THERAPY AND PREVENTION ANGINA Superiority of combined diltiazem and propranolol therapy for angina pectoris

Twenty-four patients with stable angina were evaluated in a 14 week crossover trial. A single-blind placebo period (baseline 1) was followed by two double-blind periods evaluating maximum tolerated doses of diltiazem (up to 360 mg daily) vs placebo. Over the next 1 to 4 weeks, propranolol was started and increased until clinically documented f-blockade was achieved (baseline 2). The final phase consisted of a pair of evaluation periods comparing propranolol plus the maximum tolerated dose of diltiazem to propranolol and placebo. The daily rate of angina attack was 1.6 during baseline, was unchanged during placebo therapy, but fell during treatment with diltiazem to 0.6 (p < .005). With the addition of diltiazem to propranolol, the angina rate was improved (0.3) compared with that with either propranolol alone (0.6) or propranolol and placebo (0.5) (p < .01). Total exercise duration during baseline 1 was 360 sec and increased to 497 sec with diltiazem, 481 sec with propranolol, and 527 sec with the combination of diltiazem and propranolol. Two patients with reduced ejection fractions developed congestive heart failure with propranolol. The combination of diltiazem and propranolol similarly resulted in congestive heart failure in one patient who had tolerated both drugs alone. Circulation 71, No. 5, 951-957, 1985. THE INTRODUCTION of the calcium-channel blockers provided an important addition to our armamentarium for the prophylactic treatment of stable exertional angina pectoris. Each of the three currently available drugs has been shown to be more effective than placebo.' Yet the therapy for many patients remains incomplete: a significant number of patients remain symptomatic despite treatment with either the calcium-channel blockers or "conventional" therapy, i.e., fl-blockers and the long-acting nitrates alone. Combination therapy has been used empirically in many patients, and several studies have objectively demonstrated the additional benefits of nifedipine4 or verapamil>7 added to propranolol. As has been well stressed,' the calcium-channel blockers have variable impact on coronary and peripheral vascular, myocardial, sinoatrial, and atrioventricular nodal tissues, and therefore may vary not only in their antianginal mechaFrom the Departments of Medicine, Cardiology Section, Veterans Administration Medical Center, West Roxbury, and Brigham and Women's Hospital and Harvard Medical School, Boston. Supported by the Medical Research Service of the U.S. Veterans Administration. Address for correspondence: William E. Strauss, M.D., Department of Cardiology, Veterans Administration Medical Center, 1400 V.F.W. Parkway, West Roxbury, MA 02132. Received Oct. 30, 1984; revision accepted Feb. 7, 1985. Vol. 71, No. 5, May 1985 nisms but potentially in their interactions when used in combination with fl-blockers. This study was designed to assess the efficacy and safety of diltiazem in a dose of 360 mg daily alone and in combination with propranolol. Twenty-four patients with chronic stable angina and unrestricted left ventricular function were evaluated in a randomized placebocontrolled, crossover protocol.