By Michael H. Crawford, MD
Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco
SYNOPSIS: In a post-hoc analysis of the RACING trial, researchers found the combination of moderate-intensity statin and ezetimibe therapy vs. high-intensity statin therapy alone in older subjects resulted in similar reductions in cardiovascular events over three years, but fewer adverse effects with the combination therapy.
SOURCE: Lee AJ, Lee YJ, Heo JH, et al. Combination moderate-intensity statin and ezetimibe therapy for elderly patients with atherosclerosis. J Am Coll Cardiol 2023;81:1339-1349.
Prior studies have shown older patients with atherosclerotic cardiovascular disease (ASCVD) benefit more from high-intensity statin therapy, but they experience more adverse events than younger patients. In the IMPROVE-IT trial, researchers showed adding ezetimibe to moderate-intensity statins vs. moderate-intensity statins alone in ASCVD patients resulted in lower LDL cholesterol levels and reduced ASCVD events, especially in those older than age 75 years.1 However, most guidelines recommend high-intensity statin therapy for secondary prevention.2 The RACING trial was a prospective, multicenter, randomized, open-label, non-inferiority trial. The authors compared moderate statin therapy plus ezetimibe to high-intensity statin therapy alone, which showed the combination therapy could produce efficacy comparable to high-intensity statin therapy with fewer drug-related adverse events.3
The authors of RACING enrolled 3,780 patients in 26 centers in South Korea with documented ASCVD (defined as myocardial infarction, acute coronary syndrome, coronary revascularization, ischemic stroke, or peripheral arterial disease). Patients were randomized to rosuvastatin 10 mg per day plus ezetimibe 10 mg per day or to only a dose of rosuvastatin 20 mg per day. The primary endpoint was a combination of CV mortality, major CV events, or ischemic stroke. Secondary endpoints included all-cause mortality, LDL cholesterol levels, drug discontinuation because of intolerance, new diabetes diagnoses, muscle symptoms, liver function test abnormalities, gall bladder disease, cancer, or cataract surgery within the three-year study period.
For this post-hoc analysis of RACING, Lee et al divided patients into older than (15%) or younger than age 75 years. Median LDL levels during the study period in those age 75 years and older were 58 mg/dL for patients in the combination therapy group and 62 mg/dL for the statin monotherapy group (P = 0.002). Similar results were seen in the younger than age 75 years group (58 mg/dL vs. 67 mg/dL; P < 0.001). The rates of the primary endpoint were not different between the statin with ezetimibe combination therapy group and the statin monotherapy group among patients age 75 years and older (10.6% vs. 12.3%; HR, 0.87; 95% CI, 0.54-1.42; P = 0.581) and those younger than age 75 years (8.8% vs. 9.4%; HR, 0.94; 95% CI, 0.74-1.18; P = 0.570; P for interaction = 0.797). However, combination therapy was associated with lower rates of drug intolerance and discontinuation or dose reduction compared to statin monotherapy in those age 75 years and older (2.3% vs. 7.2%; P = 0.010) and those younger than age 75 years (5.2% vs. 8.4%; P < 0.001; P for interaction = 0.159). The frequency of other adverse events did not differ between the two treatment groups, regardless of age (except for new-onset diabetes, which was more common in the high-intensity statin group among older patients). The authors concluded moderate-intensity statin plus ezetimibe therapy produced similar rates of the primary endpoint of ASCVD events as monotherapy with a high-intensity statin in elderly patients, but lower rates of drug intolerance or discontinuation.
COMMENTARY
There has been considerable concern about prescribing high-intensity statin therapy to older patients because they are more likely to experience therapy intolerance, nonadherence, and discontinuation.4 This post-hoc analysis of the RACING trial demonstrated a strategy of moderate-intensity statin therapy plus ezetimibe can lower LDL cholesterol and produce equivalent reductions in ASCVD events similar to high-intensity statin monotherapy in elderly patients. Also, the safety of this combination therapy is similar in older patients compared to high-intensity statins alone, except regarding new-onset diabetes, which favors combination therapy (10% vs. 19%, respectively; P = 0.025). Since current guidelines for secondary prevention do not recommend high-intensity statins in those older than age 75 years,2 this moderate-dose statin plus ezetimibe technique is an attractive alternative.
Nevertheless, there were weaknesses to this analysis. The older patients tended to be living with more comorbidities, such as coronary bypass surgery and stroke, and more predisposing conditions, such as hypertension and chronic kidney disease. Also, there were relatively few patients age 75 years and older in RACING (n = 574, 15%), so this post-hoc study may have been underpowered for some endpoints. In addition, this was a study of secondary prevention patients, so the results may not translate to a primary prevention cohort. Finally, there was no use of other LDL-lowering agents, such as PCSK9 inhibitors. On the other hand, these data are compelling. Perhaps one way to approach older patients for secondary prevention is to start with a moderate-dose statin, see if they tolerate it, then measure their LDL level. If that level is not at target (< 70 mg/dL), add ezetimibe. If that does not help the patient reach the goal, then discuss adding other therapies with or without the moderate-dose statin.
REFERENCES
1. 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.
2. Virani SS, Smith SC Jr, Stone NJ, Grundy SM. Secondary prevention for atherosclerotic cardiovascular disease: Comparing recent US and European guidelines on dyslipidemia. Circulation 2020;141:1121-1123.
3. Kim BK, Hong SJ, Lee YJ, et al. Long-term efficacy and safety of moderate-intensity statin with ezetimibe combination therapy versus high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease (RACING): A randomised, open-label, non-inferiority trial. Lancet 2022;400:380-390.
4. Banach M, Serban MC. Discussion around statin discontinuation in older adults and patients with wasting diseases. J Cachexia Sarcopenia Muscle 2016;7:396-399.
In a post-hoc analysis of the RACING trial, researchers found the combination of moderate-intensity statin and ezetimibe therapy vs. high-intensity statin therapy alone in older subjects resulted in similar reductions in cardiovascular events over three years, but fewer adverse effects with the combination therapy.
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