Long-term Safety and Efficacy of Achieving Very Low Levels of Low-Density Lipoprotein Cholesterol : A Prespecified Analysis of the IMPROVE-IT Trial

Abstract

Importance: In the Improved Reduction of Outcomes: Vytorin Efficacy International Trial, intensive low-density lipoprotein cholesterol (LDL-C)-reducing therapy with ezetimibe/simvastatin compared with simvastatin alone was associated with a significant reduction in cardiovascular events in 18 144 patients after acute coronary syndrome. The safety of very low LDL-C levels over the long-term is unknown.

Objective: To assess the safety and clinical efficacy of achieving a very low (<30 mg/dL) level of LDL-C at 1 month using data from the Improved Reduction of Outcomes: Vytorin Efficacy International Trial.

Design, setting, and participants: This prespecified analysis compared outcomes in patients stratified by achieved LDL-C level at 1 month in the Improved Reduction of Outcomes: Vytorin Efficacy International Trial and adjusted for baseline characteristics during 6 years' median follow-up. Patients were enrolled from October 26, 2005, to July 8, 2010, and the data analysis was conducted from December 2014 to February 2017.

Main outcomes and measures: Safety end points included adverse events leading to drug discontinuation; adverse muscle, hepatobiliary, and neurocognitive events; and hemorrhagic stroke, heart failure, cancer, and noncardiovascular death. Efficacy events were as specified in the overall trial.

Results: Among the 15 281 patients included in the study, 11 645 (76.2%) were men and the median age was 63 years (interquartile range, 56.6-70.7 years). In these patients without an event in the first month, the achieved LDL-C values at 1 month were less than 30 mg/dL, 30 to 49 mg/dL, 50 to 69 mg/dL, and 70 mg/dL or greater in 6.4%, 31%, 36%, and 26% of patients, respectively. Patients with LDL-C values less than 30 mg/dL (median, 25 mg/dL; interquartile range, 21-27 mg/dL) at 1 month were more likely randomized to ezetimibe/simvastatin (85%), had lower baseline LDL-C values, and were more likely older, male, nonwhite, diabetic, overweight, statin naive, and presenting with a first myocardial infarction. After multivariate adjustment, there was no significant association between the achieved LDL-C level and any of the 9 prespecified safety events. The adjusted risk of the primary efficacy composite of cardiovascular death, major coronary events, or stroke was significantly lower in patients achieving an LDL-C level less than 30 mg/dL at 1 month (adjusted hazard ratio, 0.79; 95% CI, 0.69-0.91; P = .001) compared with 70 mg/dL or greater.

Conclusions and relevance: Patients achieving an LDL-C level less than 30 mg/dL at 1 month had a similar safety profile (and numerically the lowest rate of cardiovascular events) over a 6-year period compared with patients achieving higher LDL-C concentrations. These data provide reassurance regarding the longer-term safety and efficacy of the continuation of intensive lipid-lowering therapy in very higher-risk patients resulting in very low LDL-C levels.

Trial registration: clinicaltrials.gov Identifier: NCT00202878.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Giugliano has received grant support from Amgen and Merck (to his institution) and honoraria from the American College of Cardiology, Amgen, Bristol-Myers Squibb, CVS Caremark, Daiichi Sankyo, GlaxoSmithKline, Merck, Pfizer, and Sanofi. Dr Wiviott has received grant support from Merck, Sanofi-Aventis, AstraZeneca, Bristol-Myers Squibb, Eisai, Arena, and Eli Lilly/Daiichi-Sankyo and honoraria from AstraZeneca, Bristol-Myers Squibb, Eisai, Arena, Eli Lilly/Daiichi-Sankyo, Sanofi-Aventis, Boehringer Ingelheim, Aegerion, Angelmed, Janssen, Xoma, ICON Clinical, and Boston Clinical Research Institute. Dr Blazing has served as an advisory board member for Merck and has provided consulting for AstraZeneca and Novartis. Dr de Ferrari has received grants and/or personal fees from Merck, Amgen, Boston Scientific, and Sigma Tau. Dr Park has received grant support from Merck. Ms Murphy has received grant support and honoraria from Merck. Dr Tershakovec is an employee and stockholder of Merck. Dr Cannon has received grants and/or personal fees from Accumetrics, Arisaph, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Janssen, Daiichi-Sankyo, Merck, Bristol-Myers Squibb, CSL Behring, Essentialis, Kowa, Takeda, Lipimedix, Pfizer, Regeneron, Sanofi, Alnylam, and Amgen. Dr Braunwald has received grant support from Merck (to his institution), Duke University, AstraZeneca, Novartis, Daiichi-Sankyo, and GlaxoSmithKline and honoraria from The Medicines Company, Medscape, Menarini International, and Theravance. He provided uncompensated consultancies and lectures for Novartis. No other disclosures were reported.

Figures

Figure 1.. Distribution of Achieved Calculated Low-Density Lipoprotein Cholesterol (LDL-C) Level at 1 Month Among Patients Who Did Not Have a Primary Efficacy or Prespecified Safety Event Prior to the Sample

The median LDL-C level was 56 mg/dL (interquartile range, 43-70 mg/dL). To convert LDL-C to millimoles per liter, multiply by 0.0259.

Figure 2.. Median Low-Density Lipoprotein Cholesterol (LDL-C) Level During the Trial Stratified by Achieved LDL-C Level at 1 Month

The time-weighted mean LDL-C concentrations after randomization were 34.4, 48.3, 63.3, and 79.9 mg/dL for the 4 groups (

Figure 3.. Safety Events by Achieved Low-Density Lipoprotein Cholesterol (LDL-C) Level at 1 Month

The adjusted risks are shown for prespecified safety events by the LDL-C level achieved at 1 month, with the group achieving the highest LDL-C level (≥70 mg/dL) as the referent. To convert LDL-C to millimoles per liter, multiply by 0.0259. ALT indicates alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; HR, hazard ratio; ULN, upper limit of normal.