By Michael H. Crawford, MD
Professor of Medicine, Associate Chief for Education, Division of Cardiology, University of California, San Francisco
Dr. Crawford reports no financial relationships relevant to this field of study.
SYNOPSIS: Investigators analyzed data on the effect of age on cardiovascular (CV) outcomes and LDL cholesterol-lowering by alirocumab vs. placebo in recent acute coronary syndrome patients. They found alirocumab can lower the rate of CV events regardless of age — and produce more absolute benefit with age.
SOURCE: Sinnaeve PR, Schwartz GG, Wojdyla DM, et al. Effect of alirocumab on cardiovascular outcomes after acute coronary syndromes according to age: An ODYSSEY OUTCOMES trial analysis. Eur Hear J 2020;41:2248-2258.
The dearth of older patients in studies of LDL cholesterol-lowering has left uncertainty about the advisability of statin therapy in patients older than age 75 years. Recently, Sinnaeve et al conducted a prespecified analysis of the Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With alirocumab (ODYSSEY OUTCOMES) trial. They assessed the effect of age on cardiovascular outcomes and LDL cholesterol-lowering effects of alirocumab vs. placebo in patients with a recent (less than 12 months) acute coronary syndrome (ACS) and LDL levels above target (> 70 mg/dL) on maximally tolerated, high-intensity statin therapy.
The investigators were blinded to the treatment assignment and LDL levels. The primary endpoint was major adverse cardiovascular events (MACE), which was a composite of cardiac death, myocardial infarction, stroke, or unstable angina requiring hospitalization. The mean age of the 18,924 patients was 59 years (27% were > age 65 years and 5% > age 75 years). Because of the paucity of patients in the latter group, the data analysis was dichotomized at age 65 years. Older patients were more likely to be women and to be living with other cardiovascular disease. Adherence to the study drug and the degree of LDL lowering were similar in both age groups.
Mean LDL levels at three years were 63 mg/dL in those younger than age 65 years and 57 mg/dL in those older than age 65 years vs. 102 mg/dL and 97 mg/dL, respectively, in the placebo groups. Relative risk reductions were similar for both groups: age > 65 years HR, 0.78; 95% CI, 0.68-0.81 and age < 65 years HR, 0.89; 95% CI, 0.80-1.0; P for the interaction = 0.19. The HR for all-cause death was 0.77 (95% CI, 0.62-0.95) in the age > 65 years group and 0.94 (95% CI, 0.77-1.15) in the < 65 years group (P interaction = 0.46).
Dichotomizing the data at age 75 years produced similar results: HR for MACE in both groups was 0.85. Analyzing age as a continuous variable showed advancing age raised the risk of MACE and the absolute reduction in MACE with alirocumab. The number needed to treat to prevent one MACE at three years was 43 at age 45 years, 26 at age 75 years, and 12 at age 85 years. More patients experienced severe adverse events in the age > 65 years group, but there was no difference between alirocumab and placebo. The authors concluded that in patients with recent ACS, alirocumab reduces MACE, regardless of age — but with increasing absolute benefit (not harm) with advancing age. Thus, aggressive LDL lowering should not be withheld from older patients.
Elderly patients with cardiovascular disease often are undertreated, presumably over fear of adverse effects, polypharmacy, potential drug-drug interactions, or the concept that they have fewer years left to gain. In this prespecified analysis of the ODYSSEY OUTCOMES study, the authors noted those older than age 65 years were on less intense statin regimens at baseline and rarely were taking ezetimibe, despite their recent ACS event. Since the safety profile of alirocumab is similar to placebo, investigators believed this might be a good way to lower LDL cholesterol to target (< 70 mg/dL) in elderly patients. Hence, this analysis of the ODYSSEY OUTCOMES trial is of interest. Sinnaeve et al showed that not only did intensive lowering of LDL reduce MACE and all-cause death in post-ACS patients age older than 65 years, but it did so with increased absolute benefit compared to younger patients. Also, these results were obtained without any increase in adverse events over placebo. This resulted in a progressively smaller number needed to treat to prevent one MACE to an impressive 12 in those age 85 years. These data are similar to two other randomized, controlled trials published while ODYSSEY OUTCOMES was conducted. In the PROVE-IT TIMI 22 study of atorvastatin vs. pravastatin in post-ACS patients, at age > 70 years, the number needed to treat was 13 vs. 44 for those < age 70 years.1 In the similar IMPROVE-IT study of adding ezetimibe to simvastatin therapy, those > age 75 years had a number needed to treat of 11.2 Other researchers confirmed these results further in the Cholesterol Treatment Trialists meta-analysis 8.3 In addition, reducing MACE in older patients should improve quality of life and lower medical care costs. Thus, a strong picture is emerging that older patients with coronary artery disease should be treated with LDL-lowering therapy as aggressively as younger patients.
There were a few limitations to the Sinnaeve et al analysis. The low end age cutoff for enrollment of 40 years and the dichotomization at age 65 years was by trial design. The number of very elderly patients was small, so estimates of effectiveness and safety in those > age 80 years is less precise. All the patients were on maximally tolerated, high-intensity statins at baseline, and few were on ezetimibe. Considering the entry criteria for the study, it is unlikely many were frail, so the results are less likely to apply to sicker elderly patients. Although the follow-up duration for this study was long (four years, median 2.8 years), it is difficult to estimate years gained beyond the trial duration. However, the consistency of the data with other studies supports the conclusion that aggressive lipid-lowering for secondary prevention in elderly patients is important.
- Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-1504.
- Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-2397.
- The Cholesterol Treatment Trialists’ (CTT) Collaboration.