Biomedical subjects
Publications and source records attributed to J S Alpert.
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Permanent therapy with oral anticoagulants offers the most consistent protection in patients with mechanical heart valves. Antiplatelet agents alone do not consistently protect patients with mechanical prosthetic heart valves, including patients in sinus rhythm with St. Jude valves in the aortic position. Levels of oral anticoagulants that prolong the INR to 2.0 to 3.0 appear satisfactory for patients with bileaflet mechanical valves in the aortic position, provided they are in sinus rhythm and the left atrium is not enlarged. Oral anticoagulant levels that prolong the INR to 2.5 to 3.2 are satisfactory for patients with bileaflet mechanical aortic valves and atrial fibrillation. Oral anticoagulant levels that prolong the INR to 2.5 to 3.5 are satisfactory for tilting disk valves and bileaflet prosthetic valves in the mitral position. Experience is sparse in patients with caged ball valves who had prothrombin time ratios reported in terms of INR. It has been suggested that the most advantageous INR level in patients with caged ball or caged disk valves should be as high as 4.0 to 4.9. However, others have shown a high rate of major hemorrhage with an INR that is even somewhat lower (3.0 to 4.5). The problem is self-limited, however, because few such valves are being inserted. Aspirin, in addition to oral anticoagulants, in patients with mechanical heart valves has been shown to diminish the frequency of thromboemboli. The risk of bleeding may not be increased if the INR is low. A low rate of both thromboemboli and bleeding has been shown with an INR of 2.5 to 3.5 in combination with aspirin at a dose of 100 mg/d. There are no investigations in which an aspirin dose of 81 mg/d in combination with oral anticoagulants was evaluated. Dipyripdamole may be effective in reducing the rate of thromboemboli without increasing the rate of bleeding, but data are insufficient to recommend dipyridamole over low doses of aspirin. Patients with bioprosthetic valves in the mitral position, as well as patients with bioprosthetic valves in the aortic position, may be at risk for thromboemboli during the first 3 months after surgery. Among patients during the first 3 months after surgery with bioprosthetic valves in the mitral position, oral anticoagulants administered at an INR of 2.0 to 2.3 were as effective as at an INR of 2.5 to 4.5: additionally, fewer bleeding complications were seen.
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Five placebo-controlled, double-blind, multicenter, parallel-design studies were performed to evaluate the antianginal and anti-ischemic characteristics of the novel T-channel-selective calcium antagonist, mibefradil, in the treatment of patients with chronic stable angina pectoris. Of the 5 studies, 2 were monotherapy dose-finding trials and 3 were conducted in patients receiving background antianginal therapy: either beta blockers (2 studies) or long-acting nitrates (1 study). A total of 865 patients were randomized to 1 of 4 mibefradil dose groups (25, 50, 100, and 150 mg; n = 565) and placebo (n = 300). The antianginal and anti-ischemic effects of mibefradil were assessed across all 5 studies by evaluating exercise tolerance test variables, weekly number of anginal attacks and short-acting nitroglycerin consumption, and in both dose-finding studies, the number and total duration of silent ischemic episodes (48-hour Holter monitoring). A statistically significant increase in exercise duration was achieved in 3 of 5 studies with the 50-mg dose of mibefradil and in 3 of 3 studies with the 100-mg dose of the compound over the effects observed in the placebo groups. A significant delay in time to onset of ischemia during exercise was induced in all studies with the 50- and 100-mg doses of mibefradil. The 25-mg dose of mibefradil was not significantly better than placebo, and the effects of the 150-mg dose of the compound were similar to those observed with the 100-mg dose. Across all studies, a dose-related decrease was observed in the number of weekly anginal attacks and in weekly nitroglycerin consumption. Similarly, a significant dose-related decrease in the number and duration of silent ischemic episodes was observed during Holter monitoring for 48 hours in the 2 dose-finding studies. The antianginal and anti-ischemic effects were associated with a dose-related decrease in heart rate and double product both at rest and at exercise termination. Treatment with the 50- and 100-mg doses of mibefradil was found to be well tolerated and safe compared with placebo, a finding that held true for patients on chronic beta-blocker or long-acting nitrate therapy. Taken together, these studies indicate that mibefradil is an effective and well-tolerated once-daily treatment for chronic stable angina pectoris at doses of 50 and 100 mg, which are the lowest and highest effective doses of the compound, respectively.
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This study assessed the safety, tolerability, and efficacy of mibefradil when added to beta-blocker monotherapy in patients with chronic stable angina pectoris. Two hundred five patients were randomized to receive double-blind treatment with either placebo (n = 70), mibefradil 25 mg (n = 67), or mibefradil 50 mg (n = 68) for 2 weeks. Exercise tolerance tests (ETTs) were performed at the end of the run-in (baseline) and double-blind treatment periods, and patients maintained an anginal diary. Compared with placebo, treatment with mibefradil 50 mg resulted in significant increases in exercise duration (36 +/- 51 seconds; p = 0.036), time to onset of angina (48 +/- 65 seconds; p = 0.002), and time to persistent 1-mm ST-segment depression (47 +/- 77 seconds; p = 0.004). Greater reductions in heart rate, blood pressure, and the rate-pressure product were more apparent at each stage of the ETT in the 50-mg mibefradil group than in the placebo group. Daily treatment with mibefradil 50 mg was associated with a significant decrease in the number of weekly anginal attacks (-2.1 +/- 4.0, p = 0.020) compared with placebo. The addition of mibefradil to existing beta-blocker therapy was well tolerated. Dizziness was the most frequently reported adverse event in the mibefradil 50-mg dose, and occurred with an incidence of 4.4%. The addition of mibefradil 50 mg, administered once daily, to patients on stable beta-blocker therapy produced additive antianginal and anti-ischemic effects and was well tolerated.