EDITORIAL

Annals of Internal Medicine

Cost-Effectiveness of Statins in Older Adults: Further Evidence That Less Is More

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ne of the most common conundrums faced by primary care clinicians, geriatricians, and cardiologists is whether to prescribe statins for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in older adults. The problem is that the many randomized clinical trials that have evaluated statins in a broad spectrum of patients have included few older adults typical of those seen in clinical practice. Accordingly, the 2013 American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults focuses almost exclusively on persons aged 21 to 75 years and provides only 2 paragraphs addressing those older than 75 years (1 each for primary and secondary prevention) (1). At first glance, simply applying findings from younger populations to older adults might seem reasonable in the absence of evidence to the contrary. After all, the incidence and prevalence of ASCVD increase progressively with age (2); the majority of deaths attributable to ASCVD occur in older adults (3); and the potential benefit of statins, in absolute terms, is at least as great in older persons as in younger ones. Unfortunately, this view fails to consider several key factors that fundamentally alter the benefit–risk relationship of statins as people age. First, the importance of cholesterol as a risk factor for ASCVD decreases with age, and epidemiologic data suggest that higher cholesterol levels are associated with increased survival in persons aged 85 years or older (4). Second, older adults seem to be at increased risk for adverse effects from statins, including myalgia (perhaps due to reduced muscle mass) (5), fatigue (6), and reduced levels of physical activity (7). In addition, statins may adversely affect cognitive function (8), although further studies are needed to clarify this issue. Finally, as they age, older adults accumulate chronic conditions that contribute to functional decline and compete with ASCVD as the cause of death, thus limiting the benefits statins can provide. These chronic conditions also lead to polypharmacy, and statins interact with many commonly used prescription and nonprescription drugs. In light of these considerations, the study by Odden and colleagues in this issue provides insight about the value of statins in older adults (9). The authors used the Cardiovascular Disease Policy Model, data from NHANES (National Health and Nutrition Examination Survey), and the findings of PROSPER (Prospective Study of Pravastatin in the Elderly at Risk of Vascular Disease) (10) to estimate the potential benefits and costs for persons aged 75 to 94 years. Because all persons in this age group have a 10-year risk for incident ASCVD of at least 7.5%, which is the threshold for consideration of statins for primary prevention in younger persons (1), the authors evaluated a scenario in which all older adults were treated with statins. Such

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a strategy would result in approximately 8 million additional statin users, prevent 105 000 myocardial infarctions and 68 000 deaths from coronary heart disease over 10 years, and add 197 000 disability-adjusted lifeyears (DALYs) at a cost of $25 200 per additional DALY. In the United States, we are willing to pay for many therapies that cost $50 000 or more for an additional DALY, so the strategy of prescribing statins for all adults aged 75 to 94 years is economically attractive. In sensitivity analyses, the primary findings were generally robust, and statins remained cost-effective unless their price exceeded $30 per month or effectiveness was less than projected from PROSPER. An important caveat, however, is that potential adverse effects and harms were not included in the primary models. Rather, the authors estimated the magnitude of harm that would be required to offset the beneficial effects of statins (see Figure 1 of the article and the related discussion). For this, they used statinrelated cognitive impairment and statin-related declines in physical function as examples of the types of harm that might reduce DALYs. For the strategy of treating all adults, a reduction in DALYs as small as 0.003 would offset the benefits of statins, and anything more would translate into a net loss of DALYs (that is, net harm). In more concrete terms, this means that under this strategy, any adverse drug effect that resulted in 1 fewer day of life free of disability would nullify the benefit of statins. How should these findings be interpreted, and what are the implications for clinical practice? Statins are inexpensive relative to most medical interventions given the widespread availability of generic versions that cost $48 to $60 per year. Statins have also been associated with reductions in ASCVD morbidity in many large-scale clinical trials, although the effect on allcause mortality has been inconsistent, especially in primary prevention studies. Nonetheless, older adults clearly are a high-risk population, and it is reasonable to project that the benefits of statins in reducing the risk for myocardial infarction and cardiovascular death would be similar in older and younger adults. Thus, it is not surprising that statins were found to be costeffective in this age group and even cost-saving in certain high-risk subgroups (such as those with a lowdensity lipoprotein cholesterol level ≥4.14 mmol/L [≥160 mg/dL]). However, the key take-home message from this study is that despite low cost and high potential benefit, even very modest adverse effects attributable to statins tip the balance in the direction of harm. Therefore, although the investigators have conducted an elegant series of analyses showing that cost should not be an important consideration in the decision to prescribe statins in older adults, I believe that the findings strongly support the view that when it comes to prescribing statins for primary prevention in older

Cost-Effectiveness of Statins in Older Adults

adults, less is more. In this context, I fully agree with the view articulated in the 2013 ACC/AHA guideline: “Accordingly, a discussion of the potential ASCVD risk reduction benefits, risk of adverse effects, drug-drug interactions, and consideration of patient preferences should precede the initiation of statin therapy for primary prevention in older individuals” (1). Michael W. Rich, MD Washington University School of Medicine St. Louis, Missouri Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje /ConflictOfInterestForms.do?msNum=M15-0535. Requests for Single Reprints: Michael W. Rich, MD, Professor

of Medicine, Cardiovascular Division, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8086, St. Louis, MO 63110; e-mail, [email protected]. Ann Intern Med. 2015;162:590-591. doi:10.7326/M15-0535

References 1. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63:2889-934. [PMID: 24239923] doi:10.1016/j.jacc.2013.11.002

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EDITORIAL 2. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics2015 update: a report from the American Heart Association. Circulation. 2015;131:e29-e322. [PMID: 25520374] doi:10.1161/CIR .0000000000000152 3. Moran AE, Forouzanfar MH, Roth GA, Mensah GA, Ezzati M, Murray CJ, et al. Temporal trends in ischemic heart disease mortality in 21 world regions, 1980 to 2010: the Global Burden of Disease 2010 study. Circulation. 2014;129:1483-92. [PMID: 24573352] doi: 10.1161/CIRCULATIONAHA.113.004042 4. Newson RS, Felix JF, Heeringa J, Hofman A, Witteman JC, Tiemeier H. Association between serum cholesterol and noncardiovascular mortality in older age. J Am Geriatr Soc. 2011;59:1779-85. [PMID: 22091490] doi:10.1111/j.1532-5415.2011.03593.x 5. Sewright KA, Clarkson PM, Thompson PD. Statin myopathy: incidence, risk factors, and pathophysiology. Curr Atheroscler Rep. 2007;9:389-96. [PMID: 18001622] 6. Golomb BA, Evans MA, Dimsdale JE, White HL. Effects of statins on energy and fatigue with exertion: results from a randomized controlled trial [Letter]. Arch Intern Med. 2012;172:1180-2. [PMID: 22688574] doi:10.1001/archinternmed.2012.2171 7. Lee DS, Markwardt S, Goeres L, Lee CG, Eckstrom E, Williams C, et al. Statins and physical activity in older men: the Osteoporotic Fractures in Men Study. JAMA Intern Med. 2014;174:1263-70. [PMID: 24911216] doi:10.1001/jamainternmed.2014.2266 8. Padala KP, Padala PR, Potter JF. Statins: a case for drug withdrawal in patients with dementia [Letter]. J Am Geriatr Soc. 2010;58: 1214-6. [PMID: 20722868] doi:10.1111/j.1532-5415.2010.02889.x 9. Odden MC, Pletcher MJ, Coxson PG, Thekkethala D, Guzman D, Heller D, et al. Cost-effectiveness and population impact of statins for primary prevention in adults aged 75 years or older in the United States. Ann Intern Med. 2015;162:533-41. doi:10.7326/M14-1430 10. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, et al; PROSPER study group. PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360:1623-30. [PMID: 12457784]

Annals of Internal Medicine • Vol. 162 No. 8 • 21 April 2015 591

Cost-effectiveness of statins in older adults: further evidence that less is more.

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