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Moderate-intensity statin therapy and ezetimibe non-inferior to high-intensity mono-therapy

A moderate-intensity statin and ezetimibe regime in atherosclerotic cardiovascular disease is non-inferior to high-intensity statin therapy

A moderate-intensity dose statin combined with ezetimibe is non-inferior to high-intensity statin mono-therapy in patients with atherosclerotic cardiovascular disease (ASCVD) and has a lower incidence of drug discontinuation or dose reduction due to adverse statin events, according to a 3-year randomised trial by South Korean researchers.

High-intensity statin regimes lower LDL cholesterol and improve vascular outcomes in comparison to less intense regimes. This was clearIy shown in a meta-analysis of 26 randomised trial with over 170,000 patients, in which high-intensity statin therapy produced a highly significant reduction in major vascular events such as coronary death or non-fatal myocardial infarction, compared to less intensive regimens.

Nevertheless, whilst effective, statin drugs are associated with intolerance and which has an overall prevalence of 9.1% but which reduces to 5.9%, depending on the definition used by various organisations.

In addition, higher potency statins have been found to be associated with a 15% higher risk of new onset diabetes compared to lower potency agents.

One potential solution to using high-intensity (or high dose) statins is to use a moderate-intensity regime but with the addition of ezetimibe. Indeed, one 2014 systematic review of 36 trials found that moderate-intensity statin therapy with ezetimibe, decreased LDL cholesterol level 5% to 15% more than high-intensity mono-therapy among patients with ASCVD. Although the authors of the review advocated a lower-intensity statin-ezetimibe combination for high-risk patients who were either intolerant or unresponsive to statins, they cautioned on the absence of long-term clinical benefits and harms from using this approach.

Consequently and with a need to gather much needed evidence, the South Korean team undertook the RAndomised Comparison of Efficacy and Safety of lipid lowerING with statin mono-therapy versus statin–ezetimibe combination for high-risk cardiovascular disease (RACING) trial.

The purpose of the trial was to compare the 3-year clinical efficacy and safety of moderate-intensity statin with ezetimibe to high-intensity statin mono-therapy in patients who are at very high risk for cardiovascular disease. Individuals were randomised 1:1 to either ezetimibe and rosuvastatin 10 mg daily or high-intensity mono-therapy (rosuvastatin 20 mg daily).

The primary endpoint was the occurrence of cardiovascular death, major cardiovascular events or non-fatal strokes within 3 years. For the secondary endpoints, the researchers considered the proportion of patients whose LDL cholesterol was reduced to under 70 mg/dL (1.81 mmol/L) over the 3 years. They set the test for non-inferiority as an upper level of the 95% confidence interval between the two groups, of less than 2%.

Moderate-intensity statin therapy and cardiovascular outcomes

A total of 3780 patients with ASCVD and a mean age of 64 years (75% male) were randomised equally to either intervention and the median duration of follow-up was 3 years.

The primary endpoint occurred in 9.1% of those receiving combination therapy and 9.9% of those with mono-therapy (hazard ratio, HR = 0.92, 95% CI 0.75 – 1.13, p = 0.43). Since the upper level of the confidence interval was 1.3% (less than the pre-specified 2%) the authors declared non-inferiority for the two regimes. Moreover, the mortality rates were not significantly different (HR = 1.34, 95% CI 0.46 – 3.85, p = 0.59).

For the secondary outcome of LDL lowering, 72% in the combination regime and 58% of those on mono-therapy, achieved the target of < 70 mg/dL (p < 0.0001).

Interestingly, discontinuation rates or dose reductions due to adverse effects were significantly less for those receiving combination therapy (4.8% vs 8.2%, p < 0.0001).

The authors concluded that the combination of moderate-intensity statin therapy and ezetimibe was non-inferior to high-intensity statin therapy but also that the combination gave rise to a lower incidence of drug discontinuation or dose reduction due to adverse effects and a higher proportion of patients reaching their LDL cholesterol level.

Kin BK 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