Lancet_RACING

Jihee Han

2023-09-08

Introduction

Background

  • high-intensity statin -> intensive lowering of LDL cholesterol concentration
  • drug combination show greater efficacy and lower risks than increasing doses of one drug
    • Ezetimibe: inhibits cholesterol absorption and increases clearance of cholesterol from the blood

Introduction

Obejctive

  • to compare 3-year clinical efficacy and safety of moderate-intensity statin with ezetimibe combination therapy versus high-intensity statin monotherapy in patients who are at very high risk for cardiovascular diseases

Methods

Study Design

  • Prospective, Multicenter, Randomized, Open-label study
CombinationGroup MonoGroup
therapy rosuvastatin 10mg + ezetimibe 10mg rosuvastatin 20mg
  • endpoint: 3-year
  • in the ITT population with NI margin of 2.0%

Methods

Participants

  • Participants: patients with ASCVD requiring achievement of LDL-C concentrations of less than 70mg/dL
    • revious myocardial infarction (MI), acute coronary syndrome, history of coronary revascularisation or other arterial revascularisation procedures, ischaemic stroke, or peripheral artery disease (PAD)

Methods

Procedures

  • Procedures: maintenance of the initial dose was strongly recommended

Methods

Outcomes

  • Primary endpoint:the occurrence of cardiovascular death, major cardiovascular events, or non-fatal stroke within 3 years
  • Secondary endpoint: clinical efficacy and safety
    • Efficacy endpoint: proportion of participants whose LDL-C concentration are reduced to less than 70mg/dL at 1, 2, and 3-years
    • Safety endpoint: discontinuation or dose reduction of study medication caused by intolerance and the occurrence of clinical adverse events

Methods

Sample Size

  • Primary objective: 1605 patients were required for each group considering a 5% one-side alpha error rate and 80% power
  • Secondary objective: 220 patients were required for each group considering a 5% two-sided alpha error rate and 80% power

Methods

Statistical Analysis

  1. Kaplan-Merier method: time-to-event analysis
  2. Log-rank test: event rates btw two groups
  3. Cox proportional hazard regression model: HRs with 95% CI
  • NI for the primary endpoint: upper CI for the difference in the incidence of the primary endpoint btw two groups was less than 2.0% = NI declared
  • log-rank tests for the secondary endpoint
primary sensitivity safety
ITT population O X X
PP population X O O

Results

Base

  • baseline characteristics: not statistically different
  • 95.8% of total completed a 3-year follow up
  • other cardiovascular medication: not statistically different

Results

Primary endpoint

Results

Primary endpoint

  • post-hoc analysis
    • upper limit of one-sided 97.5% CI of the diff was 1.13%: met the NI margin(02.69 to 1.13)

Results

Primary endpoint

  • sensitivity analysis
    • primary endpoint occured in 9.1% of combi group, 9.4% of mono group
    • post-hoc upper limit of one-sided 97.5% CI of the diff in primary endpoiont was 1.69%: met NI margin of 2.0%(95% CI: -2.28 to 1.69)

Results

Secondary endpoints

Results

Secondary endpoints

  • post-hoc analysis: LDL-C concentration of less than 55mf/dL
year_1 year_2 year_3
combi group 42% 45% 42%
mono gorup 25% 29% 25%

Results

Secondary endpoints

  • discontinuation or dose reduction: 4.8% in combination group and 8.2% in monotherapy group

Results

Subgroup analysis

Discussion

Conclusion

  1. patients with ASCVD - combination therapy was NI to monotherapy for the 3-year
  2. NI was achieved with (1) a higher proportion of LDL-C concentration of less than 70mg/dL and (2) a lower prevalence of discontinuation or dose reduction caused by intolerance to the study drug
  • patients with high risk cardiovascular diseases - combination therapy also achieve greater efficacy and lower risks
  • addition of ezetimibe expected to reduce the risk of adverse effects
  • dyslipidaemia guidelines - (1) less than 55mg/dL (2) at least 50% from baseline

Discussion

Importance

  1. reduced statin does
  2. Long-term and Large num of patients - in previous studies: 24 weeks, 891 patients
  3. Clinical primary endpoint

Discussion

Limitation

  1. Open-label study -> necebo effect
  2. Lower than anticipated event rates -> NI margin of 2.0% allowed for a more generous CI
  3. Small num of events -> comparison of the individual clinical outcomes of the primary endpoint might be difficult