Cumulative exposure to elevated low-density lipoprotein cholesterol (LDL-C) plays a causal role in atherosclerotic cardiovascular disease (ASCVD). Multiple clinical trials have shown that absolute reduction in LDL-C aids in ASCVD risk reduction, regardless of age. Every 1.0-mmol/L (38.7-mg/dL) reduction in LDL-C provides ~22% relative risk reduction for major ASCVD events.[1] Despite evidence that LDL-C lowering is effective for reducing risk for ASCVD in the elderly (age >75 years),[2] lipid-lowering therapy (LLT) use declines with increasing age, particularly in those aged >75 years.[3]
People aged >75 years are the fastest-growing segment of the population,[4] yet guidelines regarding LLT initiation in this population are ambiguous. Although lipid-lowering guidelines recommend a discussion about risks and benefits before starting statins in this population,[5] the American Board of Internal Medicine's Choosing Wisely recommends against prescribing LLT in those with advanced age.[6] This stance was based on limited life expectancy and higher risk of polypharmacy and statin-associated muscle symptoms in the elderly, particularly with high-intensity statins.[7] However, U.S. Social Security actuarial tables show that life expectancy at age 75 is 11.3 years in men and 13.1 years in women.[8] Therefore, limited life expectancy does not apply to all individuals in this age group, and many may benefit from more intensive LLT.
Although guidelines focus on high-intensity statins for high-risk individuals, combination LLT with low- and moderate-intensity statin and ezetimibe has been shown to reduce LDL-C concentrations as much and often more and with better tolerability than high-intensity statin monotherapy does[9,10] and has been recently demonstrated in the RACING (Randomized Comparison of Efficacy and Safety of Lipid-Lowering With Statin Monotherapy Versus Statin/Ezetimibe Combination for High-Risk Cardiovascular Diseases) trial to be noninferior to high-intensity statin monotherapy in reducing cardiovascular outcomes.[11] In this issue of the Journal of the American College of Cardiology, a post hoc analysis of the RACING trial[12] investigated the safety and efficacy of this approach compared with high-intensity statin monotherapy in 574 of the 3,780 patients with ASCVD in the original trial (15.2%). Among those 75 years or older, there was no significant difference in the occurrence of the primary endpoint in the combination-therapy group (29 of 273 [10.6%]) vs the high-intensity statin group (37 of 301 [12.3%]). Additionally, the combination-therapy group achieved a lower median LDL-C (58 mg/dL) compared with the high-intensity statin group (62 mg/dL) and had significantly fewer discontinuations of therapy (6 [2.3%] vs 21 [7.2%]) and incidence of new-onset diabetes (17 [10.0 %] vs 31 [18.7%]). These findings suggest similar clinical efficacy in event lowering and superior LDL-C lowering with a favorable side effect and safety profile. However, this analysis was underpowered for the subgroup aged >75 years, and individuals aged >80 years were excluded from the original study design, limiting the conclusions and generalizability of findings in the elderly population.
Patients aged ≥75 years have been historically under-represented in randomized controlled trials of LLT, despite having the highest risk. Those aged >80 years old have the highest prevalence of stroke and increased risk of this debilitating condition. Several randomized controlled trials have demonstrated that more intensive LDL-C reductions, including with combination statin and ezetimibe, reduce ASCVD and stroke risk.[13–15] IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) showed that combination therapy with ezetimibe and simvastatin led to greater reductions in stroke[16] and that the greatest absolute risk reduction for cardiovascular events occurred in people over 75 years old.[17]
EWTOPIA 75 (Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older), a multicenter randomized controlled trial that enrolled adults aged ≥75 years without history of ASCVD, found that those treated with ezetimibe had reduced risk for cardiovascular events, underscoring the importance of LDL-C lowering in this age group.[18] Retrospective analysis of U.S. veterans aged ≥75 years without ASCVD has shown that statin initiation was associated with reduced all-cause and cardiovascular mortality risk.[19] In cohort studies, statin discontinuation in individuals aged >75 years without ASCVD led to increased risk of readmission for a cardiovascular event[20] and higher risk of cardiovascular events.[21]
These previous studies and secondary analyses argue for an alternative approach of treating high-risk elderly patients with combination LLT instead of high-intensity statin therapy. Two ongoing randomized controlled trials, PREVENTABLE (Pragmatic Evaluation of Events And Benefits of Lipid-lowering in Older Adults)[22] and STAREE (A Clinical Trial of Statin Therapy for Reducing Events in the Elderly),[23] are currently testing the effect of a high-intensity statin (atorvastatin 40 mg daily) in elderly patients. Although these placebo-controlled trials are timely and assess meaningful outcomes, they do not address the critical question of the comparative effectiveness of a strategy of treating with a low- or moderate-intensity statin and ezetimibe versus a high-intensity statin in high-risk individuals aged >75 years. Future studies, including pragmatic trials, should go beyond focusing only on the efficacy of new LLTs and test the effectiveness of different approaches to implement LLT in this very important high-risk population.
J Am Coll Cardiol. 2023;81(14):1350-1352. © 2023 American College of Cardiology Foundation
