Medication Discontinuation in the IMPROVE-IT Trial

Abstract

Background: Although cholesterol-lowering medications can reduce the risk of recurrent cardiovascular events, premature discontinuation limits effectiveness. Discontinuation rates have not been systematically reported for lipid-lowering trials.

Methods and results: We evaluated medication discontinuation in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), which evaluated placebo+simvastatin versus ezetimibe+simvastatin in patients hospitalized with the acute coronary syndrome and followed longitudinally postdischarge. Reasons for discontinuation were evaluated from randomization through study end (median 71.9 [interquartile range 51.8-85.8] months). Kaplan-Meier (KM) discontinuation rates were evaluated at 30 days, 1 year, and through year 7, and compared by treatment arm and region, with Cox proportional hazards modeling used to evaluate predictors of discontinuation. Overall, 46.7% of subjects discontinued study medication (KM rate by study end 50.9% [95% CI, 50.1%-51.7%]). The risk of discontinuation was highest early in the trial but decreased with increasing time, with a terminal KM rate per 100 person-years of 8.4 (8.2-8.6) from years 1 to 7. Discontinuation was higher in the placebo+simvastatin versus ezetimibe+simvastatin arm (KM rate 52.0% versus 49.8%, P=0.049) and was highest in the United States (7-year KM rate 57.4%). In multivariable modeling, smoking, prior revascularization, hypertension, unstable angina, female sex, nonwhite race, and US location were associated with higher discontinuation rates.

Conclusions: Although discontinuation was highest early and stabilized to 8% per year, because of prolonged follow-up, most discontinuation occurred after year 1. Adding ezetimibe to statin therapy did not increase discontinuation risk. Geographic differences and patient-level factors should be considered in trial design and analysis.

Clinical trial registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00202878.

Keywords: acute coronary syndrome; cholesterol; ezetimibe; medication adherence; statin.

Figures

Figure 1

a. Discontinuation by treatment arm. A. Discontinuation by treatment arm, through year 7. Kaplan-Meier curves for treatment discontinuation by treatment arm from time of treatment initiation through year 7 of follow-up. The curves cross at approximately 1 year, showing higher discontinuation in the Ez/S arm in year 1 and lower discontinuation in years 2–7. B, Discontinuation by treatment arm, first year. This figure shows the Kaplan-Meier curves for treatment discontinuation by treatment arm from time of treatment initiation for the first 12 months of follow-up. P/S = placebo + simvastatin, and Ez/S = ezetimibe + simvastatin.

Figure 1

a. Discontinuation by treatment arm. A. Discontinuation by treatment arm, through year 7. Kaplan-Meier curves for treatment discontinuation by treatment arm from time of treatment initiation through year 7 of follow-up. The curves cross at approximately 1 year, showing higher discontinuation in the Ez/S arm in year 1 and lower discontinuation in years 2–7. B, Discontinuation by treatment arm, first year. This figure shows the Kaplan-Meier curves for treatment discontinuation by treatment arm from time of treatment initiation for the first 12 months of follow-up. P/S = placebo + simvastatin, and Ez/S = ezetimibe + simvastatin.

Figure 2.

Medication discontinuation over time and external events related to ezetimibe and simvastatin. This figure shows crude discontinuation rates by month from June 2006 through the end of the trial. ENHANCE results with no impact of ezetimibe on carotid intima-media thickness (CIMT) were published in April 2008, with results announced Jan 2008. ARBITER 6-HALTS results showing niacin superior to ezetimibe on CIMT were published in Jan 2009. SEAS possible ezetimibe/cancer link published in Sept 2008, with results announced July 2008. FDA safety communication about high-dose simvastatin released in March 2010.

Figure 3:

Discontinuation by qualifying event type. This figure shows the Kaplan-Meier curves for treatment discontinuation by qualifying event type through year 7 of follow-up. STEMI, ST-segment elevation myocardial infarction; NSTEMI, non-ST-segment elevation myocardial infarction.

Figure 4:

Discontinuation by region. The figure shows the Kaplan-Meier estimates for medication discontinuation from time of treatment initiation through year 7 of follow-up by region. US: United States, CAN: Canada, WE: Western Europe, EE: Eastern Europe, SA: South America, AUS/NZ: Australia/New Zealand.