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IMPROVE-IT: Intensive lipid-lowering therapy confers long-term safety, efficacy
At 6 years, patients who achieved very low LDL levels after 1 month of lipid-lowering therapy had a similar safety profile and the lowest rate of CV events compared with those who achieved higher LDL levels, according to new data from the IMPROVE-IT trial.
In previous analysis, IMPROVE-IT demonstrated that the combination of ezetimibe (Zetia, Merck) and simvastatin (Zocor, Merck) lowered LDL to a median level of 54 mg/dL and improved CV outcomes in patients with a recent ACS.
“These clinical benefits were achieved without an excess in adverse safety events,” Robert P. Giugliano, MD, SM, cardiovascular medicine specialist at Brigham and Women’s Hospital and a senior investigator at the Thrombolysis in Myocardial Infarction Study Group, and colleagues wrote in JAMA Cardiology. “However, there are concerns that lowering cholesterol to very low levels may be disadvantageous because cholesterol has a central role in hepatic bile production, is a main component of cell membranes and intracellular structures, and serves as a precursor in the biosynthesis of some vitamins, steroids and sex hormones.”
Study design
IMPROVE-IT was a randomized, double blind trial of patients (n = 18,144) who had LDL 125 mg/dL if not already on statin therapy, or 100 mg/dL if already on statin therapy. Patients were enrolled in the trial within 10 days of hospitalization for ACS. Median follow-up was 6 years.
The present analysis included participants without an adverse event in the first month (n = 15,281; 76.2% men; median age, 63 years). Individuals were then grouped based on LDL levels at 1 month, regardless of treatment: 6.4% had LDL < 30 mg/dL, 31% had LDL 30 mg/dL to 49 mg/dL, 36% had LDL 50 mg/dL to 69 mg/dL and 26% had LDL > 70 mg/dL.
Primary safety endpoints included abnormal elevations of liver enzyme and creatine kinase levels, myopathy, rhabdomyolysis, adverse hepatobiliary events, cancer, adverse events leading to study drug discontinuation, HF hospitalization and non-CV death. The primary efficacy endpoint was a composite of CV death, MI, unstable angina requiring hospitalization, coronary revascularization after 30 days and stroke.
Safety, efficacy results
Patients with LDL < 30 mg/dL were more likely to have lower LDL baseline values, and to be older, male, nonwhite, diabetic, overweight, statin-naive and presenting with a first MI.
The proportion of patients randomly assigned to the combination therapy arm were 85%, 72%, 44% and 22%, respectively, across the four LDL groups from lowest to highest. Continuation of the drug was significantly lower in the group with LDL 70 mg/dL, but consistent across the remaining three groups.
During follow-up, there were adverse events in 8.9% of participants that led to discontinuation of the drug after 1 month, with no significant differences across the four groups (P for trend = .21). After multivariable adjustment, there was no difference in the safety endpoints between the groups.
After adjustment, the risk for the primary efficacy endpoint was significantly lower in patients with LDL < 30 mg/dL (adjusted HR = 0.79; 95% CI, 0.69-0.91) compared with LDL 70 mg/dL, according to the researchers.
“Because ezetimibe was given to 85% of the patients who achieved the lowest LDL category of less than 30 mg/dL at 1 month, the present findings add to the totality of the evidence supporting a favorable safety profile of this agent when combined with statin as compared with statin alone,” the researchers wrote. “Several important negative findings are worthy of mention, including the lack of association between low LDL level and cancer, hemorrhagic stroke and non-CV death after multivariate adjustment. Each of these adverse had been reported in excess in unadjusted observational analyses of patients with low LDL.” – by Cassie Homer
Disclosure: The study was funded by Merck. Giugliano reports receiving grants from Amgen and Merck and honoraria from the American College of Cardiology, Amgen, Bristol-Myers Squibb, CVS Caremark, Daiichi Sankyo, GlaxoSmithKline, Merck, Pfizer and Sanofi. Please see the full study for a list of the other researchers’ relevant financial disclosures.