Statin Therapy in Older Adults for Primary Prevention of Atherosclerotic Cardiovascular Disease: The Balancing Act
It is well established that statins reduce adverse cardiovascular outcomes but it remains unclear whether this reduction applies to older adults. Although older individuals have the highest absolute risk for atherosclerotic cardiovascular disease (ASCVD) events, the US guidelines for blood pressure and cholesterol recommend lower-intensity, less-aggressive treatment strategies in this high-risk population. The 2018 American College of Cardiology (ACC)/American Heart Association (AHA) Cholesterol guidelines,1 citing the statin-associated reduction in ASCVD morbidity burden in older adults in secondary prevention, recommend ongoing use of statins in this population. However, when addressing primary prevention in older adults (>75 years), the recommendations are less direct and weigh heavily on the patient-physician discussion as well as overall concerns for polypharmacy, fraility, and life-expectancy.
The ACC/AHA 2018 cholesterol guidelines state that in adults older than 75 years with diabetes mellitus, it may be reasonable to initiate statin therapy after a clinician–patient discussion of potential benefits and risks for prevention of ASCVD events. However, in individuals >75 years free of ASCVD (and without diabetes or low-density lipoprotein cholesterol [LDL-C] ≥190 mg/dL), the currently applicable guidelines do not make a specific recommendation for statin use.
In patients age 75 and younger, the efficacy of statins for primary prevention is well-established on the basis of multiple randomized trials, which have found that they reduce the relative risk of major vascular events by 20-30%.2,3 Given the paucity of adults >70 years in clinical trials, the evidence for the efficacy of statins for primary prevention in older adults is limited. The benefit of statins in prevention of ASCVD events in older adults, therefore, is derivative of mainly post hoc and subgroup analyses of randomized trials and from meta-analyses of these studies.
The PROSPER trial evaluated the effects of pravastatin in an older adults' population (70-82 years) with and without baseline ASCVD. At 3.2 years mean follow up period, decrease in LDL-C by approximately 34% as well as reductions in myocardial infarction (MI) and coronary deaths were noted in the pravastatin group versus the placebo group.4 There was no statistically significant benefit noted on stroke reduction in the pravastatin group.4 In the predefined subgroups stratified analysis, the primary end point risk reduction was more in secondary than in primary prevention.
Ridker et al. used age-stratified data from two primary prevention statin trials (JUPITER [Justification for Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin] and HOPE-3 [Heart Outcomes Prevention Evaluation 3]) and derived that the use of rosuvastatin significantly lowered the risk for a composite outcome of nonfatal MI, nonfatal stroke, or cardiovascular death by 26%, compared with placebo, in subjects >70 years of age initially free of ASCVD.5
Recently in a compelling retrospective cohort study, Orkaby et al. showed that among 326,981 US veterans (mean age approximately 81 years) free of ASCVD at baseline, new statin use was associated with a significantly lower risk of all-cause and cardiovascular mortality.6 Over a follow up period of approximately 6.8 years, there were 66.3 and 70.4 events/1,000 person-years among statin users and nonusers, respectively, for the composite ASCVD outcome. Furthermore, the HR was 0.75 (95% CI, 0.74-0.76) for all-cause mortality, 0.80 (95% CI, 0.78-0.81) for cardiovascular mortality, and 0.92 (95% CI, 0.91-0.94) for a composite of ASCVD events when comparing statin users with nonusers after propensity score overlap weighting was applied.
With respect to the prevalence of statin use in older adults, another analysis from the Patient and Provider Assessment of Lipid Management (PALM) registry7 compared statin use and dosing between adults >75 and ≤75 years old in the setting of either primary or secondary prevention. Approximately 25% (1,704) of the 6,717 individuals enrolled were >75 years old. Overall use of statins was similar for primary prevention in those aged >75 years versus younger patients (62.6% in those >75 years old vs. 63.1% in those ≤75 years old [P=0.83]). However, older patients were slightly less likely to receive any statin for secondary prevention (80.1% vs. 84.2% [P=0.003]; adjusted odds ratio, 0.81; 95% confidence interval, 0.66–1.01 [P=0.06]), and were much less likely to receive a high‐intensity statin (23.5% vs. 36.2% [P<0.0001]; adjusted odds ratio, 0.54; 95% confidence interval, 0.45–0.65 [P=0.0001]). Furthermore, older patients were slightly less likely to report myalgias (27.3% vs. 33.3%; P<0.001) or any symptoms (41.3% vs. 46.6%; P=0.003).
Zhou et al. recently conducted a post hoc analysis of independent, community-dwelling adults >70 years of age without ASCVD, dementia, or physical disability using data from the ASPREE (Aspirin in Reducing Events in the Elderly) trial.8 In this cohort of older adults followed for a median of 4.7 years, baseline statin use was not associated with extended disability-free survival, risk for death, or incident dementia. However, the use of statins at baseline did significantly lower risk for physical disability over a period of approximately 6 years follow up. This study demonstrated the association of statin use with disability-free survival – an earnest goal in the practical approach to care for older adults.
On the flip side, a recent study by Odden et al. estimated that any statin-related adverse effect that contributes to a mild decline in functioning and cognition may counterbalance its cardiovascular benefits in primary prevention in older adults (>75 years).9 Moreover, there is a consideration of the competing risk from non-ASCVD disease in older people who may experience immediate harms from statins but not live long enough to accrue the benefits.
Risk Assessment in Older Adults: New Goals for Assessment and Treatment Strategies
The most common strategies that have clinically come to fruition in the care of older adults are primarily based on extrapolation of data from studies involving younger adults. There are several concerns with this approach; mainly that older adults are likely to be more susceptible to cardiovascular events and are also less tolerant of drug-related side effects compared with younger adults because of age-related decline and increased burdens of disease and the likelihood of being on multiple medications.
An important consideration in the treatment of older adults is, perhaps, the identification of the highest risk individuals in the older adult primary prevention cohort. A major gap in ASCVD prevention for older adults is that the pooled cohort equations (PCE) derived 10-year ASCVD event risk is valid only for ages 20–79; older individuals are not included in the guideline-recommended risk prediction algorithm.10,11 For the guideline recommended "clinician–patient discussion" in lieu of definitive primary prevention recommendations in those aged ≥75 years, it is difficult to discuss potential benefits without being able to assess ASCVD risk for the ≥11 million Americans aged ≥80 years (approximately 25% of the Medicare population).
The use of coronary artery calcium score (CACs) in this cohort may be the single most important tool to quantify risk and discuss the potential use of statin therapy. A study by Yano et al. sought to evaluate whether the use of CACs could serve as a surrogate marker for age as a predictor of ASCVD events in older adults among three population based cohorts with a representative sample of over 4,778 older adults (mean age 70.1 years).12 Over a time period of 11 years follow up, addition of CACs to models including traditional cardiovascular risk factors, (without age) improved discrimination for incident coronary heart disease events (C statistic, 0.735 vs. 0.703; C statistics difference, 0.032) but not for stroke. However, the age-specific (<75 years and ≥75 years) analysis with the inclusion of an interaction term suggested that there were no significant interactions between CAC score and age in association with all cardiovascular outcomes. The authors postulated that the major limiting factor for the predictive power of CACs may be due to its inability to predict stroke, a common ASCVD event in older adults. Indeed, in the 2018 ACC/AHA guidelines, a CACs of zero is highlighted as a potential gate keeper to discontinue long term statin therapy in those older adults without ASCVD events. It is to be noted that the hypothesis whether CACs associated initiation of statin therapy amongst older adults yields overall benefits in individuals or composite ASCVD outcomes has yet to be tested in clinical trials per our knowledge.
Another recent approach highlighted from the Atherosclerosis Risk in Communities (ARIC) study13 postulated the use of biomarkers as a better ASCVD event risk prediction tool for older adults. The authors compared the "PCE model" of ASCVD risk prediction to a more robust "Complete model" (PCE variables plus the NT-proBNP, hc-cTnT and hs-CRP biomarkers) to predict coronary artery disease (CAD), stroke and heart failure events in older adults. The study design evaluated this model over a "short term period" follow up (approximately 4 years) compared to the traditional "10-year" risk prediction window which may be a time frame inapt for individuals with <10 years of life expectancy. The "complete model" outperformed the PCE model in older adults from the ARIC study Visit 5 (mean age 75 years) for prediction of ASCVD events and heart failure. This study concluded that while the traditional risk factors work for risk prediction in younger individuals, the ASCVD risk factors such as hypertension are present in the vast majority of the older population (70% in this specific study).13 Thus, the use of PCE in the older adult population may be more refined by using the aforementioned biomarkers which can serve as indicators of subclinical injury and provide greater benefit in predicting a shorter-term risk.
Much remains in question with respect to statin therapy use and risk prediction in older adults for primary prevention of ASCVD. Is there a need for a better risk prediction model over a shorter-term time period which is most relevant for older adults? Are statins safe and overall, a beneficial and cost-effective addition among older adults to prevent ASCVD events?
The future outlook overall is hopeful. Two large trials namely, PREVENTABLE (Pragmatic Evaluation of Events and Benefits of Lipid-Lowering in Older Adults) trial (National Heart, Lung, and Blood Institute grant U19AG065188) and an Australian randomized, placebo-controlled trial called STAREE (A Clinical Trial of Statin Therapy for Reducing Events in the Elderly) are ongoing. The PREVENTABLE trial is aiming to enroll 20,000 community-dwelling primary prevention patients age ≥75 and randomize individuals to atorvastatin 40 mg daily, or placebo. The primary outcomes include dementia and physical disability over 4 years. Meanwhile, the STAREE trial will assess the efficacy of atorvastatin 40 mg daily versus placebo in the improvement of overall survival or disability-free survival in 18,000 community-dwelling patients age ≥70 years.
As such, these trials are bound to answer important questions of whether there are meaningful outcomes associated with use of statins in older adults and if yes, are the 'benefits' worth the overall risk?
Figure: Practical Barriers in Statin Utilization Amongst Older Adults
- Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol. J Am Coll Cardiol 2019;73:3168-3209.
- Mihaylova B, Emberson J, Blackwell L, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581-90.
- Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated c-reactive protein. N Engl J Med 2008;359:2195-2207.
- Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360:1623-30.
- Ridker PM, Lonn E, Paynter NP, Glynn R, Yusuf S. Primary prevention with statin therapy in the elderly: new meta-analyses from the contemporary JUPITER and HOPE-3 randomized trials. Circulation 2017;135:1979-81.
- Orkaby AR, Driver JA, Ho YL, et al. Association of statin use with all-cause and cardiovascular mortality in US Veterans 75 Years and older. JAMA 2020;324:68-78.
- Nanna MG, Navar AM, Wang TY, et al. Statin use and adverse effects among adults ˃75 years of age: insights from the Patient and Provider Assessment of Lipid Management (PALM) Registry. J Am Heart Assoc 2018;7:e008546.
- Zhou Z, Ofori-Asenso R, Curtis AJ, et al. Association of statin use with disability-free survival and cardiovascular disease among healthy older adults. J Am Coll Cardiol 2020;76:17-27.
- Odden MC, Pletcher MJ, Coxson PG, 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.
- Jung KJ, Jang Y, Oh DJ, et al. The ACC/AHA 2013 pooled cohort equations compared to a Korean Risk Prediction Model for atherosclerotic cardiovascular disease. Atherosclerosis 2015;242:367-75.
- Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2935-9.
- Yano Y, O'Donnell CJ, Kuller L, et al. Association of coronary artery calcium score vs age with cardiovascular risk in older adults: an analysis of pooled population-based studies. JAMA Cardiol 2017;2:986-94.
- Saeed A, Nambi V, Sun W, et al. Short-term global cardiovascular disease risk prediction in older adults. J Am Coll Cardiol 2018;71:2527-36.
Keywords: Primary Prevention, Secondary Prevention, Cholesterol, LDL, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Propensity Score, Prevalence, American Heart Association, Risk Factors, Life Expectancy, Coronary Artery Disease, Aged, 80 and over, Veterans, Goals, Atherosclerosis, Follow-Up Studies, Independent Living, Cost-Benefit Analysis, Aspirin, Calcium, Cardiovascular Diseases, Blood Pressure, Confidence Intervals, Myalgia, Odds Ratio, Pravastatin
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