Evaluation of Nifedipine and Cerivastatin On Recovery of coronary Endothelial function - ENCORE I

Description:

The goal of ENCORE I was to evaluate the effects of a statin and/or a calcium antagonist on coronary endothelial function in patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI).

Study Design

Study Design:

Patients Screened: 368
Patients Enrolled: 343
Mean Follow Up: 6 months

Patient Populations:

Age >18 years, LDL cholesterol <180 mg/dL, and a left coronary artery segment with <=40% stenosis

Exclusions:

Q wave MI within 2 weeks; stroke, peripheral revascularization or major surgery within 3 months; unstable angina unless stabilized by intervention, unstable diabetes, symptomatic hypotension, or uncontrolled hypertension; left ventricular ejection fraction <40%; creatinine 2X upper limit of normal (ULN); CPK 3X ULN, amylase 1.5X ULN, transaminases 2X ULN, history of liver or gastrointestinal diseases; and lipid-lowering or calcium channel blocker treatment for >2 months.

Primary Endpoints:

Effect of treatment compared with placebo on acetylcholine-induced coronary vascular response at the highest dose of acetylcholine applied both at baseline and at follow-up.

Secondary Endpoints:

Change in mean coronary lumen diameter of the index segment in patients not undergoing ACE inhibitor therapy; change in mean coronary lumen diameter of all evaluable segments.

Drug/Procedures Used:

After PCI, all patients received intracoronary adenosine (1.2 mg/mL) and nitroglycerin (250 ug). Patients were then randomized to nifedipine 30 mg/d increased to 60 mg/d (n=84), cerivastatin 0.4 mg/d (n=85), and their combination (n=89) or placebo (n=85). Follow-up angiography was performed at 6 months.

Concomitant Medications:

Intracoronary adenosine (1.2 mg/mL) and nitroglycerin (250 ug)

Principal Findings:

The change from baseline of mean luminal diameter at the highest comparable dose of acetylcholine in the most constricted segment averaged 10.0+/-3.0% with placebo, 18.8+/-3.0% with nifedipine (p=0.04), 11.1+/-3.0% with cerivastatin (p=NS), and 12.9+/-3.3% with combination treatment (p=NS). Complete coronary occlusion (diameter <=0.2 mm) occurred at any of the 3 doses of acetylcholine in 6.5% of patients with placebo (vs 8.1% at baseline), 0% with nifedipine (vs 10.5% at baseline), 6.6% with cerivastatin (vs 14.8% at baseline), and 5.7% with combination treatment (unchanged from baseline).

Analysis of all evaluable coronary segments (~3 segments per patient) showed changes from baseline of acetylcholine-induced vasoconstriction of 5.8+/-1.6% for placebo, 9.6+/-1.8% for nifedipine therapy (p=NS), 9.1+/-1.8% for cerivastatin therapy (p=NS) and 10.4+/-1.8% for combination therapy (p=0.05 vs placebo).

Patients not taking angiotensin converting enzyme (ACE) inhibitors showed a smaller improvement in most constricted segment in the placebo group compared with those taking ACE inhibitors (6.0+/-3.6% vs 21.2+/-8.0%, p=0.11). When patients taking ACE inhibitors were excluded from the analysis (n=49), nifedipine remained associated with an improved acetylcholine-induced vasoconstriction compared with placebo (17.0+/-3.6%, p=0.0278). Cerivastatin lowered LDL cholesterol by 35% (p<0.001).

Interpretation:

Among patients with CAD undergoing PCI, treatment with nifedipine but not cerivastatin improved coronary endothelial function in the most constricted segment at 6-month follow-up as demonstrated by reduced vasoconstriction to acetylcholine. Combination therapy with nifedipine and cerivastatin tended to be associated with improved coronary endothelial function in the most constricted segment but only reached significance in a secondary analysis of all coronary segments. A significant interaction with ACE inhibitors was observed in the trial and may warrant further investigation.

In August 2001, cerivastatin was withdrawn from the market in due to possible cases of rhabdomyolysis with fatal outcome. As a result, the ENCORE I study analyzed muscle enzymes carefully. Two patients were withdrawn due to experiencing elevated liver enzymes, and 2 patients experienced a 10-fold increase in creatinine phosphokinase (CPK). The ENCORE II study is currently underway and is designed to detect the effects of nifedipine on coronary morphology.

References:

Circulation. 2003;107:422-428.

Clinical Topics: Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Heart Failure and Cardiac Biomarkers, Interventions and Coronary Artery Disease

Keywords: Coronary Artery Disease, Vasodilation, Cholesterol, LDL, Pyridines, Creatinine, Constriction, Pathologic, Vasoconstriction, Nifedipine, Calcium Channel Blockers, Peptidyl-Dipeptidase A, Percutaneous Coronary Intervention, Rhabdomyolysis, Fatal Outcome, Liver, Coronary Occlusion, Nitroglycerin


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