Ezetimibe Plus Pitavastatin Fails to Lower Risk of CVD Events in ACS Patients: HIJ-PROPER

The addition of a cholesterol absorption inhibitor to statin therapy fails to reduce the risk of cardiovascular outcomes in patients with acute coronary syndrome and dyslipidemia, a new study shows.

Adding ezetimibe (Zetia, Merck/Schering-Plough) to pitavastatin (Livalo, Kowa Pharmaceuticals) reduced the absolute risk of the primary endpoint—a composite of all-cause mortality, nonfatal MI, nonfatal stroke, unstable angina, and coronary revascularization—by 4.1% compared with giving pitavastatin alone, but the reduction was not statistically significant (HR 0.89; 95% CI 0.76-1.04). 

The results of the study, known as HIJ-PROPER (Heart Institute of Japan—Proper Level of Lipid Lowering with Pitavastatin and Ezetimibe in Acute Coronary Syndrome), were presented yesterday at the European Society of Cardiology (ESC) Congress 2016 in Rome, Italy, by Nobuhisa Hagiwara, MD (Tokyo Women's Medical University, Japan).

For ESC spokesperson Heinz Drexel, MD (Academic Teaching Hospital Feldkirch, Austria), though, the lack of benefit is likely an issue of statistical power. In a similarly designed trial—IMPROVE-IT—the addition of ezetimibe to simvastatin 40 mg resulted in incremental lowering of LDL cholesterol and a small, but statistically significant, reduction in cardiovascular events. In contrast to HIJ-PROPER, which included 1,734 ACS patients with dyslipidemia, the 7-year IMPROVE-IT study included more than 18,100 patients with ACS. 

“IMPROVE-IT had to be prolonged and prolonged and prolonged,” said Drexel. “The time of exposure in that trial was very long. If you have two different branches of a very similar treatment, with the difference in LDL cholesterol observed in the [HIJ-PROPER] study and patients were followed for only 3 years, we couldn’t expect much more.” 

Brian Ference, MD (Wayne State University School of Medicine, Detroit, MI), said the 11% nonsignificant reduction in the primary endpoint is in line with what would be expected based on the 20 mg/dL difference in LDL cholesterol levels achieved with the two treatment therapies. “In some sense, these data are consistent with IMPROVE-IT,” Ference told TCTMD. “If you were to analyze these data in a meta-analysis with IMPROVE-IT, adjusted for the reduction in LDL cholesterol, they would have nearly identical point estimates.”

In December 2015, the US Food and Drug Administration voted against approving a claim that adding ezetimibe to statin therapy reduces the risk of cardiovascular events. The members of the FDA advisory committee felt the reduction in hard clinical events was not persuasive enough to grant the new indication, with most considering the benefit modest, if not weak. The advisory panel also noted the 6.4% reduction in the primary endpoint in IMPROVE-IT—which was the same used in HIJ-PROPER—was driven by reductions in the risk of MI and ischemic stroke, with no impact on all-cause mortality.  

Subgroup Stratified by Sitosterol Levels 

In HIJ-PROPER, for 869 patients treated with pitavastatin and ezetimibe, the treatment goal was an LDL cholesterol level less than 70 mg/dL. A target of 90 to 100 mg/dL was the goal for 865 patients treated with pitavastatin, a moderate-intensity statin primarily used in Japan. From a baseline LDL cholesterol level of approximately 135 mg/dL in both arms, those treated with combination therapy achieved an LDL level of 65.1 mg/dL while those treated with pitavastatin alone had an on-treatment LDL cholesterol level of 84.6 mg/dL (P < 0.001). 

After a mean follow-up of 3.9 years, the primary endpoint occurred in 36.9% of pitavastatin-treated patients and 32.8% of individuals treated with pitavastatin and ezetimibe.  

In a subgroup analysis of patients with higher baseline levels of sitosterol, which is a marker of cholesterol absorption, there was a significant 29% reduction in the risk of the primary endpoint among patients treated with pitavastatin and ezetimibe versus statin monotherapy. Among patients with lower baseline levels of sitosterol—those less than 2.2 µg/mL—there was no difference between the two treatment arms. 

Ezetimibe is a selective inhibitor of cholesterol absorption, blocking the NPC1L1 protein receptor and lowering the uptake of cholesterol in the gut. 

Commenting on the subgroup analysis, Hagiwara said sitosterol might “offer a potential therapeutic target for the treatment of dyslipidemia in ACS patients.” However, sitosterol is not a commonly measured marker in standard lipid panels and at the present time Japanese physicians are not measuring it in clinical practice. In Europe and the United States, it is also not measured commonly, although it can be ordered if necessary. 

HIJ-PROPER and IMPROVE-IT are in line with the ESC and European Atherosclerosis Society (EAS) guidelines for the treatment of dyslipidemia, which were published just days ago in the European Heart Journal to coincide with the start of ESC Congress 2016. The ESC/EAS guideline experts currently promote LDL cholesterol as the primary target for treatment and recommended treating patients at very high risk for cardiovascular events, including those with ACS, to an LDL cholesterol target of less than 70 mg/dL. 

In light of the HIJ-PROPER findings, “it is clear that the guidelines are fortified, not contradicted,” said Drexel. 

Source:

• Hagiwara N. Heart Institute of Japan: Proper level of lipid-lowering with pitavastatin and ezetimibe in acute coronary syndrome. Presented at: European Society of Cardiology Congress 2016. August 29, 2016, Rome Italy.

Disclosures:

• Hagiwara reports receiving honoraria from Nippon Boehringer Ingelheim and Bristol-Myers Squibb and research grants from Daiichi-Sankyo, Astellas Pharma, Takeda Pharmaceutical, Mitsubishi Tanabe Pharma, Shionogi & Co, Eisai Company, and Otsuka Pharmaceuticals.

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