Statin plus ezetimibe combination ‘alternative strategy’ to doubled statin dose in ASCVD
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Among adults with atherosclerotic CVD at very high risk, moderate-intensity statin plus ezetimibe combination therapy was noninferior to high-intensity statin monotherapy for major CV outcomes at 3 years, including CV death, data show.
The findings suggest that ezetimibe combination therapy might be considered earlier in the use of moderate-intensity statin therapy, rather than doubling the statin dose for patients at high risk for adverse effects or statin intolerance with high-intensity statin therapy.
“Compared with high-intensity statin alone, the addition of ezetimibe to lower-intensity statin could provide an alternative strategy to not only achieve adequate LDL cholesterol concentrations but also reduce the required dose of statins,” Yangsoo Jang, MD, PhD, of CHA Bundang Medical Center and CHA University College of Medicine in Seongnam, South Korea, and colleagues wrote in The Lancet. “This would contribute to a reduction in the adverse effects or potential intolerances related to high-intensity statin therapy.”
In the RACING study, Jang and colleagues analyzed data from 3,780 adults with ASCVD from 26 clinical centers in South Korea, enrolled between February 2017 and December 2018 (mean age, 64 years; 75% men; 40% with previous MI; 37% with diabetes). Researchers randomly assigned participants to moderate-intensity statin with ezetimibe combination therapy (rosuvastatin 10 mg with ezetimibe 10 mg) or high-intensity statin monotherapy (rosuvastatin 20 mg). The primary endpoint was the 3-year composite of CV death, major CV events or nonfatal stroke. Median follow-up was 3 years.
The primary endpoint occurred in 9.1% of participants in the combination therapy group and 9.9% in the high-intensity statin monotherapy group, for an absolute difference of –0.78 percentage points (90% CI, –2.39 to 0.83).
LDL concentrations of less than 70 mg/dL at 1, 2 and 3 years were observed in 73%, 75%, and 72%, respectively, of patients in the combination therapy group, and in 55%, 60% and 58%, respectively, of patients in the high-intensity statin monotherapy group (absolute differences = 17.5 percentage points at 1 year; 14.9 percentage points at 2 years; 14.8 percentage points at 3 years; P for all = .0001).
In a post hoc analysis, LDL concentrations of less than 55 mg/dL at 1, 2 and 3 years were observed in 42%, 45%, and 42%, respectively, of patients in the combination therapy group and 25%, 29% and 25%, respectively, of patients in the high-intensity statin monotherapy group, for absolute differences of 17.5 percentage points at 1 year (95% CI, 14.3-20.7), 14.9 percentage points at 2 years (95% CI, 11.7-18.2) and 14.8 percentage points at 3 years (95% CI, 11.2-18.3).
“Importantly, the extent of LDL cholesterol reduction was the strongest independent predictor of a reduction in the risk of major vascular events,” the researchers wrote. “The effects of ezetimibe unrelated to cholesterol lowering could be another explanation [for the noninferior findings], for example, ezetimibe-related potentiation of plaque regression, modulation of genes related to inflammation or oxidative stress, inhibition of monocyte or macrophage differentiation, inhibition of smooth muscle cell proliferation, and inhibition of platelet aggregation.”
Perspective
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Christie M. Ballantyne, MD, FACC, FACP, FAHA, FNLA
It is wonderful that this trial has finally been conducted. Ezetimibe was approved 20 years ago. In the IMPROVE-IT study, researchers tested an approach where you titrate a statin to the highest dose and then add ezetimibe. Here, the authors looked at something different: If you use a moderate-intensity statin and add ezetimibe, could that be more effective vs. using the top dose of the statin alone?
In a related editorial published in The Lancet (Abushamat LA, et al. Lancet. 2022;doi:10.1016/S0140-6736(22)01352-6), we note that this is an approach that has been done in hypertension for some time. We realized long ago that if you keep titrating one hypertension drug, you see adverse effects and not much more efficacy. Rosuvastatin 10 mg is a common starting dose; the top dose is 40 mg. Yet, we have known for many years that 10 mg of rosuvastatin plus 10 mg of ezetimibe leads to greater LDL reductions compared with 40 mg of rosuvastatin alone. However, no one has shown that approach is equally effective for reducing events.
This was a pragmatic trial conducted in South Korea with 26 centers and was open-label, which is far less expensive to do. The authors found combination therapy was noninferior to monotherapy for clinical events; there were fewer discontinuations and more LDL reduction. With open-label studies, there is often a “nocebo” effect; people know high-dose statins might cause muscle pain, and that is a limitation scientifically. However, we practice medicine in the real world; the patients know what they are taking. In the real world, when patients move to a higher dose of a medication, they become more worried about adverse effects.
This is an important study. We have these fantastic lipid therapies, yet in practice, we are not doing well at getting the LDLs down. Other approaches may be necessary. It is important that a group finally looked at combination therapy, which may be more desirable for some individuals.
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