Addition of felodipine to metoprolol vs. replacement of metoprolol by felodipine in patients with angina pectoris despite adequate beta-blockade - FEMINA
FEMINA was a multicenter, randomized, parallel, double-blind, controlled trial to evaluate addition of felodipine to metoprolol or the replacement of metoprolol with felodipine in patients with stable angina despite optimal beta blockade.
The addition of the calcium channel blocker, felodipine, to optimal beta blockade would improve symptoms in patients with angina.
Patients Enrolled: 356
Mean Follow Up: Five weeks
Mean Patient Age: 18 to 75
Men and women ages 18-75 with typical angina complaints. All patients had to be treated with metoprolol controlled release 100 or 200 mg daily for at least four weeks prior to entering the study. The response to beta blockade had to be adequate (hazard ratio <65) and no contraindications to beta blockade could be present. Myocardial ischemia despite beta blockade had to be confirmed with exercise testing with at least 1 mm horizontal or downsloping change of ST segments (80 ms after J point) within 80% of the maximal predicted workload.
A difference in total exercise duration of more than 15% between two consecutive tests separated in time by 1-7 days; angina at rest or unstable angina; anginal attacks that were progressively more frequent, longer lasting, or difficult to relieve; concomitant anti-anginal therapy other than beta-blockers or short-acting nitrates; type II or III AV block; myocardial infarction, CABG, angioplasty, or stroke in the past three months, overt congestive heart failure, hypotension (systolic blood pressure <100 mm Hg); severe renal, hepatic, or hematological disorders; known intolerance to dihydropyridines; any drug known to influence the ST segment; documented left ventricular hypertrophy on echo with typical ECG changes; left bundle branch block; suspected alcohol or drug abuse; pregnancy or women of childbearing age without oral contraceptives; women during lactation; or participation in other studies
Total exercise time, time to chest pain, and time to 1 mm ST depression during exercise testing results at five weeks; occurrence of chest pain during exercise testing; and adverse events
Amount of ST depression at highest comparable workload, amount of maximal ST depression, and rate pressure product during exercise testing at five weeks
Patients were randomized to one of three arms: continuation of metoprolol ER alone (control group, 200 mg or 100 mg daily), dual therapy with metoprolol ER plus felodipine ER (10 mg daily), or replacement of metoprolol with felodipine alone. The patients were followed for five weeks. Bicycle exercise testing was performed at the end of week two and week five.
Aspirin (84% control vs. 89% dual therapy vs. 84% felodipine alone). Medical treatment for hypercholesterolemia (specific drugs not reported, 35% control vs. 30% dual therapy vs. 35% felodipine alone). Long acting nitrates were not allowed.
The three groups were well matched at baseline in terms of age, percent female, resting blood pressure and heart rate, and medical history. Compared to the control arm (metoprolol alone), there was no change in total exercise time or time to chest pain for either the dual therapy group or the felodipine alone group at five weeks.
The dual therapy arm had a significant improvement in time to 1 mm ST depression, amount of ST depression at highest comparable workload, amount of maximal ST depression, and resting rate pressure product compared to the control group at five weeks. The felodipine alone arm had a significant worsening of resting and maximal rate pressure product compared to the control arm at five weeks.
Among patients in the dual therapy arm with chest pain during exercise at baseline (51 patients), 50% had no chest pain during exercise at the end of five weeks (p<0.05 vs. control group). For the felodipine alone arm, this occurred in 33% of patients with chest pain at baseline (p=0.3 vs. control arm, which had improvement in 24% of patients from baseline). Adverse events were more common in the felodipine alone arm (50 patients) versus the dual therapy arm (28 patients) or the control arm (19 patients). Most of the adverse events in the felodipine arm were related to vasodilation (edema, headaches, flushing, and palpitations).
Among patients with stable angina despite optimal beta blockade, the addition of felodipine to metoprolol was associated with significant improvement in time to ST-segment depression during exercise testing and occurrence of symptoms during exercise, but was not associated with changes in total exercise time or time to chest pain. Replacement of metoprolol with felodipine in these patients was associated with comparable exercise results, an increase in resting and exercise rate pressure products, and an increase in adverse events.
Dunselman P, Liem A, Verdel G, Kragten H, Bosma A, Bernik P. Addition of felodipine to metoprolol vs replacement of metoprolol by felodipine in patients with angina pectoris despite adequate beta-blockade. Results of the Felodipine ER and Metoprolol CR in Angina (FEMINA) Study. Working Group on Cardiovascular Research, The Netherlands (WCN). Eur Heart J 1997;18:1755-64.
Keywords: Depression, Felodipine, Myocardial Ischemia, Vasodilation, Angina, Stable, Coronary Disease, Blood Pressure, Edema, Heart Rate, Headache, Calcium Channel Blockers, Workload, Metoprolol, Exercise Test
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