By Michael H. Crawford, MD
Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco
SYNOPSIS: A comparison of rosuvastatin 10 mg/day plus ezetimibe (10 mg/day) to 20 mg/day of rosuvastatin alone showed non-inferiority in three-year major cardiovascular outcomes, with lower LDL cholesterol levels and fewer episodes of drug discontinuation or dose reductions in the combination therapy group.
SOURCE: 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 randomized, open-label, non-inferiority trial. Lancet 2022;400:380-390.
Instead of raising the dose during statin monotherapy, adding ezetimibe could lower LDL cholesterol levels to appropriate targets and prevent adverse effects. However, long-term clinical outcome data for this approach are sparse.
Investigators from South Korea conducted a multicenter, randomized, controlled trial that included 3,780 patients from 26 centers. These patients presented with documented atherosclerotic cardiovascular disease (CVD), which included coronary, peripheral, and cerebral arterial disease, and the target LDL cholesterol was lower than 70 mg/dL. Subjects were randomized to receive either rosuvastatin 10 mg/day plus ezetimibe 10 mg/day or 20 mg/day of rosuvastatin alone. The authors followed patients for three years, and they permitted titration of study medications beyond the initial doses to achieve the LDL target. The primary endpoint was a combination of major CV events, CV death, or stroke. Secondary endpoints were clinical efficacy (LDL at target) and safety.
The primary analysis was conducted in the intention-to-treat population. Researchers assessed other outcomes in the per protocol population, excluding patients who did not receive the allocated therapy for > 5% of the study period. The average age of the study population was 64 years, 75% were men, and 96% completed the three-year follow-up. More than 90% of patients in both groups were taking the assigned therapy for all three years. Baseline characteristics, such as diabetes (37%), were not different between the two groups. The primary endpoint occurred in 9.1% of the combined therapy group and 9.9% of the monotherapy group, which met the non-inferiority margin of a < 2% difference. Investigators observed an LDL cholesterol reading of < 70 mg/dL in 72% of the combination group at three years vs. 58% of the monotherapy group (P < 0.0001). The authors noted a dose reduction or discontinuation of the study drug(s) in 4.8% of the combination group vs. 8.2% of the monotherapy group (P < 0.0001). The authors concluded moderate-intensity statin therapy plus ezetimibe was non-inferior to high-intensity statin monotherapy for the three-year composite clinical endpoint. More patients achieved LDL cholesterol levels lower than 70 mg/dL, and there were fewer intolerance-related drug discontinuation or dose reduction events in the combination group.
COMMENTARY
Guidelines recommend adding ezetimibe to statins if LDL cholesterol levels are above target despite maximum doses of high-intensity statins or non-tolerance.1 There were two studies of outcomes comparing a moderate-intensity statin at the same dose, with or without the addition of ezetimibe: IMPROVED-IT (simvastatin) and HIJ-PROPER (pitavastatin).2,3 These studies showed a clinical benefit of adding ezetimibe. Since adverse effects caused by statins are dose-related, the concept of adding ezetimibe instead of simply increasing the statin dose is attractive. Until this RACING study, there were no outcome data on such an approach. RACING showed adding ezetimibe was non-inferior to doubling the moderate dose of a potent statin for reducing a composite of CV outcomes and was more effective at lowering LDL cholesterol, with less drug discontinuation or dosage reductions caused by intolerance.
There were several limitations to the RACING study. It was open label, so biases in reporting adverse effects could have occurred. However, there was an independent outcomes adjudication committee. There was no placebo arm, but a placebo-controlled study of such high-risk patients could be considered unethical. There was a low event rate, which precluded conducting a superiority analysis and analyzing individual endpoints. About the time the study started, the European Society of Cardiology changed their guidelines on cholesterol-lowering targets in CVD patients to < 55 mg/dL.4 Those achieving this level at three years were 42% in the combination group and 25% in the higher-dose monotherapy group. Perhaps meeting these new targets will require even higher doses of statins and could reduce the influence of adding ezetimibe. Also, more than 90% of patients were on a statin before entering the trial, so the study population was largely tolerant of statins.
In this regard, it is interesting to see the top three adverse events: new diabetes (8% combo vs. 9% mono), muscle issues (1.1% combo vs. 1.9% mono), and neurocognitive decline (0.2% combo vs. 0.1% mono). In addition, 100% of patients in the RACING study were South Koreans, so applicability to other ethnic groups is unknown. Finally, the incremental cost of two drugs vs. one at a higher dose usually would favor the latter course. Adding ezetimibe before raising the statin dose is worth considering in a broader range of patients than those suggested in the current guidelines. For example, patients reluctant to go to a higher dose of statin because of adverse information they have heard, or a general resistance to higher doses of drugs.
REFERENCES
1. Vavlukis M, Vavlukis A. Adding ezetimibe to statin therapy: Latest evidence and clinical implications. Drugs Context 2018;7:212534.
2. 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.
3. Hagiwara N, Kawada-Watanabe E, Koyanagi R, et al. Low-density lipoprotein cholesterol targeting with pitavastatin + ezetimibe for patients with acute coronary syndrome and dyslipidaemia: The HIJ-PROPER study, a prospective, open-label, randomized trial. Eur Heart J 2017;38:2264-2276.
4. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111-188.
A comparison of rosuvastatin 10 mg/day plus ezetimibe (10 mg/day) to 20 mg/day of rosuvastatin alone showed non-inferiority in three-year major cardiovascular outcomes, with lower LDL cholesterol levels and fewer episodes of drug discontinuation or dose reductions in the combination therapy group.
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