Reduction in Estimated Risk for Coronary Artery Disease After Use of Ezetimibe With a Statin

Sampalis JS, Bissonnette S, Habib R, Boukas S; Ezetrol Add-On Investigators. Ann Pharmacother. 2007;41:1345-1351.

Elevated serum cholesterol levels are associated with an increased risk of coronary artery disease (CAD). The first-line pharmacologic intervention to achieve management of hypercholesterolemia usually includes statin therapy, in conjunction with therapeutic lifestyle change. However, for many patients, statin monotherapy is not sufficient for reaching target levels of low-density lipoprotein cholesterol (LDL-C). The addition of ezetimibe for patients not achieving treatment goals with statins alone can provide a potential solution, as demonstrated by recent clinical trials that have shown such coadministrations are well tolerated, more effective in reducing LDL-C, and better for improving other lipid parameters than statin monotherapy.

The Framingham model can be used to calculate estimated 10-year risks for CAD (E-R_CAD). It has provided high accuracy for predicting risks of cardiovascular morbidity and mortality, thereby demonstrating its efficacy as a clinical decision-making tool for treatment with lipid-lowering medications. This cohort of the Ezetrol Add-On study utilized the Framingham model to assess the impact of ezetimibe coadministered with a statin on E-R_CAD.

This was a prospective, single-cohort, 6-week, open-label trial conducted in 221 offices of physicians selected from a stratified random sample of Canadian general practitioners and family physicians. Inclusion criteria for patients were ≥ 18 years of age; confirmed diagnosis of hypercholesterolemia and elevated plasma LDL-C levels ≥ 96.5 mg/dL among patients with high E-R_CAD, ≥ 135.1 mg/dL for patients at moderate risk, and ≥ 173.7 mg/dL for individuals at low risk; and stable diets and statin therapy ≥ 4 weeks prior to entry and for the duration of the study. Patients who had conditions or used medications that could either render them unable to complete the trial or cause significant health risks for them and patients who received treatment with any other investigational compounds within the preceding 30 days were excluded. During the initial 2 weeks of screening, blood was drawn for measurements of LDL-C, total cholesterol (TC), triglycerides, and high-density lipoprotein cholesterol (HDL-C). All eligible patients were treated with ezetimibe 10 mg per day along with unaltered doses of their current statins. Participants were instructed to maintain their current diet strategy, and approximately 6 weeks after baseline visits, the final study assessments and collection of blood samples were conducted.

The primary outcome measures of this analysis were absolute and percent changes in E-R_CAD from baseline to week 6 calculated with the Framingham model. The E-R_CAD calculation was based on sex-specific logistic regression models that predict 10-year probability of CAD as a function of the age of each patient and their TC, HDL-C, systolic blood pressure (BP), smoking status, presence of diabetes, and confirmed left ventricular hypertrophy. The E-R_CAD data obtained at baseline and week 6 were analyzed as continuous and ordinal categorical scales, with predefined cutoff points of ≤ 5.0%, 5.1% to 10.0%, 10.1% to 15.0%, 15.1% to 20.0%, and ≥ 20.1%. Data were also analyzed by the presence or absence of diabetes and metabolic syndrome.

Among the 1141 patients screened, 953 (83.5%) fulfilled the inclusion criteria and were enrolled in the study, and 825 (86.6%) of them completed the 6-week follow-up. Their mean ± SD age was 62 ± 10.5 years (range 21-89), and 62.3% were male. Prior to the study, 328 (39.8%) patients were treated with moderate or high doses of statin (defined as 40 to 80 mg/day, depending on the type of statin). Hypertension, the most frequently reported comorbidity, occurred among 423 (51.3%) patients, and 375 (45.5%) patients had CAD. Of the 342 (41.5%) patients with type 2 diabetes, 107 (31.3%) did not have metabolic syndrome. Among the 395 (47.9%) who had metabolic syndrome, 160 (40.5%) did not have comorbid diabetes. Although almost one-third of the patients had both diabetes and metabolic syndrome (n = 235, 28.5%), nearly 100 more of them had neither (n = 323, 39.2%). More than half (489; 59.3%) had a family history of cardiovascular disease.

During 6 weeks of treatment, TC (mean ± SD) decreased from 216 ± 38.6 to 169.9 ± 38.6 mg/dL, the TC/HDL-C ratio from 4.8 ± 1.3 to 3.8 ± 1.1, and LDL-C from 131.3 ± 34.7 mg/dL to 92.7 ± 34.7 mg/dL (all P < .001). There were also significant decreases in mean systolic BP, from 132.0 ± 14.0 to 128.2 ± 13.7 mm Hg (P < .001), and in HDL-C, from 47.1 ± 11.6 to 46.7 ± 11.6 mg/dL (P = .038). The mean absolute and mean percent E-R_CAD decreased significantly for all comorbidity subgroups (T2DM, metabolic syndrome, T2DM and metabolic syndrome, neither; P < .001). The greatest absolute and percent changes in E-R_CAD occurred among patients who had both diabetes and metabolic syndrome.

At the end of the study, the proportion of patients with E-R_CAD ≥ 20.1% decreased from 27.3% to 10.4%, and the proportion of patients with E-R_CAD of 15.1% to 20.0% decreased from 21.2% to 14.9%. Among the 782 participants with E-R_CAD ≥ 5.1% at baseline, 458 (58.6%) of them reached a lower E-R_CAD category by the end of the study. The greatest rate of conversion to a lower E-R_CAD category occurred among the 175 patients with baseline E-R_CAD of 15.1% to 20.0%, of whom 135 (77.1%) entered a lower category, while nearly two-thirds of the 225 in the highest E-R_CAD category at baseline converted to a lower one (n = 144, 64.0%). There were significant changes for all patient subgroups according to baseline E-R_CAD categories (P <. 001), with the greatest mean percent reduction occurring among those with the highest baseline E-R_CAD category of ≥ 20.1%.

This study demonstrated that patients with hyperlipidemia who have not reached LDL-C goals with statin monotherapy can reap benefits from coadministration of ezetimibe, including a reduction in 10-year risk of CAD. These results have substantial clinical implications for patients who have had difficulty reducing elevated cholesterol levels and are therefore at risk for development of disease-defining events and/or worsening of an existing condition. In addition, decreases in E-R_CAD occurred among patients with comorbid conditions that can significantly increase their risk of CAD, including diabetes and metabolic syndrome. This trial was designed to emulate "real-life" routine clinical settings in which patients often fail to reach treatment goals and are frequently changed to different therapies prior to receiving the maximum doses of statins. The results demonstrated that addition of ezetimibe to stain monotherapy can provide significant benefits, including reduced risk of CAD.