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.


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


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.


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

Clinical Topics: Acute Coronary Syndromes, Cardiac Surgery, Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Prevention, ACS and Cardiac Biomarkers, Aortic Surgery, Cardiac Surgery and Arrhythmias, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and ACS, Interventions and Coronary Artery Disease

Keywords: Acute Coronary Syndrome, AHA Annual Scientific Sessions, Angina, Unstable, Aspirin, Cholesterol, LDL, Cholesterol, HDL, Coronary Artery Bypass, Coronary Artery Disease, Coronary Stenosis, C-Reactive Protein, Diabetes Mellitus, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipids, Metabolic Syndrome X, Myocardial Infarction, Myocardial Ischemia, Myocardial Revascularization, Percutaneous Coronary Intervention, Primary Prevention, Stroke, AHA17

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