Randomized Comparison of Efficacy and Safety of Lipid Lowering With Statin Monotherapy Versus Statin-Ezetimibe Combination for High-Risk Cardiovascular Disease - RACING

Mar 22, 2023
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC; Neil Keshvani, MD
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Hanmi Pharmaceutical
Date Published:
07/18/2022
Date Updated:
03/22/2023
Original Posted Date:
08/05/2022
References

Contribution To Literature:

Highlighted text has been updated as of March 22, 2023.

The RACING trial showed that, among patients with ASCVD, moderate-intensity statin with ezetimibe combined therapy was noninferior to high-intensity monotherapy with respect to the primary endpoint of cardiovascular death, major cardiovascular events, or nonfatal stroke.

Description:

The goal of the trial was to compare the clinical efficacy and safety of moderate-intensity statin with ezetimibe combination therapy versus high-intensity statin monotherapy in patients at very high risk for cardiovascular diseases.

Study Design

The RACING trial was a multicenter, open-label trial among 26 centers in South Korea. Patients with documented atherosclerotic cardiovascular disease (ASCVD) were randomized in a 1:1 fashion to ezetimibe and moderate-intensity statin (rosuvastatin 10 mg with ezetimibe 10 mg once daily; n = 1,894) or high-intensity statin monotherapy (rosuvastatin 20 mg once daily; n = 1,886). Results were analyzed in an intention-to-treat fashion.

  • Total randomized participants: 3,780
  • Median duration of follow-up: 3 years
  • Mean patient age: 64 years
  • Percentage female: 25%

Inclusion criteria:

  • Age 19-80 years
  • Documented ASCVD (previous myocardial infarction [MI], acute coronary syndrome, coronary or arterial revascularization, ischemic stroke, peripheral artery disease) with goal low-density lipoprotein (LDL) cholesterol <70 mg/dL

Exclusion criteria:

  • Acute liver disease or elevated AST/ALT greater than two-fold the normal upper limit
  • Allergy or insensitivity to statin or ezetimibe
  • Solid-organ transplant
  • History of adverse reaction to a statin
  • Pregnant women
  • Life-expectancy <3 years

Other salient features/characteristics:

  • Previous MI: 40%
  • Prior percutaneous coronary intervention (PCI): 66%
  • Diabetes: 37%

Principal Findings:

The primary outcome, occurrence of cardiovascular death, major cardiovascular events, or nonfatal stroke within 3 years, for moderate-intensity statin + ezetimibe vs. high-intensity statin, was 9.1% vs. 9.9% (p = 0.43).

The secondary efficacy endpoint, a composite of all-cause death, major cardiovascular event, or nonfatal stroke, was 9.8% vs. 10.4% (p = 0.94).

Secondary outcomes for moderate-intensity statin + ezetimibe vs. high-intensity statin:

  • All-cause death: 1.4% vs. 1.2% (p = 0.56)
  • Major cardiovascular events: 8.1% vs. 8.9% (p = 0.41)
  • Cardiovascular death: 0.4% vs. 0.3% (p = 0.59)

Proportion of patients with LDL cholesterol <70 mg/dL at 3 years, for moderate-intensity statin + ezetimibe vs. high-intensity statin, was 72% vs. 58% (p < 0.001).

Discontinuation or dose reduction due to adverse effects, for moderate-intensity statin + ezetimibe vs. high-intensity statin, was 4.8% vs. 8.2% (p < 0.001).

Subgroup analysis of diabetes mellitus cohort (n = 1,398; 37% of total patients), for moderate-intensity statin + ezetimibe vs. high-intensity statin monotherapy:

  • Primary outcome (cardiovascular death, major cardiovascular events, or nonfatal stroke within 3 years): 10.0% vs. 11.3% (p = 0.46)
  • LDL cholesterol <70 mg/dL at 3 years: 79.9% vs. 66.8% (p < 0.001)
  • Discontinuation or dose reduction due to adverse effects: 5.2% vs. 8.7% (p = 0.014)

Interpretation:

The results of this trial show that, among patients with ASCVD, treatment with a moderate-intensity statin and ezetimibe was noninferior to treatment with high-intensity statin with respect to the composite of cardiovascular death, major cardiovascular events, or nonfatal stroke at 3 years. Results were preserved in the diabetes mellitus cohort subgroup analysis. This study shows that a drug combination strategy can be utilized to achieve reductions in LDL cholesterol. Importantly, patients with moderate-intensity statin and ezetimibe had lower rates of drug discontinuation or dose reduction than patients receiving high-intensity statin. However, the study is limited by its open-labeled design, which may have impacted reporting of patient-adverse effects. It also included East Asian patients only. The long follow-up time (3 years), as compared to other trials of lower-intensity statin and ezetimibe versus a higher-intensity statin, and assessment of clinical outcomes provides evidence for possible adoption of this strategy to achieve LDL reductions among patients with ASCVD.

References:

Lee YJ, Cho JY, You SC, et al. Moderate-intensity statin with ezetimibe vs. high-intensity statin in patients with diabetes and atherosclerotic cardiovascular disease in the RACING trial. Eur Heart J 2023;44:972-83.

Editorial: Stone NJ. RACING to judgement: weighing the value of pre-specified subgroup analyses. Eur Heart J 2023;44:984-5.

Kim BK, Hong SJ, Lee YJ, et al., on behalf of the RACING Investigators. 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;400:380-90.

Editorial Comment: Abushamat LA, Ballantyne CM. Lowering LDL cholesterol in clinical practice: time for change? Lancet 2022;400:341-3.

Clinical Topics: Acute Coronary Syndromes, Cardiac Surgery, Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Aortic Surgery, Cardiac Surgery and Arrhythmias, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and ACS, Interventions and Vascular Medicine

Keywords: Acute Coronary Syndrome, Atherosclerosis, Cardiovascular Diseases, Cholesterol, LDL, Diabetes Mellitus, Drug Combinations, Dyslipidemias, Ezetimibe, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Ischemic Stroke, Lipids, Metabolic Syndrome, Myocardial Infarction, Myocardial Revascularization, Percutaneous Coronary Intervention, Peripheral Arterial Disease, Primary Prevention, Rosuvastatin Calcium, Stroke, Vascular Diseases


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