In five controlled studies in normal healthy subjects, the same daily doses of metoprolol succinate extended-release and immediate release metoprolol were compared in terms of the extent and duration of beta 1-blockade produced. Both formulations were given in a dose range equivalent to 100 to 400 mg of immediate release metoprolol per day. In these studies, metoprolol succinate extended-release was administered once a day and immediate release metoprolol was administered once to four times a day. A sixth controlled study compared the beta 1-blocking effects of a 50 mg daily dose of the two formulations. In each study, beta 1-blockade was expressed as the percent change from baseline in exercise heart rate following standardized submaximal exercise tolerance tests at steady state. Metoprolol succinate extended-release administered once a day, and immediate release metoprolol administered once to four times a day, provided comparable total beta 1-blockade over 24 hours (area under the beta 1-blockade versus time curve) in the dose range 100 to 400 mg. At a dosage of 50 mg once daily, metoprolol succinate extended-release produced significantly higher total beta 1-blockade over 24 hours than immediate release metoprolol. For metoprolol succinate extended-release, the percent reduction in exercise heart rate was relatively stable throughout the entire dosage interval and the level of beta 1-blockade increased with increasing doses from 50 to 300 mg daily. The effects at peak/trough (i.e. at 24-hours post-dosing) were: 14/9, 16/10, 24/14, 27/22 and 27/20% reduction in exercise heart rate for doses of 50, 100, 200, 300 and 400 mg metoprolol succinate extended-release tablets once a day, respectively. In contrast to metoprolol succinate extended-release, immediate release metoprolol given at a dose of 50 to 100 mg once a day produced a significantly larger peak effect on exercise tachycardia, but the effect was not evident at 24 hours. To match the peak to trough ratio obtained with metoprolol succinate extended-release over the dosing range of 200 to 400 mg, a t.i.d. to q.i.d. divided dosing regimen was required for immediate release metoprolol. A controlled cross-over study in heart failure patients compared the plasma concentrations and beta 1-blocking effects of 50 mg immediate release metoprolol administered t.i.d., 100 mg and 200 mg metoprolol succinate extended-release once daily. A 50 mg dose of immediate release metoprolol t.i.d. produced a peak plasma level of metoprolol similar to the peak level observed with 200 mg of metoprolol succinate extended-release. A 200 mg dose of metoprolol succinate extended-release produced a larger effect on suppression of exercise-induced and Holter-monitored heart rate over 24 hours compared to 50 mg t.i.d. of immediate release metoprolol.
In a double-blind study, 1092 patients with mild-to-moderate hypertension were randomized to once daily metoprolol succinate extended-release tablets (25, 100, or 400 mg), PLENDIL ® (felodipine extended release tablets), the combination, or placebo. After 9 weeks, metoprolol succinate extended-release alone decreased sitting blood pressure by 6 to 8/4 to 7 mmHg (placebo-corrected change from baseline) at 24 hours post-dose. The combination of metoprolol succinate extended-release with PLENDIL has greater effects on blood pressure.
In controlled clinical studies, an immediate release dosage form of metoprolol was an effective antihypertensive agent when used alone or as concomitant therapy with thiazide-type diuretics at dosages of 100 to 450 mg daily. Metoprolol succinate extended-release, in dosages of 100 to 400 mg once daily, produces similar β 1-blockade as conventional metoprolol tablets administered two to four times daily. In addition, metoprolol succinate extended-release administered at a dose of 50 mg once daily lowered blood pressure 24-hours post-dosing in placebo-controlled studies. In controlled, comparative, clinical studies, immediate release metoprolol appeared comparable as an antihypertensive agent to propranolol, methyldopa, and thiazide-type diuretics, and affected both supine and standing blood pressure. Because of variable plasma levels attained with a given dose and lack of a consistent relationship of antihypertensive activity to drug plasma concentration, selection of proper dosage requires individual titration.
14.1 Angina Pectoris
By blocking catecholamine-induced increases in heart rate, in velocity and extent of myocardial contraction, and in blood pressure, metoprolol reduces the oxygen requirements of the heart at any given level of effort, thus making it useful in the long-term management of angina pectoris.
In controlled clinical trials, an immediate release formulation of metoprolol has been shown to be an effective antianginal agent, reducing the number of angina attacks and increasing exercise tolerance. The dosage used in these studies ranged from 100 to 400 mg daily. Metoprolol succinate extended-release tablets, in dosages of 100 to 400 mg once daily, has been shown to possess beta-blockade similar to conventional metoprolol tablets administered two to four times daily.
14.2 Heart Failure
MERIT-HF was a double-blind, placebo-controlled study of metoprolol succinate extended-release conducted in 14 countries including the U.S. It randomized 3991 patients (1990 to metoprolol succinate extended-release) with ejection fraction ≤0.40 and NYHA Class II to IV heart failure attributable to ischemia, hypertension, or cardiomyopathy. The protocol excluded patients with contraindications to beta-blocker use, those expected to undergo heart surgery, and those within 28 days of myocardial infarction or unstable angina. The primary endpoints of the trial were (1) all-cause mortality plus all-cause hospitalization (time to first event) and (2) all-cause mortality. Patients were stabilized on optimal concomitant therapy for heart failure, including diuretics, ACE inhibitors, cardiac glycosides, and nitrates. At randomization, 41% of patients were NYHA Class II; 55% NYHA Class III; 65% of patients had heart failure attributed to ischemic heart disease; 44% had a history of hypertension; 25% had diabetes mellitus; 48% had a history of myocardial infarction. Among patients in the trial, 90% were on diuretics, 89% were on ACE inhibitors, 64% were on digitalis, 27% were on a lipid-lowering agent, 37% were on an oral anticoagulant, and the mean ejection fraction was 0.28. The mean duration of follow-up was one year. At the end of the study, the mean daily dose of metoprolol succinate extended-release tablets was 159 mg.
The trial was terminated early for a statistically significant reduction in all-cause mortality (34%, nominal p= 0.00009). The risk of all-cause mortality plus all-cause hospitalization was reduced by 19% (p= 0.00012). The trial also showed improvements in heart failure-related mortality and heart failure-related hospitalizations, and NYHA functional class.
The table below shows the principal results for the overall study population. The figure below illustrates principal results for a wide variety of subgroup comparisons, including U.S. vs. non-U.S. populations (the latter of which was not pre-specified). The combined endpoints of all-cause mortality plus all-cause hospitalization and of mortality plus heart failure hospitalization showed consistent effects in the overall study population and the subgroups, including women and the U.S. population. However, in the U.S. subgroup (n=1071) and women (n=898), overall mortality and cardiovascular mortality appeared less affected. Analyses of female and U.S. patients were carried out because they each represented about 25% of the overall population. Nonetheless, subgroup analyses can be difficult to interpret and it is not known whether these represent true differences or chance effects.
Clinical Endpoints in the MERIT-HF Study