Low-density lipoprotein cholesterol targeting with pitavastatin + ezetimibe for patients with acute coronary syndrome and dyslipidaemia: the HIJ-PROPER study, a prospective, open-label, randomized trial

Eur Heart J. 2017 Aug 1;38(29):2264-2276. doi: 10.1093/eurheartj/ehx162.


Aims: To elucidate the effects of intensive LDL-C lowering treatment with a standard dose of statin and ezetimibe in patients with dyslipidaemia and high risk of coronary events, targeting LDL-C less than 70 mg/dL (1.8 mmol/L), compared with standard LDL-C lowering lipid monotherapy targeting less than 100 mg/dL (2.6 mmol/L).

Methods and results: The HIJ-PROPER study is a prospective, randomized, open-label trial to assess whether intensive LDL-C lowering with standard-dose pitavastatin plus ezetimibe reduces cardiovascular events more than standard LDL-C lowering with pitavastatin monotherapy in patients with acute coronary syndrome (ACS) and dyslipidaemia. Patients were randomized to intensive lowering (target LDL-C < 70 mg/dL [1.8 mmol/L]; pitavastatin plus ezetimibe) or standard lowering (target LDL-C 90 mg/dL to 100 mg/dL [2.3-2.6 mmol/L]; pitavastatin monotherapy). The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, unstable angina, and ischaemia-driven revascularization. Between January 2010 and April 2013, 1734 patients were enroled at 19 hospitals in Japan. Patients were followed for at least 36 months. Median follow-up was 3.86 years. Mean follow-up LDL-C was 65.1 mg/dL (1.68 mmol/L) for pitavastatin plus ezetimibe and 84.6 mg/dL (2.19 mmol/L) for pitavastatin monotherapy. LDL-C lowering with statin plus ezetimibe did not reduce primary endpoint occurrence in comparison with standard statin monotherapy (283/864, 32.8% vs. 316/857, 36.9%; HR 0.89, 95% CI 0.76-1.04, P = 0.152). In, ACS patients with higher cholesterol absorption, represented by elevated pre-treatment sitosterol, was associated with significantly lower incidence of the primary endpoint in the statin plus ezetimibe group (HR 0.71, 95% CI 0.56-0.91).

Conclusion: Although intensive lowering with standard pitavastatin plus ezetimibe showed no more cardiovascular benefit than standard pitavastatin monotherapy in ACS patients with dyslipidaemia, statin plus ezetimibe may be more effective than statin monotherapy in patients with higher cholesterol absorption; further confirmation is needed.

Trial no: UMIN000002742, registered as an International Standard Randomized Controlled Trial.

Keywords: Acute coronary syndrome; Clinical trial; Combination therapy; Ezetimibe; Lipid-lowering; Pitavastatin.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Acute Coronary Syndrome / complications
  • Acute Coronary Syndrome / drug therapy*
  • Acute Coronary Syndrome / mortality
  • Aged
  • Angina, Unstable / drug therapy
  • Angina, Unstable / mortality
  • Anticholesteremic Agents / administration & dosage*
  • Anticholesteremic Agents / adverse effects
  • Cholesterol, LDL / drug effects
  • Cholesterol, LDL / metabolism
  • Dose-Response Relationship, Drug
  • Drug Therapy, Combination
  • Dyslipidemias / complications
  • Dyslipidemias / drug therapy*
  • Dyslipidemias / mortality
  • Ezetimibe / administration & dosage*
  • Ezetimibe / adverse effects
  • Female
  • Follow-Up Studies
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / adverse effects
  • Kaplan-Meier Estimate
  • Male
  • Non-ST Elevated Myocardial Infarction / complications
  • Non-ST Elevated Myocardial Infarction / drug therapy
  • Non-ST Elevated Myocardial Infarction / mortality
  • Prospective Studies
  • Quinolines / administration & dosage*
  • Quinolines / adverse effects
  • ST Elevation Myocardial Infarction / complications
  • ST Elevation Myocardial Infarction / drug therapy
  • ST Elevation Myocardial Infarction / mortality
  • Treatment Outcome


  • Anticholesteremic Agents
  • Cholesterol, LDL
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Quinolines
  • Ezetimibe
  • pitavastatin