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Long-Term Efficacy and Safety of Moderate-Intensity Statin With Ezetimibe Combination Therapy vs High-Intensity Statin Monotherapy in Patients With ASCVD
TAKE-HOME MESSAGE
- This multicenter randomized controlled trial compared the efficacy and safety of a combined moderate-intensity statin and ezetimibe therapy with those of high-intensity statin monotherapy in 3780 patients with atherosclerotic cardiovascular disease (ASCVD). The primary composite endpoint of cardiovascular death, major cardiovascular events, and nonfatal stroke at 3 years occurred in 9.1% and 9.9% of patients in the combination and monotherapy group, respectively. Combination therapy was associated with effective reductions in LDL cholesterol concentrations and lower rates of discontinuation or dose reduction owing to intolerance.
- These findings suggest that ezetimibe in combination with moderate-intensity statin therapy is noninferior and is a safe and effective alternative to high-intensity statin therapy in patients with ASCVD at high risk of adverse events or statin intolerance.
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
Drug combinations rather than increasing doses of one drug can achieve greater efficacy and lower risks. Thus, as an alternative to high-intensity statin monotherapy, moderate-intensity statin with ezetimibe combination therapy can lower LDL cholesterol concentrations effectively while reducing adverse effects. However, evidence from randomised trials to compare long-term clinical outcomes is needed.
METHODS
In this randomised, open-label, non-inferiority trial, patients with atherosclerotic cardiovascular disease (ASCVD) at 26 clinical centres in South Korea were randomly assigned (1:1) to receive either 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 cardiovascular death, major cardiovascular events, or non-fatal stroke, in the intention-to-treat population with a non-inferiority margin of 2·0%. This trial is registered with ClinicalTrials.gov, NCT03044665 and is complete.
FINDINGS
Between Feb 14, 2017, and Dec 18, 2018, 3780 patients were enrolled: 1894 patients to the combination therapy group and 1886 to the high-intensity statin monotherapy group. The primary endpoint occurred in 172 patients (9·1%) in the combination therapy group and 186 patients (9·9%) in the high-intensity statin monotherapy group (absolute difference -0·78%; 90% CI -2·39 to 0·83). LDL cholesterol concentrations of less than 70 mg/dL at 1, 2, and 3 years were observed in 73%, 75%, and 72% of patients in the combination therapy group, and 55%, 60%, and 58% of patients in the high-intensity statin monotherapy group (all p<0·0001). Discontinuation or dose reduction of the study drug by intolerance was observed in 88 patients (4·8%) and 150 patients (8·2%), respectively (p<0·0001).
INTERPRETATION
Among patients with ASCVD, moderate-intensity statin with ezetimibe combination therapy was non-inferior to high-intensity statin monotherapy for the 3-year composite outcomes with a higher proportion of patients with LDL cholesterol concentrations of less than 70 mg/dL and lower intolerance-related drug discontinuation or dose reduction.
FUNDING
Hanmi Pharmaceutical.
Additional Info
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 Jul 18;[EPub Ahead of Print], BK Kim, SJ Hong, YJ Lee, SJ Hong, KH Yun, BK Hong, JH Heo, SW Rha, YH Cho, SJ Lee, CM Ahn, JS Kim, YG Ko, D Choi, Y Jang, MK HongFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Lowering low-density lipoprotein cholesterol (LDL-C) is one of the most important ways to reduce cardiovascular (CV) risk. It has been over 50 years that clinical trials have shown that lowering LDL-C leads to reductions in CV events, beginning with diet, then bile acid sequestrants, then statins, and, later, many other new classes of drugs.1 The most data come with the use of statins, and, indeed, higher doses of statins lead to further reductions in LDL-C and reductions in CV events. Statins have been the mainstay of therapy since they have the most trials and largest evidence base for efficacy, but other agents also have randomized trials showing reductions in LDL-C and CV events, notably ezetimibe and PCSK9 inhibitors.
“Lower is better” is the mantra that has been borne out over all these trials.1
Side effects with statins, although rare and usually reversible, have been somehow found to be a major worry for patients, potentially because so many patients are recommended to take them for atherosclerosis, which is largely an asymptomatic disease (until a clinical event occurs). A recent meta-analysis of over 4 million patients in 176 trials found that statin intolerance occurs in about 9% of patients using standard definitions,2 but perceptions and worry about side effects occur in many more patients, which lead patients to stopping medication (or not starting it despite recommendations). Two side effects are most common: myalgia and new-onset diabetes. Risk of other symptoms thought to be potential side effects, such as cognitive dysfunction, have been shown not to increase with statins in blinded randomized trials. It should be noted that a side effect can occur in any given patient despite the broader experience in trials. For new-onset diabetes, meta-analyses have found that statins lead to a higher rate of new-onset diabetes than placebo and also a larger effect with high doses compared with standard doses.3 As such, for patients with statin intolerance, using lower doses is one of the recommended strategies.4
The RACING trial nicely provides evidence that a strategy of using a lower dose of statin combined with ezetimibe is a way to provide potent LDL-C lowering, with a similar efficacy observed on CV event prevention as a high-dose statin but with a more favorable side-effect profile.4 This had been proposed as a strategy when ezetimibe was first approved, but there was no evidence to show that the lowering of LDL-C with ezetimibe would provide a similar reduction in CV events. With the IMPROVE-IT trial,5 we found that additional lowering of LDL-C did indeed lower CV events, and the amount of CV event reduction was proportional to the amount of LDL-C lowering, as it is for statins. But now we have direct evidence of this strategy of using a lower statin dose with ezetimibe as a way to provide CV event reduction with fewer side effects. I hope that these data can help open up the use of ezetimibe more broadly for physicians to offer to patients, thereby having more patients getting effective LDL-C lowering and CV risk prevention.
References