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.

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 (<30, 30-49, 50-69, and ≥70 mg/dL, respectively) as identified by LDL-C level at 1 month. QE indicates qualifying event (at time of admission); R, randomization. To convert LDL-C to millimoles per liter, multiply by 0.0259.

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.