At the recent European Society of Cardiology (ESC) Congress in Rome Italy, the Japanese study HIJ-PROPER (Heart Institute of Japan-PRoper level of lipid lOwering with Pitavastatin and Ezetimibe in acute coRonary syndrome) reported results suggesting that dual therapy with pivastatin and ezetimibe does not reduce cardiovascular adverse events any better than statin monotherapy in patients with acute coronary syndrome (ACS) and dyslipidemia.1
The trial is important because several professional organizations have begun to endorse the “lower the better” concept when it comes to dyslipidemia. While an LDL goal of <100 mg/dL is generally recommended in patients at high risk for coronary heart disease (CHD), such as those with diabetes, even more stringent goals are recommended for certain other groups. For example, the Third Report of the National Cholesterol Education Program Adult Treatment Panel, recommends a target LDL of <70 mg/dL in patients at very high risk for CHD.2 The American Diabetes Association (ADA) and the American College of Cardiology (ACC), both recommend a target LDL of <70 mg/dL for patients with CHD.3
In 2013 the ACC/American Heart Association (AHA) proposed a new paradigm. They recommended high intensity statins for high risk patients (barring any safety concerns), and moderate intensity statins for primary prevention in lower risk patients (or in high risk patients who have safety concerns with high intensity statins). Many countries have subsequently adopted this approach.4
The problem is that achieving stricter goals in clinical practice is not always easy. Adverse events related to statins, such as rhabdomyolysis, are dose-dependent and may limit therapy. HIJ-PROPER was designed to evaluate whether dual therapy with pitavastin plus ezetimibe, which may allow for lower statin doses, could improve cardiovascular outcomes better than statin monotherapy. Pitavastatin is a high intensity statin, while ezetimibe selectively inhibits intestinal cholesterol absorption.
HIJ-PROPER, led by Nobuhisa Hagiwara, MD, PhD, FJCC, of Tokyo Women's Medical University, (Tokyo, Japan), was a prospective, randomized open-label trial conducted at 19 hospitals in Japan between January 2010 and April 2013. It included 1734 participants with ACS, LDL ≥100 mg/dL, and recent coronary angiography (mean age 65.5 years, 75.5% male, 83.3% statin-naïve). Researchers randomized participants to intensive LDL lowering (target LDL of <70 mg/dL) using pitavastatin (starting dose 2 mg/day) plus ezetimibe (starting dose 10 mg/day), or standard LDL lowering (target LDL 90–100 mg/dL)* using pitavastatin monotherapy (starting dose 2 mg/day). Over the course of the study, the pitavastatin dose could be adjusted by 1-4 mg/day to keep the LDL within the target range for each group.
The primary endpoint was assessed at 3, 6, 12, 24, and 36 months, and was a composite score of all-cause death, non-fatal myocardial infarction, non-fatal stroke, unstable angina, or revascularization with either percutaneous coronary intervention or coronary-artery bypass grafting. 6
Key results at three years1:
- Pitavastatin + ezetimibe: 32.8% reduction in adverse events
- Pitavastatin monotherapy: 36.9% reduction in adverse events
- No significant difference in the primary endpoint between dual therapy with pitavastatin + ezetimibe vs pitavastatin monotherapy (p=0.152)
The study concluded: “The addition of a second cholesterol-lowering drug to standard statin therapy to patients with acute coronary syndrome and dyslipidemia did not significantly improve the primary endpoint rates.”
- Professional organizations have begun endorsing the idea of the “lower the better” when it comes to dyslipidemia; but achieving stricter goals may be difficult in clinical practice
- The prospective, randomized open-label trial HIJ-Proper trial tested whether dual therapy with pivastatin plus exetimibe could decrease cardiovascular adverse events in patients with ACS and dyslipidemia vs pitavastatin alone.
- Three-year results were not significantly different for dual therapy vs statin monotherapy in decreasing a composite endpoint of all-cause death, non-fatal myocardial infarction, non-fatal stroke, unstable angina, or revascularization with either percutaneous coronary intervention or coronary-artery bypass grafting
*following recommendations of the Japanese Atherosclerosis Society [JAS]4)
The trial was funded by the Japan Research Promotion Society for Cardiovascular Diseases, sponsored by Pfizer Japan Inc., AstraZeneca K.K., Daiichi Sankyo Company, Limited, Novartis Pharma K.K., Bristol-Myers K.K., Kowa Pharmaceutical Co. Ltd., MSD K.K, Nippon Boehringer Ingelheim Co., Ltd., Sanofi K.K., Takeda Pharmaceutical Company Limited, Eli Lilly Japan K.K., Edwards Lifesciences Corporation, Medtronic, Inc., Boston Scientific Corporation, and Abbott Vascular Japan Co., Ltd. All members of the research group report research support from the Japan Research Promotion Society for Cardiovascular Diseases.
One or more authors report honorary and/or grants from one o rmore of the following: Abbott Vascular Japan Co., Ltd., Daiichi Sankyo Company, Limited, Nippon Boehringer Ingelheim Co., Ltd., Bristol-Myers K.K., Astellas Pharma Inc., Takeda Pharmaceutical Company Limited, Mitsubishi Tanabe Pharma Corporation, Shionogi & Co., Ltd., Eizai Co., Ltd., and/or Otsuka Pharmaceutical Co., Ltd.
1. Hagiwara N. The Heart Institute of Japan PRoper level of lipid lOwering with Pitavastatin and Ezetimibe in acute coronary syndrome (HIJ-PROPER). Presented at the European Society of Cardiology (ESC) Congress, Rome, Italy. August 2016. Accessed Sept 14 2016 at https://professional.heart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_487842.pdf
2. Grundy SM, Cleeman JI, Merz CN, et al for the Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Arterioscler Thromb Vasc Biol. 2004 Aug;24(8):e149-61.
3. Brunzell JD, M. Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care, 31 (2008), pp. 811–822
4. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol, 63 (2014), pp. 2889–2934
5. Teramoto T, Sasaki J, Ueshima H, et al. Executive summary of Japan Atherosclerosis Society (JAS) guideline for diagnosis and prevention of atherosclerotic cardiovascular diseases for Japanese. J Atheroscler Thromb, 14 (2007), pp. 45–50
6. Kawada-Watanabe E, Ogawa H, Koyanagi R, et al. Rationale, design features, and baseline characteristics: The Heart Institute of Japan-PRoper level of lipid lOwering with Pitavastatin and Ezetimibe in acute coRonary syndrome (HIJ-PROPER). J Cardiol. 2016 Jun 24. pii: S0914-5087(16)30083-1. doi: 10.1016/j.jjcc.2016.05.002.
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