Anthony B. Davies

Combined therapy with verapamil and propranolol in chronic stable angina

The comparative efficacy of verapamil (360 mg daily) and propranolol (240 mg daily) was evaluated with computerized treadmill exercise in 22 patients with chronic stable angina in a placebo-controlled double-blind crossover study with 4 weeks on each active phase. Fourteen of these patients still had angina despite active drug therapy and they were further treated with a combination of verapamil (360 mg) and propranolol (120 mg) for 4 weeks. The mean exercise time for these patients taking placebo was 4.8 +/- 0.22 minutes (mean +/- standard error of the mean) and this increased to 6.8 +/- 0.64 minutes with propranolol and 8.0 +/- 0.5 minutes with verapamil. A further increase to 10.1 +/- 0.88 minutes was observed with the combination of both drugs and seven patients became symptom-free. S-T segment criteria improved with both drugs, and combination therapy produced a further reduction in peak S-T depression. Electrocardiographic ambulatory monitoring showed no evidence of conduction defects and mean hourly heart rates were similar to those seen with propranolol alone. Left ventricular function indexes were not significantly different from those obtained with propranolol. Combination therapy with verapamil and propranolol appears to be efficacious in the treatment of selected patients with severe chronic stable angina. The patients need to be carefully monitored for adverse effects.

Randomized double-blind comparison of verapamil and nifedipine in chronic stable angina

A randomized double-blind crossover trial was performed in 32 patients with chronic stable angina to compare the antianginal actions of verapamil (120 mg 3 times daily) and nifedipine (20 mg 3 times daily). Efficacy was assessed using objective end points obtained by computer-assisted exercise testing and 24 hour ambulatory monitoring for S-T segment shift. Twenty-eight patients completed the trial. The mean exercise time to produce angina improved from 5.7 +/- 0.3 minutes (mean +/- standard error of the mean) in patients on placebo, to 7.9 +/- 0.5 minutes in those on nifedipine and 10.0 +/- 0.7 minutes in those on verapamil. Similar improvement was seen in all other objective variables. Generally verapamil produced mild bradycardia and nifedipine mild tachycardia. Four patients complained of palpitations and angina after ingestion of nifedipine and were identified by ambulatory monitoring to have tachycardia and persistent S-T depression. These opposite effects on heart rate may explain the differences in efficacy between these 2 potent calcium ion antagonists.

Rationale for the choice of calcium antagonists in chronic stable angina

The effectiveness and safety of verapamil, nifedipine, and placebo in patients with chronic stable angina pectoris were evaluated and compared in two double-blind randomized crossover trials. In the first study, nifedipine (10 mg 3 times daily) was compared with placebo in 24 patients with chronic effort-related angina pectoris; no significant differences in exercise performance were observed with nifedipine compared with placebo. In the second study, the effects of verapamil (120 mg 3 times daily), nifedipine (20 mg 3 times daily), and placebo were compared in 32 patients with chronic stable angina using a double-blind crossover study design. Compared with placebo, both nifedipine and verapamil prolonged exercise duration (5.7 +/- 0.3 minutes with placebo, 7.9 +/- 0.5 minutes with nifedipine [p less than 0.001], and 10.0 +/- 0.7 minutes with verapamil [p less than 0.001]), but the improvement with verapamil was greater than that seen with nifedipine (p less than 0.01). Seven patients had increasing angina with nifedipine, none did with verapamil; the exacerbation of angina during nifedipine therapy appeared related to our observation that, compared with placebo, patients receiving nifedipine had higher heart rates, while patients receiving verapamil had slower heart rates. This study indicates that, at the doses used, verapamil was more effective and better tolerated than nifedipine in patients with chronic stable angina pectoris.

Long-term antianginal action of verapamil assessed with quantitated serial treadmill stress testing

The long-term efficacy of verapamil in a dose of 360 mg daily in patients with chronic stable angina pectoris was assessed by quantitated serial treadmill exercise tests. Twenty-eight patients were investigated with a placebo-controlled, double-blind, crossover protocol of 2 weeks each and afterward all patients were put on long-term therapy. Exercise tests were performed at the end of the placebo period and after 2, 4, 8, 16, 24 and 52 weeks of verapamil therapy. All 28 experienced angina during treadmill tests on placebo and the mean (+/- standard error of the mean) exercise time was 6.6 +/- 0.5 minutes. This increased to 9.2 +/- 0.8 minutes at 2 weeks and 50 11.2 +/- 0.8 minutes at 4 weeks. Fifteen and 20 of the 28 patients became angina-free during treadmill exercise at 2 and 4 weeks, respectively. The consumption of nitroglycerin showed a similar improvement. The improvement was maintained at 1 year of follow-up. The on-line computer-analyzed S-T segment changes showed a statistically significant improvement at all follow-up periods. Withdrawal of verapamil produced a return to pretreatment levels. The adverse effects noted were constipation in seven patients and reversible P-R interval prolongation in two. No heart failure occurred in any patient. These findings suggest that verapamil possesses a powerful and sustained antianginal action and, in a dose of 360 mg daily, merits a place as a primary therapeutic agent in the management of chronic stable angina.

Circadian rhythm of blood pressure in patients dependent on ventricular demand pacemakers.

The reported circadian rhythm of blood pressure variability with a rise in pressure before awakening has been the subject of controversy. Previous studies have suggested that since heart rate continues to fall before awakening while blood pressure is rising these physiological variables are subject to different control mechanisms. To evaluate further the dissociation of heart rate and blood pressure changes in a group of patients with a fixed heart rate, 11 patients who were dependent on ventricular demand pacemakers underwent intra-arterial ambulatory blood pressure monitoring. Nine aged matched control subjects followed the same protocol. Circadian curves plotted from pooled hourly mean data showed that despite a fixed heart rate the circadian pattern persisted, although attenuated, with blood pressure rising several hours before its rapid rise on awakening. Physiological testing showed that despite a fixed heart rate systolic blood pressure rose in response to bicycle exercise, there was a postural fall in the blood pressure on tilting and a modified Valsalva response. There was considerable beat to beat variability resulting presumably from asychronous pacing. Hour to hour changes did not contribute to the differences between the two groups and were not responsible for attenuation of the circadian rhythm. It is concluded that blood pressure and heart rate control mechanisms may be dissociated, particularly in the period before awakening.

Changes of Q wave amplitude during exercise for the prediction of coronary artery disease

We have examined the changes of Q wave amplitude during exercise in 156 patients with chest pain with a view to improving the accuracy of stress testing for the diagnosis of coronary artery disease. Coronary arteriography showed significant disease in 127 patients and normal arteries or minimal disease in 29. The Q wave amplitude was measured in lead CM5 from the computer-derived average of 25 consecutive beats immediately before and at the peak of maximal treadmill exercise. The amplitude was greater in the normal subjects at rest and increased with exercise, but the reverse occurred in those with coronary disease. Using the criterion of decrease or no change of Q wave amplitude during exercise as indicating a positive test, the discriminative capacity of Q wave changes was equivalent to that of ST segment depression and was maintained when patients with myocardial infarction were excluded. Using either an abnormal Q wave or ST segment response to exercise improved the tests sensitivity with a loss of specificity but no change of predictive value. In 42% of patients with coronary disease when both the Q wave and ST segment exercise responses were abnormal coronary disease was predicted with an accuracy of 91%. Analysis of subgroups of patients with coronary artery disease suggested a possible explanation for the observed changes in Q wave amplitude, measurement of which can improve the stress tests accuracy for predicting obstructive coronary artery disease.

Double-blind randomized crossover trial of verapamil and propranolol in chronic stable angina

Propranolol (240 mg daily) and verapamil (360 mg daily) were objectively compared for their respective efficacy in the treatment of chronic stable angina pectoris. Twenty-two patients were studied in a randomized placebo controlled, double-blind crossover trial with 4 weeks on each active drug treatment. Multistage treadmill exercise with computer-assisted ECG analysis was performed after 2 weeks on placebo and at the end of each 4-week active drug treatment. The mean exercise time to produce angina was 5.5 minutes (SEM +/- 0.4 minutes) on placebo and this increased to 7.8 (+/- 0.5) minutes on propranolol and 9.1 (+/- 0.5) minutes on verapamil. The improvement in exercise time of verapamil over propranolol was statistically significant (p less than 0.01). Ten patients became free of angina with verapamil and four with propranolol. Resting and maximal exercise heart rates were significantly reduced by propranolol; verapamil did not reduce the maximal heart rate but reduced the resting heart rate slightly. However, the heart rate increase per minute of exercise was significantly diminished (p less than 0.001). ST segment changes showed improvement with both drugs despite marked differences in heart rate profile. The overall efficacy of the slow calcium channel blocker, verapamil, compares favorably with that of a standard beta-adrenoreceptor blocking drug (propranolol), thus providing a new perspective in the management of angina pectoris. These two classes of drugs seem to act by different mechanisms and it is suggested that if patients are resistant or intolerant to one of these drugs, the other can be used to yield a beneficial response.

Multiple unipolar lead electrocardiographic monitoring during exercise in severe coronary artery disease: a comparison with bipolar lead monitoring

A system of 21-lead electrocardiography was used to assess 21 patients with severe angina during and after exercise using on-line computerised ST segment analysis. A direct comparison was made between the results obtained from 18 unipolar precordial leads and those from bipolar leads CM5 and CC5. Treadmill exercise was performed 48 hr prior to cardiac catheterization, which revealed luminal narrowing of at least 70% in one or more major coronary arteries in all cases. In all cases the ST depression exceeded 1 mm in both CM5 and CC5 at the peak of exercise. The magnitude of ST depression was greater in the bipolar leads in 75% of cases and in the remaining 25% the greatest peak ST depression occurred in a single unipolar lead. There was no correlation between the magnitude of ST depression and the number of coronary vessels involved. Isopotential surface mapping in the anterior, lateral and inferior projections from the unipolar leads at each stage of exercise failed to show a correlation between the area or distribution of ST segment change and the number or anatomical location of the vessels involved. It was not possible to show that the multiple-lead system could differentiate the site and severity of coronary artery disease in these patients with angina. The multiple-lead system was cumbersome and time-consuming in application and therefore cannot be recommended for routine exercise testing.

Alpha-adrenoreceptor blockade with indoramin in hypertension.

We have evaluated the effects of indoramin, an alpha-adrenoreceptor blocking drug, used as sole therapy in a group of 27 patients with essential hypertension. Blood pressure and heart rate were measured continuously over prolonged ambulatory periods using an established invasive technique before and after six weeks of therapy. The protocol was randomised, double-blind, and with double-dummy placebo control. A standardised programme of physiological stress testing was also performed during each study. Placebo produced no appreciable change in the levels or patterns of blood pressure over 24-h periods, but indoramin produced a significant reduction, which was particularly marked during the night. Physiological testing did not reveal any postural hypotension, and the response to dynamic and isometric exercise was modified in level but not in degree of change. There were many unwanted effects, which may limit the clinical value of this drug.

Simultaneous recording of arterial blood pressure, heart rate and ST segment in the ambulant patient: a new system

A system developed for the accurate and simultaneous recording of blood pressure, heart rate and ST segment level in the unrestricted patient is described, with laboratory validation and experience of its clinical use. The recording system uses a brachial artery cannula, a transducer/perfusion unit and a miniature f.m.e.c.g. tape recorder (Oxford Medilog Mark II), one channel of which is modified to enable the recording of a blood pressure signal. Data are initially presented as analogue trend charts, with further detailed analysis being carried out by an automated digital system with interactive software enabling data editing and averaging. Laboratory evaluation demonstrated that the modified blood pressure channel had a satisfactory frequency response, linearity, signal-tonoise ratio, and temperature stability. Battery depletion produced a consistent increase in gain which could be compensated by repeated calibration throughout the period of recording. The system has been found to be reliable when used for recording periods of up to 24 h on patients with ischaemic heart disease.