Ez-PAVE: Initial Statin-Ezetimibe Combination No Better than Statins Alone

Initiating lipid-lowering therapy with a statin plus ezetimibe produced cardiovascular outcomes similar to starting with a statin alone when therapy was titrated to an assigned LDL cholesterol (LDL-C) target in patients with atherosclerotic cardiovascular disease (ASCVD), according to a prespecified secondary analysis of the Ez-PAVE trial presented at the American Heart Association (AHA) Scientific Sessions 2026 and published in Circulation.^1,2

At 3 years, the primary composite end point occurred in 8.5% of patients starting combination therapy and 7.9% of patients starting statin monotherapy (hazard ratio [HR], 1.07; 95% CI, 0.83–1.37; P = .60).¹ Mean LDL-C was lower with combination therapy in both the intensive-target group (53 vs 62 mg/dL) and the conventional-target group (63 vs 70 mg/dL).² Among patients starting monotherapy, more than 34% in the intensive-target group and nearly 25% in the conventional-target group had ezetimibe added to reach their goal.²

“Starting with a statin and adding ezetimibe as needed appears to be a reasonable strategy for people with long-term, stable heart or blood vessel disease whose cholesterol levels are checked regularly and medication doses are adjusted to reach their goals,” said Byeong-Keuk Kim, MD, PhD, study author and professor of cardiology at Yonsei University College of Medicine’s Severance Hospital in Seoul, South Korea. “Starting with combination therapy can lower cholesterol more quickly and may be a practical option, particularly for people whose LDL cholesterol numbers are much higher than their goal LDL level.”²

Ez-PAVE design and statin-ezetimibe combination results

Ez-PAVE was a multicenter, open-label, randomized trial with a 2-by-2 factorial design, enrolling 3048 patients with ASCVD at 17 sites in South Korea from January 2021 through July 2022.² Patients were randomized to an intensive LDL-C target below 55 mg/dL or a conventional target below 70 mg/dL, and separately to initial rosuvastatin plus ezetimibe (n = 1525) or statin monotherapy with rosuvastatin or atorvastatin (n = 1523).^1,2 Therapy was titrated at follow-up visits to reach the assigned target, and the primary end point was a composite of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, any revascularization, or hospitalization for unstable angina.^1,2

Mean age was 64.4 years, 20.9% of patients were women, and median baseline LDL-C was 76 mg/dL in both groups.^1,2 Results were consistent within the intensive-target group (7.1% vs 6.1%; HR, 1.17; 95% CI, 0.79–1.73) and the conventional-target group (9.8% vs 9.7%; HR, 1.01; 95% CI, 0.73–1.40).¹ Rates of cardiovascular death (1.2% vs 1.0%), nonfatal MI (1.4% vs 1.1%), nonfatal stroke (0.5% vs 0.7%), and any revascularization (6.6% vs 5.7%) did not differ significantly.¹

Safety and LDL-C targeting benefit by initial regimen in Ez-PAVE

The benefit of intensive vs conventional LDL-C targeting was consistent regardless of the initial regimen, with HRs of 0.72 (95% CI, 0.50–1.02) for combination therapy and 0.62 (95% CI, 0.43–0.90) for monotherapy (P for interaction = .58).¹ In the primary Ez-PAVE analysis, intensive targeting reduced the primary end point compared with conventional targeting (HR, 0.67; 95% CI, 0.52–0.86).³

Safety end points were similar between regimens, including new-onset diabetes (17.1% vs 15.6%; HR, 1.11; 95% CI, 0.87–1.42), statin-associated muscle symptoms (0.7% vs 0.9%), and aminotransferase elevation (2.3% vs 1.6%).¹ The investigators noted the second randomization was not powered to compare clinical outcomes between regimens, and the open-label design may have influenced treatment adjustment.¹ Other limitations included limited PCSK9 inhibitor use, no use of bempedoic acid or inclisiran, a predominantly male East Asian population, and 3-year follow-up.^1,2

“We expected that starting with combination therapy would lead to fewer heart attacks, strokes and other heart problems, but this was not the case,” said Kim. “A previous large study published in the New England Journal of Medicine showed that adding ezetimibe to a statin reduced the rate of cardiovascular deaths, nonfatal heart attacks, unstable angina requiring rehospitalization, coronary revascularization or nonfatal stroke. However, that study was not primarily designed to adjust treatment to reach a target LDL cholesterol goal, and medication dose changes were limited. We believe the difference was that in our study, medication doses in both treatment groups were adjusted to reach the target LDL cholesterol goal.”²

The investigators concluded achieving the assigned LDL-C target through timely treatment adjustment may matter more for outcomes than the choice of initial regimen.¹ According to the AHA, future research is needed to identify which patients would benefit most from starting with combination therapy.²

References

1. Lee SH, Byun YS, Kim JW, et al. Statin-ezetimibe combination therapy vs statin monotherapy in atherosclerotic cardiovascular disease: a prespecified secondary analysis of the randomized Ez-PAVE trial. Circulation. Published online November 7, 2026. doi:10.1161/CIRCULATIONAHA.126.083811

2. American Heart Association. Starting with a statin or statin plus ezetimibe to lower LDL led to similar heart outcomes. Published November 7, 2026. Accessed November 7, 2026. https://newsroom.heart.org/news/starting-with-a-statin-or-statin-plus-ezetimibe-to-lower-ldl-led-to-similar-heart-outcomes

3. Lee YJ, Lee SJ, Kim JW, et al. Intensive LDL cholesterol targeting in atherosclerotic cardiovascular disease. N Engl J Med. 2026;394(14):1365-1375. doi:10.1056/NEJMoa2600283