Moderate-intensity statin plus ezetimibe as an alternative to high-intensity statin in ASCVD patients ≥75 years

Combination Moderate-Intensity Statin and Ezetimibe Therapy for Elderly Patients With Atherosclerosis

Literature - Lee SH, Lee YJ, Heo JH, et al. - J Am Coll Cardiol. 2023 Apr 11;81(14):1339-1349. doi: 10.1016/j.jacc.2023.02.007

Background

While high-intensity statin therapy is recommended for patients with ASCVD [1-2], this is less likely to be used in elderly patients because of the increased risk of adverse events. In patients >75 years of age, moderate-intensity statins may therefore be preferable to high-intensity statins [2-3].

Recently, the RACING (Randomized Comparison of Efficacy and Safety of Lipid Lowering With Statin Monotherapy versus Statin-Ezetimibe Combination for High-Risk Cardiovascular Disease) trial showed that combination therapy consisting of a moderate-intensity statin plus ezetimibe was as effective as monotherapy with a high-intensity statin in preventing a composite of CV events and was associated with a lower rate of intolerance-related drug discontinuation or dose reduction [4].

Aim of the study

In a post-hoc analysis of the RACING trial, the authors evaluated the efficacy and safety of moderate-intensity statin with ezetimibe combination therapy compared with high-intensity statin monotherapy in elderly ASCVD patients, especially those aged ≥75 years.

Methods

The RACING trial was a multicenter, prospective, open-label, noninferiority RCT in which 3780 patients with documented ASCVD from South Korea were included. Patients were randomized to combination therapy with a moderate-intensity statin (rosuvastatin 10 mg) plus ezetimibe 10 mg once daily or high-intensity statin monotherapy (rosuvastatin 20 mg) once daily. 574 patients were ≥75 years and 3206 patients were <75 years.

Outcomes

The primary endpoint was a composite outcome of CV death, major CV events, or nonfatal stroke within 3 years. Secondary efficacy endpoints were a composite outcome of all-cause mortality, major CV events, or nonfatal stroke; individual components of the primary endpoint; and LDL-c levels at 1, 2, and 3 years.

Secondary safety endpoints included rates of discontinuation or dose reduction of the study drug caused by intolerance; clinical adverse events including new-onset DM; adverse events associated with muscles, liver, or gallbladder; cancer diagnosis; or cataract surgery. An independent clinical endpoint committee adjudicated all endpoints.

Main results

Primary endpoint and secondary efficacy endpoints

  • Among patients aged ≥75 years, the incidence of the primary endpoint did not differ between the group receiving moderate-intensity statin-ezetimibe combination therapy and the group on high-intensity statin monotherapy (10.6% vs. 12.3%; HR: 0.87; 95%CI: 0.54–1.42; P=0.581). Similar results were seen in patients aged <75 years (8.8% vs. 9.4%; HR: 0.94; 95%CI: 0.74–1.18; P=0.570) (P for interaction=0.797).
  • There was also no difference in the rate of the secondary composite efficacy endpoint between the ezetimibe combination therapy group and monotherapy group among patients aged ≥75 years (13.6% vs. 12.6%; HR: 1.08; 95%CI: 0.69–1.70; P=0.730) and those <75 years of age (9.2% vs. 10.0%; HR: 0.91; 95%CI: 0.73–1.14; P=0.428) (P for interaction=0.508).
  • In addition, the rates of all-cause mortality, CV death, major CV events, or nonfatal stroke did not differ between the treatment groups, nor was there a significant interaction between age and treatment strategy for these endpoints.
  • In the group aged ≥75 years, median LDL-c levels were consistently lower in patients in the ezetimibe combination therapy group than in the monotherapy group at 1 year (59 vs. 63 mg/dL; P=0.004), 2 years (58 vs. 62 mg/dL; P=0.013), and 3 years (57 vs. 64 mg/dL; P=0.036). Similar results were observed in the group aged <75 years.

Secondary safety endpoints

  • Ezetimibe combination therapy was associated with a lower rate of intolerance-related drug discontinuation or dose reduction among both patients aged ≥75 years (2.3% vs. 7.2%; P=0.010) and those aged <75 years (5.2% vs. 8.4%; P<0.001) (P for interaction=0.159).
  • The rate of new-onset DM was lower in the ezetimibe combination therapy group compared with the monotherapy group among patients aged ≥75 years (10.0% vs 18.7%; P=0.025) but did not differ among those aged <75 years (12.8% vs. 12.9%; P=0.938) (P for interaction=0.041).
  • The rates of the other secondary safety endpoints did not differ between the treatment groups, regardless of age.

Conclusion

In a post-hoc analysis of the RACING trial, combination therapy with a moderate-intensity statin plus ezetimibe showed similar CV benefits over 3 years as high-intensity statin monotherapy in elderly ASCVD patients, regardless of age group (<75 years vs. ≥75 years). Ezetimibe combination therapy was associated with a larger LDL-c reduction and lower intolerance-related drug discontinuation or dose reduction in the entire study population, and with a reduced rate of new-onset DM in patients aged ≥75 years.

References

1. Catapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J. 2016;37:2999–3058.

2. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;73:e285–e350.

3. Nanna MG, Navar AM, Wang TY, et al. Statin use and adverse effects among adults >75 years of age: insights from the Patient and Provider Assessment of Lipid Management (PALM) registry. J Am Heart Assoc. 2018;7:e008546.

4. Kim BK, Hong SJ, Lee YJ, 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;400:380–390.

Find this article online at - J Am Coll Cardiol.

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