Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy With Pitavastatin in Coronary Artery Disease - REAL-CAD

Contribution To Literature:

The REAL-CAD trial showed that high-dose pitavastatin 4 mg/day is superior to low-dose pitavastatin 1 mg/day in reducing adverse cardiovascular events among patients with established stable CAD.

Description:

The goal of the trial was to assess the safety and efficacy of high-dose compared with low-dose statin therapy among Japanese patients with stable coronary artery disease (CAD).

Study Design

Japanese patients with established stable CAD were randomized in a 1:1 fashion to either low-dose pitavastatin 1 mg/day (n = 6,528) or high-dose pitavastatin (n = 6,526). These doses are approximately comparable to 5 mg and 20 mg of atorvastatin, respectively. All patients underwent a run-in period with pitavastatin 1 mg/day for at least 1 month.

Inclusion criteria:

  • Men and women, 20-80 years of age
  • Stable CAD:
    • Acute coronary syndrome (ACS) or percutaneous coronary intervention/coronary artery bypass grafting >3 months
    • Clinical diagnosis of CAD with coronary stenosis ≥50% diameter stenosis
  • Low-density lipoprotein cholesterol (LDL-C) <120 mg/dl on pitavastatin 1 mg/day during the run-in period
  • Total number of enrollees: 13,054
  • Duration of follow-up: 3.9 years (median)
  • Mean patient age: 68 years
  • Percentage female: 17%
  • History of ACS: 72% (24% within 1 year of randomization)
  • Percentage on aspirin: 93%

Principal Findings:

The primary outcome, cardiovascular death, myocardial infarction (MI), ischemic stroke, unstable angina for high-dose vs. low-dose pitavastatin, was 4.3% vs. 5.4%, hazard ratio 0.81, 95% confidence interval 0.69-0.95, p = 0.01. Number needed to treat for 5 years = 63.

  • Cardiovascular death: 1.4% vs. 1.8%, p = 0.09
  • MI: 0.6% vs. 1.2%, p = 0.004
  • Ischemic stroke: 1.4% vs. 1.3%, p = 0.84

Secondary outcomes for high-dose vs. low-dose pitavastatin:

  • Primary endpoint + coronary revascularization: 7.9% vs. 9.7%, p = 0.002
  • All coronary revascularization: 8.5% vs. 10.1%, p = 0.008
  • LDL-C at 3 years: 76.6 vs. 91.0 mg/dl, p < 0.001
  • High-density lipoprotein cholesterol at 3 years: 52.3 vs. 51.7, p < 0.001
  • High-sensitivity C-reactive protein (hs-CRP) at 6 months: 0.49 vs. 0.59 mg/L, p < 0.001
  • Muscle complaints: 1.9% vs. 0.7%, p < 0.001
  • New-onset diabetes mellitus: 4.5% vs. 4.3%, p = 0.76

Interpretation:

The results of this trial indicate that high-dose pitavastatin 4 mg/day is superior to low-dose pitavastatin 1 mg/day in reducing adverse cardiovascular events among patients with established stable CAD. In addition to LDL-C lowering, there were also salutary effects on other lipoproteins and hs-CRP with high-dose pitavastatin. The higher dose seemed to be fairly well tolerated. These statin doses would technically count as moderate- versus low-intensity statin therapy based on current American College of Cardiology/American Heart Association statin guidelines (dose of atorvastatin ≥40 mg/day defined as high-dose). Results are directionally consistent with trials such as PROVE-IT, IDEAL, and TNT, which have resulted in a Class I indication for high-dose statin therapy among patients with established CAD.

References:

Presented by Dr. Takeshi Kimura at the American Heart Association Annual Scientific Sessions (AHA 2017), Anaheim, CA, November 13, 2017.


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