Coronary artery disease
Impact of Adding Ezetimibe to Statin to Achieve Low-Density Lipoprotein Cholesterol Goal (from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation [COURAGE] Trial)

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In the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) study, a revascularization strategy trial with optimal medical therapy in both arms, the low-density lipoprotein (LDL) cholesterol goal was 60 to 85 mg/dl; this was revised to <70 mg/dl in 2004. COURAGE patients (n = 2,287) were titrated with increasing statin doses to achieve the initial LDL cholesterol goal using a prespecified protocol. Ezetimibe was not available when study enrollment began in 1999 but became available after approval in 2003. After maximizing statin dose, ezetimibe was added to reach the LDL cholesterol goal in 34% of patients (n = 734). Median baseline LDL cholesterol was higher in patients who received ezetimibe than in those who did not (109 vs 96 mg/dl). At baseline, 18% of patients who would later receive ezetimibe had LDL cholesterol <85 mg/dl, and 8% had LDL cholesterol <70 mg/dl. On maximum tolerated statin (with or without other lipid-lowering drugs), 40% had LDL cholesterol <85 mg/dl and 23% had LDL cholesterol <70 mg/dl before starting ezetimibe. At the final study visit, 68% of ezetimibe patients achieved LDL cholesterol <85 mg/dl, and 46% achieved LDL cholesterol <70 mg/dl. Using Cox regression analysis, the most significant factors associated with achieving LDL cholesterol goals were lower baseline LDL cholesterol, average statin dose, and ezetimibe use. In conclusion, after maximizing statin dose, the addition of ezetimibe results in a substantial increase in the percentage of patients who reach LDL cholesterol goal, a key component of optimal medical therapy.

Section snippets

Methods

The methods used in COURAGE (ClinicalTrials.gov identifier NCT00007657) have been reported previously.1, 2, 3 The study protocol was approved by the human rights committee at the coordinating center and by local institutional review boards. An independent data and safety monitoring board monitored the trial. Data management and analyses were performed solely by the data coordinating center and overseen by the trial's executive committee, which had full access to the data and analyses and

Results

Figure 1 shows patient flow during the trial. Patients who never took statins or ezetimibe before or during the trial tended to be older, were less likely to smoke, and had lower diastolic blood pressures (Table 1). In addition, those patients who were not prescribed ezetimibe during the trial had lower median LDL cholesterol at baseline.

Table 2 lists baseline and on-trial lipid and lipoprotein values and frequency of lipid medication use during the trial. Values for the 2 treatment groups were

Discussion

After titrating statin therapy to the maximum tolerated dose, the addition of ezetimibe was a highly effective strategy to get patients to LDL cholesterol goal. The addition of ezetimibe increased the percentage of those who achieved the 60 to 85 mg/dl goal from 40% to 72% and increased the percentage of those who achieved the <70 mg/dl goal from 23% to 53%. This observation is in contrast with LDL cholesterol goal attainment in patients with coronary disease in real-world practice, in which

Acknowledgment

We wish to thank Joanne E Tomassini, PhD, of Merck Sharp & Dohme Corporation for editorial assistance and creating figures for this report.

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      The rosuvastatin + ezetimibe combination in the doses that were used in this study also allowed more patients to reach LDL-C level targets. Several studies have demonstrated that the addition of ezetimibe to treatment with statins provides important synergistic decrease in LDL­C concentrations.22–32 In a previous study that included participants with coronary heart disease or type 2 diabetes, the addition of ezetimibe 10 mg to run-in therapy with simvastatin 20 mg proved to be a more effective strategy than doubling the simvastatin dose to 40 mg/d, resulting in more intense reduction of LDL-C, total cholesterol, and total cholesterol to HDL-C ratio, as well as significantly increasing the likelihood of achieving LDL-C levels <100 mg/dL, regardless of the level of LDL-C at the beginning of treatment.33

    • Combination therapy in dyslipidemia: Where are we now?

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    • Prevalence of dyslipidaemia in patients treated with lipid-lowering agents in China: Results of the DYSlipidemia International Study (DYSIS)

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    This work was supported by the Cooperative Studies Program of the US Department of Veterans Affairs Office of Research and Development (Veterans Affairs Cooperative Studies Program No. 424), Washington, District of Columbia, in collaboration with the Canadian Institutes of Health Research, Ottawa, Ontario, Canada, and by unrestricted research grants from Merck Sharp & Dohme Corporation, Whitehouse Station, New Jersey; Pfizer, Inc., New York, New York; Bristol-Myers Squibb, New York, New York; Fujisawa, Tokyo, Japan; Kos Pharmaceuticals, Cranbury, New Jersey; Datascope, Fairfield, New Jersey; AstraZeneca, Wilmington, Delaware; Key Pharmaceutical, Summit, New Jersey; Sanofi-Aventis, Paris, France; First Horizon, Alpharetta, Georgia; and GE Healthcare, Milwaukee, Wisconsin. All industrial funding in support of the trial was directed through the Department of Veterans Affairs.

    See page 1562 for disclosure information.

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