses.30 Polypharmacy, defined as taking ≥4 chronicmedications, is associated with non-adherence33 as well asinappropriate prescribing, drug interactions, adverse drugevents, hospitalization, and mortality. Adverse consequencesincluding poor adherence are not only related to the numberof medications but also to the regimen complexity.34 Studieshave estimated that 50% of older adults are taking at least one

medication with no ongoing indication, and many of thesedrugs are initiated during hospitalization, such as stress ulcerprophylaxis and antipsychotics for delirium.35 Paradoxically, afurther consequence of polypharmacy is therapeutic omissionsby patient or provider of potentially beneficial medications.36

Ensuring patients are on as few medicines as necessary tomanage their diseases and provide evidence based mortalitybenefit should be the optimal goal. This also leads to improve-ment in adherence and patient safety, and reduce medicationcosts for the patient.

Frailty

Frailty is an emerging and important geriatric syndromeaffecting approximately 20% of community dwelling adultsover 80.37 It encompasses a biological decline across multipleinterrelated organ systems and a subsequent loss of reserve inresponse to stressors, suchas acute illness.38,39 In older patientshospitalizedwithCVD it is estimated that the prevalence is over50%.40 Frailty is an independent predictor of subclinical CVD,41

coronary artery disease,42 and congestive heart failuremortality.43 It confers an increased risk of hospitalization, andinstitutionalization, and ≥2 fold mortality.37,44,45 Currently,there is no widespread standard for assessment of frailty inthe CV setting despite the recognition as a significant factor inthe evaluation of an older adult with CVD. There are numerousmultidimensional assessment tools that have been developedto measure physical frailty46 and range from a composite scoreof clinical deficits to physical performance based criteria.37,47,48

As a prognostic tool, assessment of frailty in combination withother risk factors is an invaluable addition to assist providers indefining the optimummanagement strategy.

Cognitive impairment

The presence of dementia significantly increases the financialcost, management complexity and mortality rates for an olderadult.49,50 Hypertension and frailty are now recognized inassociation with and may well be significant risk factors forthe development of mild cognitive impairment, a prodromalphase of Alzheimer's type dementia.51,52 For an individual whohas both HTN and mild cognitive impairment, institutionaliza-tion andmortality rates are similar to those with dementia andsignificantly higher than those with HTN alone.53 In olderadults who are classified as frail the prevalence of cognitiveimpairment is 5 times greater than those who are not frail andthe coalescing of these factors causes a more rapid decline incognition and disability.54 High rates of unidentified cognitiveimpairment in older adults suggest that periodic screening isnecessary to accurately establish future risk and determinebenefits of simplification of treatment strategies.

Evaluation methods

A comprehensive evaluation incorporating all contributingrisks is essential to provide the most accurate assessment of

Fig 1 – Overview of proposed comprehensive assessment for risk stratification in adult over 80.

Table 1 – Summary of assessment tools for screening forcommon geriatric conditions.

Assessment Tool

Frailty Fried Frailty Scale: Grip strength, gaitspeed, exhaustion, weight loss andactivity questionnaire37

Short Physical Performance Battery56

Functional status Katz Activities of Daily Living57

Lawton Instrument of Activities ofDaily Living58

Timed up and Go59

Functional Reach60

Cognition Montreal Cognitive Assessment(www.mocatest.org)Mini-COG61

Weight loss/sarcopenia Grip strengthBody mass index change loss >5%

Depression Geriatric Depression Scale62

Patient Health Questionnaire63

200 P R O G R E S S I N C A R D I O V A S C U L A R D I S E A S E S 5 7 ( 2 0 1 4 ) 1 9 7 – 2 0 3

absolute risk and benefit of treatment strategies. Inquiringabout primary concerns and symptoms provides an initialframework to direct interpretation of further findings. Althoughdisease focused evaluation of symptoms may allow forassessment of the primary CVD, they may well not becongruent with the most significant or problematic symptomsof the patient. Allowing the older adult to prioritize concernsand functional limitations can allow for amorepatient centeredassessment of risk and hence care plan. Fig 1 highlightsessential elements of the process of evaluation. After establish-ing primary concerns, a comprehensive assessment shouldallow for interpretation of the severity and acuity of the primaryCV problem as well as other CV disease processes, complica-tions and the presence of traditional CVD risk factors amenableto intervention. Assessment of multimorbidity should includecontributions of chronic and acute disease processes as well asan evaluation for co-existing geriatric syndromes and functionalstatus. Table 1 provides an overviewof commonlyused valuabletools for assessment of the geriatric population.

201P R O G R E S S I N C A R D I O V A S C U L A R D I S E A S E S 5 7 ( 2 0 1 4 ) 1 9 7 – 2 0 3

Prognostication andmanagement decisionmaking

Contributing factors to management choices involves bothprognosis and patient preferences and goals. Prognosis maynot only includemortality but also disability and dependence.Although median future life expectancy for a person aged80 is approximately 7 years the range can vary significantlydepending on functional status, and the presence of significantcomorbid disease.55 For example, the presence of Alzheimer'sdisease is associated with a 2–4 times risk of mortality at anyage.49 By evaluating the contributing risk of all factors theprovider can gaugewhether an individual has a higher, averageor lower risk of the potential outcome. Patient preferencesand priority of goals should also be balanced with prognosticevaluation. All interactions within and among current condi-tions, therapies and future therapies should be consideredbefore communicating a detailed plan to the patient andsignificant family involved in the care. This should include thediscussion of all benefits and harms to the patient withoutinfluence of theprovider's personal priorities andvalues. Finally,for the very elderly the importance of frequent reassessmentof symptom priority, benefit and risk, adherence and alignmentwith patient centered goals is essential.

Conclusions

The challenges of stratifying risk in the very elderly and hencebalancing patient centered management strategies are im-mense due to the vast heterogeneity seen in this population.Although CV clinicians are adept at calculating diseasecentered risk in younger populations, their sensitivity of riskstratification and judgment for detecting overall risk burdenfrom multimorbidity is imperfect. A comprehensive geriatricbased evaluation incorporating all contributing factors isessential to provide themost accurate assessment of absoluterisk and benefit of treatment strategies to guide managementdecisions in older adults. Assessment of geriatric syndromes,complexity of multimorbidity and polypharmacy along withpatient preferences and goals into management plans canlead to optimum patient centered care.

R E F E R E N C E S

1. http://www.aoa.gov/AOARoot/AgingProjected Future Growthof the Older Population. 2008. [Accessed January 15th, 2014].

2. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and strokestatistics–2013 update: a report from the American HeartAssociation. Circulation. 2013;127(1):e6-e245.

3. Forman DE, Rich MW, Alexander KP, et al. Cardiac care forolder adults. Time for a new paradigm. J Am Coll Cardiol.2011;57(18):1801-1810.

4. Forman D, Wenger NK. What do the recent American HeartAssociation/American College of Cardiology FoundationClinical Practice Guidelines tell us about the evolvingmanagement of coronary heart disease in older adults?J Geriatr Cardiol. 2013;10(2):123-128.

5. Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score forunstable angina/non-ST elevation MI: a method forprognostication and therapeutic decision making.JAMA. 2000;284(7):835-842.

6. Kannel WB, D'Agostino RB, Silbershatz H, Belanger AJ, WilsonPW, Levy D. Profile for estimating risk of heart failure.Arch Intern Med. 1999;159(11):1197-1204.

7. Wilson PW, D'Agostino RB, Levy D, Belanger AM, SilbershatzH, Kannel WB. Prediction of coronary heart disease using riskfactor categories. Circulation. 1998;97(18):1837-1847.

8. Lee PY, Alexander KP, Hammill BG, Pasquali SK, Peterson ED.Representation of elderly persons and women in publishedrandomized trials of acute coronary syndromes.JAMA. 2001;286(6):708-713.

9. Heiat A, Gross CP, Krumholz HM. Representation of theelderly, women, and minorities in heart failure clinical trials.Arch Intern Med. 2002;162(15):1682-1688.

10. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis andmanagement of patients with stable ischemic heart disease:a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines,and the American College of Physicians, AmericanAssociation for Thoracic Surgery, Preventive CardiovascularNurses Association, Society for Cardiovascular Angiographyand Interventions, and Society of Thoracic Surgeons.Circulation. 2012;126(25):e354-e471.

11. Hochman JS, Sleeper LA,Webb JG, et al. Early revascularizationin acute myocardial infarction complicated by cardiogenicshock. SHOCK Investigators. Should We EmergentlyRevascularize Occluded Coronaries for Cardiogenic Shock.N Engl J Med. 1999;341(9):625-634.

12. Krumholz HM, Murillo JE, Chen J, et al. Thrombolytic therapyfor eligible elderly patients with acute myocardial infarction.JAMA. 1997;277(21):1683-1688.

13. O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHAguideline for the management of ST-elevation myocardialinfarction: a report of the American College of CardiologyFoundation/American Heart Association Task Force onPractice Guidelines. Circulation. 2013;127(4):e362-e425.

14. Hunt SA, Abraham WT, Chin MH, et al. 2009 focused updateincorporated into the ACC/AHA 2005 Guidelines for theDiagnosis and Management of Heart Failure in Adults: areport of the American College of Cardiology Foundation/American Heart Association Task Force on PracticeGuidelines: developed in collaboration with the InternationalSociety for Heart and Lung Transplantation. Circulation.2009;119(14):e391-e479.

15. Messerli FH, Sundgaard-Riise K, Ventura HO, Dunn FG, GladeLB, Frohlich ED. Essential hypertension in the elderly:haemodynamics, intravascular volume, plasma reninactivity, and circulating catecholamine levels. Lancet. 1983;2(8357):983-986.

16. Staessen JA, Gasowski J, Wang JG, et al. Risks of untreated andtreated isolated systolic hypertension in the elderly: meta-analysis of outcome trials. Lancet. 2000;355(9207):865-872.

17. Beckett NS, Peters R, Fletcher AE, et al. Treatment ofhypertension in patients 80 years of age or older. N Engl J Med.2008;358(18):1887-1898.

18. Aronow WS, Fleg JL, Pepine CJ, et al. ACCF/AHA 2011 expertconsensus document on hypertension in the elderly: a reportof the American College of Cardiology Foundation Task Forceon Clinical Expert Consensus Documents developed incollaboration with the American Academy of Neurology,American Geriatrics Society, American Society for PreventiveCardiology, American Society of Hypertension, AmericanSociety of Nephrology, Association of Black Cardiologists, and

202 P R O G R E S S I N C A R D I O V A S C U L A R D I S E A S E S 5 7 ( 2 0 1 4 ) 1 9 7 – 2 0 3

European Society of Hypertension. J Am Soc Hypertens. 2011;5(4):259-352.

19. James PA, Oparil S, Carter BL, et al. 2014 evidence-basedguideline for the management of high blood pressure inadults: report from the panel members appointed to theEighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-520.

20. Heart Protection Study Collaborative G. MRC/BHF HeartProtection Study of cholesterol lowering with simvastatin in20,536 high-risk individuals: a randomised placebo-controlledtrial. Lancet. 2002;360(9326):7-22.

21. Miettinen TA, Pyorala K, Olsson AG, et al. Cholesterol-lowering therapy in women and elderly patients withmyocardial infarction or angina pectoris: findings from theScandinavian Simvastatin Survival Study (4S). Circulation.1997;96(12):4211-4218.

22. Sacks FM, Pfeffer MA, Moye LA, et al. The effect ofpravastatin on coronary events after myocardial infarctionin patients with average cholesterol levels. Cholesterol andRecurrent Events Trial investigators. N Engl J Med. 1996;335(14):1001-1009.

23. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderlyindividuals at risk of vascular disease (PROSPER): arandomised controlled trial. Lancet. 2002;360(9346):1623-1630.

24. Goff Jr DC, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHAGuideline on the Assessment of Cardiovascular Risk: a reportof the American College of Cardiology/American HeartAssociation Task Force on Practice Guidelines. Circulation.2013;12:2935-2959.

25. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHAGuideline on the Treatment of Blood Cholesterol to ReduceAtherosclerotic Cardiovascular Risk in Adults: a report ofthe American College of Cardiology/American HeartAssociation Task Force on Practice Guidelines. Circulation.2013;129(25 Suppl 2):S1-S45.

26. Hermanson B, Omenn GS, Kronmal RA, Gersh BJ. Beneficialsix-year outcome of smoking cessation in older men andwomen with coronary artery disease. Results from the CASSregistry. N Engl J Med. 1988;319(21):1365-1369.

27. Selvin E, Marinopoulos S, Berkenblit G, et al. Meta-analysis:glycosylated hemoglobin and cardiovascular disease indiabetes mellitus. Ann Intern Med. 2004;141(6):421-431.

28. SueKirkmanM, BriscoeVJ, ClarkN, et al. Diabetes in older adults:a consensus report. J Am Geriatr Soc. 2012;60(12):2342-2356.

29. Group AS, Gerstein HC, Miller ME, et al. Long-term effects ofintensive glucose lowering on cardiovascular outcomes.N Engl J Med. 2011;364(9):818-828.

30. Boyd CM, Darer J, Boult C, Fried LP, Boult L, Wu AW. Clinicalpractice guidelines and quality of care for older patients withmultiple comorbid diseases: implications for pay forperformance. JAMA. 2005;294(6):716-724.

31. Guiding principles for the care of older adults withmultimorbidity: an approach for c. Guiding principles for thecare of older adults with multimorbidity: an approach forclinicians: American Geriatrics Society Expert Panel on theCare of Older Adults with Multimorbidity. J Am Geriatr Soc.2012;60(10):E1-E25.

32. Suaya JA, Stason WB, Ades PA, Normand SL, Shepard DS.Cardiac rehabilitation and survival in older coronary patients.J Am Coll Cardiol. 2009;54(1):25-33.

33. Wilson IB, Schoen C, Neuman P, et al. Physician-patientcommunication about prescription medicationnonadherence: a 50-state study of America's seniors. J GenIntern Med. 2007;22(1):6-12.

34. Claxton AJ, Cramer J, Pierce C. A systematic review of theassociations between dose regimens and medicationcompliance. Clin Ther. 2001;23(8):1296-1310.

35. Morandi A, Vasilevskis E, Pandharipande PP, et al.Inappropriate medication prescriptions in elderly adultssurviving an intensive care unit hospitalization. J Am GeriatrSoc. 2013;61(7):1128-1134.

36. Wehling M. Multimorbidity and polypharmacy: how to reducethe harmful drug load and yet add needed drugs in theelderly? Proposal of a new drug classification: fit for the aged.J Am Geriatr Soc. 2009;57(3):560-561.

37. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults:evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56(3):M146-M156.

38. Fried L, ed Frailty. 6th ed: McGraw- Hill; 2009. HazzardW, Halter,J, Ouslander, J, Tinetti, M, Studenski, S, High, K, Asthana, S, ed.Hazzard's Geriatric Medicine and Gerontology.

39. Fried LP, Xue QL, Cappola AR, et al. Nonlinear multisystemphysiological dysregulation associated with frailty in olderwomen: implications for etiology and treatment. J Gerontol ABiol Sci Med Sci. 2009;64(10):1049-1057.

40. Afilalo J, Karunananthan S, Eisenberg MJ, Alexander KP,Bergman H. Role of frailty in patients with cardiovasculardisease. Am J Cardiol. 2009;103(11):1616-1621.

41. Newman AB, Gottdiener JS, McBurnie MA, et al. Associationsof subclinical cardiovascular disease with frailty. J Gerontol A:Biol Med Sci. 2001;56(3):M158-M166.

42. Chaves PH, Semba RD, Leng SX, et al. Impact of anemia andcardiovascular disease on frailty status of community-dwelling older women: the Women's Health and AgingStudies I and II. J Gerontol A Biol Sci Med Sci. 2005;60(6):729-735.

43. Cacciatore F, Abete P, Mazzella F, et al. Frailty predicts long-term mortality in elderly subjects with chronic heart failure.Eur J Clin Investig. 2005;35(12):723-730.

44. Woods NF, LaCroix AZ, Gray SL, et al. Frailty: emergence andconsequences in women aged 65 and older in the Women'sHealth Initiative Observational Study. J Am Geriatr Soc. 2005;53(8):1321-1330.

45. Purser JL, Kuchibhatla MN, Fillenbaum GG, Harding T,Peterson ED, Alexander KP. Identifying frailty in hospitalizedolder adults with significant coronary artery disease. J AmGeriatr Soc. 2006;54(11):1674-1681.

46. de Vries NM, Staal JB, van Ravensberg CD, Hobbelen JS, OldeRikkert MG, Nijhuis-van der Sanden MW. Outcomeinstruments to measure frailty: a systematic review. AgeingRes Rev. 2011;10(1):104-114.

47. Rockwood K, Stadnyk K, MacKnight C, McDowell I, Hebert R,Hogan DB. A brief clinical instrument to classify frailty inelderly people. Lancet. 1999;353(9148):205-206.

48. Mitnitski AB, Mogilner AJ, MacKnight C, Rockwood K. Themortality rate as a function of accumulated deficits in a frailtyindex. Mech Ageing Dev. 2002;123(11):1457-1460.

49. Xie J, Brayne C, Matthews FE. Medical Research CouncilCognitive F, Ageing Study c. Survival times in people withdementia: analysis from population based cohort study with14 year follow-up. BMJ. 2008;336(7638):258-262.

50. Hill JW, Futterman R, Duttagupta S, Mastey V, Lloyd JR, Fillit H.Alzheimer's disease and related dementias increase costs ofcomorbidities inmanagedMedicare.Neurology. 2002;58(1):62-70.

51. Wilkins CH, Roe CM, Morris JC, Galvin JE. Mild physicalimpairment predicts future diagnosis of dementia of theAlzheimer's type. J Am Geriatr Soc. 2013;61(7):1055-1059.

52. Hajjar I, Quach L, Yang F, et al. Hypertension, white matterhyperintensities, and concurrent impairments in mobility,cognition, and mood: the Cardiovascular Health Study.Circulation. 2011;123(8):858-865.

53. Rockwood K, Wentzel C, Hachinski V, Hogan DB, MacKnight C,McDowell I. Prevalence and outcomes of vascular cognitiveimpairment. Vascular Cognitive Impairment Investigators of theCanadian StudyofHealth andAging.Neurology. 2000;54(2):447-451.

203P R O G R E S S I N C A R D I O V A S C U L A R D I S E A S E S 5 7 ( 2 0 1 4 ) 1 9 7 – 2 0 3

54. Dumont C, Voisin T, Nourhashemi F, Andrieu S, Koning M,Vellas B. Predictive factors for rapid loss on the mini-mentalstate examination in Alzheimer's disease. J Nutr Health Aging.2005;9(3):163-167.

55. Walter LC, Brand RJ, Counsell SR, et al. Development andvalidation of a prognostic index for 1-year mortality inolder adults after hospitalization. JAMA. 2001;285(23):2987-2994.

56. Volpato S, Cavalieri M, Guerra G, et al. Performance-basedfunctional assessment in older hospitalized patients:feasibility and clinical correlates. J Gerontol A Biol Sci Med Sci.2008;63(12):1393-1398.

57. Katz S, Downs TD, CashHR, Grotz RC. Progress in developmentof the index of ADL. The Gerontologist. 1970;10(1):20-30.

58. Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental activities of daily living. TheGerontologist. 1969;9(3):179-186.

59. Podsiadlo D, Richardson S. The timed “Up & Go”: a test of basicfunctional mobility for frail elderly persons. J Am Geriatr Soc.1991;39(2):142-148.

60. Duncan PW, Weiner DK, Chandler J, Studenski S. Functionalreach: a new clinical measure of balance. J Gerontol. 1990;45(6):M192-M197.

61. Borson S, Scanlan J, Brush M, Vitaliano P, Dokmak A. Themini-cog: a cognitive ‘vital signs’ measure for dementiascreening in multi-lingual elderly. Int J Geriatr Psychiatry.2000;15(11):1021-1027.

62. Hoyl MT, Alessi CA, Harker JO, et al. Development and testingof a five-item version of the Geriatric Depression Scale. J AmGeriatr Soc. 1999;47(7):873-878.

63. Kroenke K, Spitzer RL, Williams JB, Lowe B. The Patient HealthQuestionnaire Somatic, Anxiety, and Depressive SymptomScales: a systematic review. Gen Hosp Psychiatry. 2010;32(4):345-359.