Research Article: Effectiveness of Ezetimibe in Reducing the Estimated Risk for Fatal Cardiovascular Events in Hypercholesterolaemic Patients with Inadequate Lipid Control While on Statin Monotherapy as Measured by the SCORE Model

Date Published: October 31, 2011

Publisher: SAGE-Hindawi Access to Research

Author(s): John S. Sampalis, Stéphane Bissonnette, Stella Boukas.


Objectives. The aim of this prospective cohort, multicentre study was to assess the effect of coadministrating ezetimibe 10 mg/day with an ongoing statin on the estimated risk for Cardiovascular (CVD) mortality in patients with persistently elevated LDL-C after statin monotherapy. Methods. The Systematic Coronary Risk Evaluation (SCORE) function was used to estimate the 10-year risk for cardiovascular mortality at baseline and 6 weeks. Primary outcome measures were absolute and percent changes in estimated Coronary Heart Disease (CHD) Mortality Risk, and general CVD Mortality Risk (Total CVD Mortality Risk). Results. 825 patients were included in the analysis. Mean (SD) age was 62 (10.5) years and 62.3% were males. The mean (SD) estimated Total CVD Mortality Risk decreased from 0.068 (0.059) at baseline to 0.053 (0.046) at 6 weeks (RR = 0.77; 95% CI:0.689–0.867), while the estimated CHD Mortality Risk decreased from 0.047 (0.040) at baseline to 0.034 (0.029) at 6 weeks (RR = 0.72; 95% CI:0.624–0.826). Conclusions. Co-administration of ezetimibe with a statin is effective in significantly reducing the estimated risk for cardiovascular mortality as measured by the SCORE model.

Partial Text

Cardiovascular disease is the major cause of mortality in Canada, accounting for one-third of all deaths, with an incidence expected to increase within the next decade [1]. Increased serum cholesterol, particularly low-density lipoprotein cholesterol (LDL-C), is directly associated with an increased risk for cardiovascular disease (CVD) [2–5]. Initiation of lipid-lowering pharmacologic intervention for the management of hypercholesterolaemia is generally dependent on the individual patient’s estimated risk for cardiovascular events [3, 6, 7]. Ultimately, the aim of lipid-lowering treatment is to effectively reduce the individual patient’s risk for CVD, thus decreasing related mortality, morbidity and burden of illness. A cardiovascular risk prediction model was developed by the SCORE (Systemic COronary Risk Evaluation) project group in accordance to the recommendations from the Second Joint Task Force of European and other Societies on Coronary Prevention [7]. The SCORE model is based on pooled data from 12 European cohort studies, including data on over 205,000 individuals and representing 2.7 million person-years of followup. The model predicts the individual’s 10-year risk for fatal cardiovascular events on the basis of age, gender, smoking status, systolic blood pressure (SBP), and total cholesterol (TC). The total SCORE risk is further subdivided into the risk for fatal CHD and other non-CHD cardiovascular death.

A total of 1,141 patients were screened between November 2003 and April 2005, among which 953 (83.5%) fulfilled the study inclusion criteria and were enrolled in the study. Of the 953 patients enrolled, 825 (86.6%) completed the six-week follow-up with sufficient data for SCORE risk estimation at baseline and at six weeks. There were 128 patients who discontinued from the study prior to the follow-up assessment and cannot be included in this analysis since change in the outcome parameters could not be computed. These included 50 (5.2%) patients who were lost to followup, 45 (4.7%) who were withdrawn by the study investigators because they changed or stopped their statin treatment, 19 (2.0%) who withdrew due to adverse events, 2 (0.2%) who withdrew consent prior to initiation of treatment, and 12 (1.3%) who were missing data for SCORE estimation.

An important proportion of patients with hypercholesterolaemia do not achieve target cholesterol levels with statin monotherapy [10–12]. In these patients, combination of ezetimibe with low-dose statin has been shown to be effective in improving the lipid profile, providing an additional 20% to 25% reduction in low density lipoprotein cholesterol (LDL-C) compared to statin monotherapy [9, 25], while potentially protecting from the risk of adverse events associated with high-dose statins through moderating the dose of co-administrated statin [20–22]. To date, the direct effect of ezetimibe co-administered with a statin on the risk of cardiovascular mortality from a population perspective has not been reported. The current study applied the SCORE model to estimate the change in 10-year risk for cardiovascular mortality in patients that had persistent elevated LDL-C while on statin monotherapy, upon co-administration of ezetimibe with their existing statin regimen. The SCORE cohort consists of 205,178 patients with more than 2.7 million person-years of followup and a total of 7,934 observed cardiovascular deaths (5,652 from coronary heart disease) [7]. The sample size, high number of events, and duration of followup of the cohort ensure high predictive validity of the model.

For patients who remain at increased risk for cardiovascular morbidity or mortality due to persistent hypercholesterolaemia while on statin monotherapy, co-administration of ezetimibe with a statin is effective in significantly reducing the estimated long-term risk for cardiovascular mortality. However, additional population studies to confirm the long-term effect of combination therapy with ezetimibe and statins on cardiovascular mortality are required.

JSS Medical research was hired by Merck & Co to conduct this study and perform the data analysis. S. Boukas and J. S. Sampalis are employees of JSS Medical Research Inc.; S. Bissonnette was an employee of Merck & Co during the analysis and writing the paper. This study was supported by Merck & Co and JSS Medical Research Inc.