Hemodynamic comparison of primary venous or arteriolar dilatation and the subsequent effect of furosemide in left ventricular failure after acute myocardial infarction

The hemodynamic effect of venous dilatation (intravenous isosorbide dinitrate [ISDN]) and arteriolar dilatation (intravenous hydralazine), both as firstline treatment and then combined with intravenous furosemide, were evaluated in a randomized, between-group comparison in 20 men with severe acute left-sided cardiac failure after myocardial infarction (MI). Both ISDN (50 to 200 micrograms/kg/hour) (Group 1) and hydralazine (0.15 mg/kg) (Group 2) reduced systemic arterial pressure (p less than 0.05) and vascular resistance (p less than 0.05). Pulmonary artery occluded pressure was reduced (p less than 0.01) only by ISDN, whereas heart rate (p less than 0.01), cardiac output (p less than 0.01) and stroke volume (p less than 0.05) were increased only after hydralazine. After ISDN, furosemide (1 mg/kg) decreased left-sided cardiac filling pressure by 1 mm Hg (p greater than 0.05), whereas after hydralazine, furosemide in a similar dose reduced pulmonary artery occluded pressure by 5 mm Hg (p less than 0.01). In both groups of patients, furosemide transiently increased systemic arterial pressure (p less than 0.05). Cardiac output was reduced (p less than 0.05) and systemic vascular resistance increased (p less than 0.05) in Group 1 patients after furosemide. Similar changes in both variables in Group 2 patients did not attain statistical significance. In conclusion, ISDN-induced venous dilatation is preferable to primary arteriolar dilatation by hydralazine as first-line treatment in acute left-sided cardiac failure. However, hydralazine and furosemide in combination were equally effective in reducing pulmonary artery occluded pressure and increasing cardiac output. The influences of each regimen on prognosis await further investigation.     

Rest and exercise hemodynamic effects of sequential alpha-1-adrenoceptor (trimazosin) and beta-adrenoceptor (propranolol) antagonism in essential hypertension

The efficacy of acute beta blockade in essential hypertension is limited by reflex vasoconstriction. The aim of this study was to determine whether the latter response was modified by prior selective alpha-1-adrenoceptor blockade. A single-blind, within-patient, placebo-controlled evaluation of the immediate hemodynamic effects of sequential alpha-1 (trimazosin)- and beta (propranolol)-adrenoceptor blockade was undertaken in 10 men (34 to 58 years) with previously untreated essential hypertension. The study commenced with a 4-minute control period of constant-load (600 to 900 kpm/min) upright bicycle exercise, and measurements were made before (control) and 30 minutes after intravenous trimazosin (2 mg/kg) and exercise was then repeated; measurements at rest were again made 4 minutes after intravenous propranolol (0.2 mg/kg) before a final exercise period. Trimazosin at rest reduced systolic and diastolic arterial pressure and systemic vascular resistance without change in heart rate, cardiac output, or left ventricular (LV) filling pressure. During upright bicycle exercise the reductions in blood pressure were sustained without change in their rest-to-exercise increments. Other circulatory variables did not differ from control values. At rest the addition of propranolol further reduced systolic arterial pressure. Heart rate and cardiac output fell and systemic vascular resistance increased to its pretreatment control value. During exercise the changes at rest were sustained and the rest-to-exercise increments in blood pressure, heart rate, and cardiac output were reduced. LV filling pressure was significantly increased. In conclusion, alpha-1-adrenoceptor blockade modified the adverse effects of acute beta blockade at rest but not during exercise.     

Hemodynamic trial of sequential treatment with diuretic, vasodilator, and positive inotropic drugs in left ventricular failure following acute myocardial infarction

The circulatory effects induced by two sequential intravenous treatment programs with a diuretic, arteriolar or venodilator , and a positive inotropic drug were studied in a randomized between-group trial in 20 male patients with radiographic and hemodynamic evidence of left ventricular (LV) failure following acute myocardial infarction (AMI). Furosemide induced a substantial diuresis in both groups of patients, in association with reductions in LV filling pressure (p less than 0.01) and cardiac output (p less than 0.05), without significant change in heart rate or systemic arterial pressure. The addition of isosorbide dinitrate was followed by reductions in the systemic arterial (p less than 0.01) and LV filling pressures (p less than 0.01) without significant change in the heart rate or cardiac output. Hydralazine after furosemide reduced systemic vascular resistance (p less than 0.01), but the fall in mean blood pressure (p less than 0.01) was limited by the increase in cardiac output (p less than 0.01); heart rate was also increased (p less than 0.01) and LV filling pressure fell (p less than 0.05). The final addition of the beta-1 adrenoceptor agonist, prenalterol, increased systemic arterial systolic pressure (p less than 0.05), cardiac output (p less than 0.05), and heart rate (p less than 0.01), and reduced systemic vascular resistance (p less than 0.01) in both groups; these changes were greatest in those pretreated with furosemide and isosorbide dinitrate. In both treatment pathways compared with control the reductions in systemic vascular resistance and left heart filling pressure were accompanied by increases in heart rate and cardiac output without substantial changes in systemic blood pressure. Which of these hemodynamic pathways offers the optimum prognosis awaits further study.     

Intrinsic sympathomimetic activity: Clinical fact or fiction?

The therapeutic importance of the ancillary pharmacologic property of partial agonist activity, or intrinsic Sympathomimetic activity (ISA), of a beta-adrenoceptor antagonist is controversial. Its pharmacologic definition and accepted physiologic potential are Now joined by convincing evidence that ISA may have important therapeutic implications. The ability to support basal cardiac functions while preventing the potential hazards of random sympathetic stimulation is an important attribute of this property, particularly in the damaged heart. The beneficial effects of ISA on peripheral blood flow, systemic vascular resistance and left ventricular afterload are established. Although all beta-blocking drugs are contraindicated in patients with asthma, ISA appears to be at least as important as cardioselectivity in offsetting some of the increase in airway resistance that results from beta blockade alone both at rest and during exertion. These pharmacodynamic consequences of ISA may explain the lesser reduction in exercise tolerance afforded by beta-blocking drugs with ISA than by those without. ISA may also enhance the primary oxygen-sparing effects of beta blockade in the ischemic myocardium by reducing coronary resistance, enhancing coronary blood flow, and reducing anaerobic metabolism. The adverse effects of beta-blocking drugs on blood lipids and carbohydrate metabolism also appear to be largely negated in drugs with ISA. The risks of rebound effects from abrupt withdrawal are significantly less in drugs with ISA than in those without.     

Comparison of haemodynamic dose-response effects of beta- and alpha-beta-blockade in acute myocardial infarction

The comparative haemodynamic dose-response effects of beta- (propranolol) or alpha- plus beta-blockade (labetalol) were evaluated in a randomised between-group study of 16 patients with an uncomplicated acute myocardial infarction. In equivalent beta-blocking doses both drugs equally reduced myocardial stroke work index and presumably myocardial oxygen requirements. However, although propranolol reduced heart rate and cardiac output, these haemodynamic changes were accompanied by an augmentation of systemic vascular resistance. In contrast, labetalol reduced heart rate, cardiac output without change in systemic vascular resistance. Moreover, concomitant alpha- and beta-blockade with labetalol resulted in lesser depression of cardiac output at equivalent beta-blocking doses to propranolol. These results suggest that the addition of alpha to beta-blockade may attenuate some of the adverse reflex circulatory consequences of pure beta-blockade; the usefulness of this pharmacological approach to the manipulation of the circulation in the early post-infarction period merits further study.     

Oxprenolol in the treatment of hypertension in the elderly

Controversy continues to surround the value of drug treatment of hypertension in the elderly. Epidemiologic evidence implicates hypertension as a major risk factor in the precocious development of stroke and coronary heart disease in the elderly subject as clearly as it is implicated in the younger person. The hemodynamic and neuroendocrine profiles of the older patient with essential hypertension are similar to those of younger patients in the stable phase of the disease. However, the arterial ravages induced by many years of sustained hypertension render the circulation of the elderly subject more sensitive to pharmacologic intervention. The benefit-risk ratio of most antihypertensive drugs appears to be inversely related to age. Diuretics reduce the blood pressure at rest but have no influence on the increases in systolic pressure during normal activity; in addition, they carry potentially serious metabolic hazards in the elderly hypertensive patient. Centrally acting drugs likewise lower the blood pressure at rest without influencing the high systolic pressures induced by exercise. They also enhance the tendency to endogenous depression. Adrenergic-neurone blocking drugs and alpha-adrenoceptor antagonists are contraindicated because of the frequency of impaired cardiovascular reflexes in the elderly. The beta-blocking drugs can reduce the risk of coronary and cerebrovascular disease in the older patient with hypertension. They appear to be well tolerated, but because of their impaired metabolic handling in many elderly patients they should probably be used in smaller doses than those prescribed in younger patients. The influence of antihypertensive treatment on cardiovascular morbidity and mortality in the elderly hypertensive patient is not known.     

Pharmacotherapeutic stature of doxazosin and its role in coronary risk reduction

In hypertension the primary pathophysiologic abnormality is a generalized increase in the peripheral vascular resistance as a result of concentric narrowing of the systemic arterioles, as a result of α₁-receptor stimulation. Such stimulation is attenuated by the selective α₁-inhibitor doxazosin. The pharmacologic attributes of doxazosin are transiated into direct relaxation of the peripheral arteriolar resistance vessels and venous capacitance system, particularly those with a high α-adrenoceptor population. The direct effects of such vascular dilatation are immediately beneficial to the heart in reducing systemic and pulmonary vascular pressures that reduce left ventricular wall stress and myocardial oxygen consumption. In clinical studies doxazosin has been found to have a plasma half-life of 19 to 22 hours, of which a single daily dose is sufficient to control hypertension. The antiatherogenic changes in the blood lipid profile resulting from long-term treatment with doxazosin can also be expected to advance its primary prevention potential in hypertensive patients, which is in marked contrast to the potentially disadvantageous changes in the blood lipid profile that follow treatment with β-blockers and thiazide diuretics. The therapeutic efficacy of doxazosin has been confirmed, irrespective of hypertension severity, age and race of the patients, or the presence of renal impairment or diabetes mellitus. Its side-effect profile is not substantially different from that of placebo or other antihypertensive drug treatment. Given its unique actions regarding antihypertensive efficacy, together with favorable effects on blood lipids, doxazosin probably holds more promise for the prevention of precocious coronary heart disease in hypertensive patients than any other currently available antihypertensive agent.     

A comparison of doxazosin and enalapril in the treatment of mild and moderate essential hypertension

The antihypertensive efficacy and safety of doxazosin, a selective α₁-adrenoceptor antagonist, were compared with that of the angiotensin-converting enzyme inhibitor enalapril in an 18-week double-blind, parallel-group trial. Sixty-seven hypertensive patients entered the three-phase study, which involved a 4-week placebo washout period, a 10-week titration period with doxazosin, 1 to 16 mg, or enalapril, 10 to 40 mg once daily followed by a 4-week maintenance period. The target response was a standing diastolic blood pressure ≤90 mm Hg. In the 62 efficacy evaluable patients the mean final daily dose of doxazosin was 5.6 mg and 25.5 mg for enalapril. The percentages of therapeutic successes were 74% in the doxazosin- and 81% in the enalapril-treated groups; the proportions in whom standing diastolic blood pressure ≤90 mm Hg were 55% and 61%, respectively. Both sitting and standing blood pressures were significantly reduced at all visits during the 14-week treatment period in both groups. Twelve patients receiving doxazosin reported 14 adverse events and nine patients administered enalapril reported 19 adverse events; therapy was stopped in three patients in each group because of side effects. The overall assessment of efficacy was excellent or good for 71% of the doxazosin-treated and 67% of the enalapril-treated patients, respectively. Toleration of therapy was excellent or good for 91% of the doxazosin-treated and 88% of the enalapril-treated patients, raspectively. No clinically significant changes were observed in the serum lipids, plasma blochemistry, or hematologic profiles. The results of this study indicate that doxazosin and enalapril have comparable antihypertensive efficacy and possess similar primary prevention potential.     

Diurnal pattern of water and electrolyte excretion and body weight in idiopathic orthostatic hypotension: The effect of three treatments

The diurnal pattern of water and solute excretion and body weight were examined in five control subjects and in a patient with idiopathic orthostatic hypotension before and during treatment. The patient had a reversed diurnal pattern of excretion of sodium, urea and water but not of potassium and creatinine, and there was an excessive diurnal variation in body weight. The effects of three treatments, high salt diet alone and then with the addition of head-up tilt, and later fludrocortisone, were studied. Fludrocortisone caused marked clinical improvement and retention of sodium and water. Once a steady state was achieved none of the treatments had any significant effect either on the diurnal variation in weight or on the water and solute excretion pattern except for a small reduction in sodium excretion at night when the patient slept with a head-up tilt. It is concluded that these treatments cause symptomatic improvement in idiopathic orthostatic hypotension through an increase in extracellular fluid volume rather than through any change in the abnormal diurnal pattern of water and salt excretion.     

Hemodynamic evaluation of the Ionescu-Shiley pericardial xenograft in the mitral position

Hemodynamic studies were performed in 27 patients at a mean interval of 40.3 (range 24 to 59) months following mitral valve replacement with pericardial xenografts. Six patients had sequential studies, one before operation and two separate investigations at mean intervals of 11.2 and 42.8 months following valve replacement. The results showed significant increase in cardiac index, reduction in mean pulmonary artery and wedge pressures, and decrease in pulmonary vascular resistance both at rest and during exercise, when compared with the preoperative values. The mean diastolic gradient across the pericardial xenografts was 6.4 mm. Hg at rest and 15.3 mm. Hg during exercise. The calculated xenograft surface area was 2.0 and 2.3 cm.2, respectively. The sequential studies established that the maximum hemodynamic improvement was achieved within the first year following valve replacement and that the functional performance of the xenografts was maintained, unaltered, with the passage of time.     

Nifedipine therapy for stable angina pectoris: preliminary results of effects on angina frequency and treadmill exercise response.

Ten patients with stable angina pectoris secondary to atherosclerotic coronary artery disease received nifedipine (10 mg and 20 mg orally three times daily, each for 2 weeks) or placebo (for 2 weeks) in a single-blind manner during a 6 week period. One patient was excluded because nocturnal and resting angina developed while he was receiving placebo. The frequency of anginal attacks in the remaining nine patients decreased from 11.2 ± 2.2 (mean ± standard error of the mean) per patient per week during administration of placebo to 7.1 ± 1.6 during therapy with nifedipine at 10 mg and to 6.3 ±1.7 during administration of 20 mg of nifedipine (P < 0.05 for both doses of active drug versus placebo). Nitroglycerin consumption similarly decreased from 8.9 ± 2.3 tablets per patient per week (placebo) to 4.8 ± 1.4 tablets during administration of 10 mg of nifedipine and to 4.2 ± 1.2 during therapy with 20 mg of the drug (P < 0.05 for both doses of drug versus placebo). Duration of treadmill exercise increased from 368 ± 50 seconds (placebo) to 471 ± 72 seconds at the 10 mg dose of nifedipine and 522 ± 79 seconds at 20 mg (P < 0.05 for both doses versus placebo). Maximal S-T segment shift and product of heart rate × systolic blood pressure did not differ between the placebo period and that of active drug therapy. Treadmill exercise performed during subsequent double-blind, randomized crossover treatment with placebo and nifedipine revealed increased exercise duration after nifedipine therapy (524 ± 49 seconds) compared with that after placebo (462 ± 52 seconds) (P < 0.005) but, again, maximal S-T shift and the product of heart rate × systolic blood pressure did not differ. Side effects from nifedipine were minor and easily tolerable. The results seem to indicate that nifedipine prolongs exercise time by decreasing heart rate × systolic blood pressure product at a given work load, possibly in a manner similar to that of long-acting nitrate therapy.     

Hemodynamic responses to ergometer exercise in children and young adults with left ventricular pressure or volume overload

This study determines (1) the hemodynamic responses to exercise in groups of young patients with either left ventricular (LV) pressure or volume overload, (2) whether these responses differed from healthy subjects when the variables of sex, age, race and body surface area were controlled (analysis of covariance), and (3) whether any of the exercise variables could predict noninvasively the severity of the gradient in aortic valve stenosis (AS). We tested 137 patients, including 70 with AS, 25 with aortic isthmic coarctation, 20 with aortic regurgitation and 22 with mitral regurgitation, and compared them with a control population of 405 healthy children. The children underwent a continuous, graded, maximal test with 3-minute stages. The variables evaluated were peak heart rate, systolic blood pressure, maximal work load (kgm/min), peak working capacity index (kg-m/min/ kg body weight) and ischemia on electrocardiography.In patients with pressure overload, the maximal exercise values for work load, heart rate and peak working capacity index were significantly different (p < 0.05) from control values. The patients with volume overload had higher blood pressure values than either control subjects or patients with pressure overload. Similarly, the values for heart rate in patients with volume overload were lower than values for control subjects and patients with pressure overload. No exercise variable was predictive of severity of AS. These data confirm some previous investigators' findings with respect to LV volume and pressure overload, but do not support the concept that exercise test results are sensitive and specific for the prediction of severity in AS.     

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.     

Hemodynamic effects of intravenous diltiazem with impaired left ventricular function

The acute hemodynamic effects of intravenous diltiazem were studied in 8 patients with coronary artery disease, left ventricular (LV) failure (New York Heart Association functional class III), a rest ejection fraction (EF) less than 40% or a cardiac index less than 2.4 liters/min/m2. Hemodynamic measurements and LV angiograms were performed at rest before and after the administration of diltiazem, 0.5 mg/kg, administered at a speed of 5 mg/min. Diltiazem treatment induced a decrease in heart rate from 68 +/- 12 to 55 +/- 9 beats/min (p less than 0.001). Mean aortic pressure decreased from 94 +/- 14 to 81 +/- 15 mmHg (p less than 0.05). Thus, the pressure-rate product significantly decreased under the influence of the drug, from 8,791 +/- 2,465 to 6,342 +/- 1,808 beats mm Hg/min, (p less than 0.001). Diltiazem induced no significant change of LV end-diastolic pressure, pulmonary wedge pressure, cardiac index and LV stroke work index. Systemic vascular resistance decreased (p less than 0.01), whereas pulmonary vascular resistance showed no change. End-systolic volume diminished (p less than 0.02), which accounts for the increase of stroke volume and ejection fraction (p less than 0.001). Disorders of regional contractility were not aggravated by diltiazem, and even improved in individual cases. Thus, intravenous diltiazem may be used safely in patients with heart failure. However, in view of the marked bradycardic effects seen in some cases, heart rate should be carefully monitored.     

Hemodynamic effects of felodipine at rest and during exercise in exertional angina pectoris

To examine the antianginal effects of felodipine, a new calcium antagonist, 8 patients with coronary artery disease and exertional angina pectoris were studied. Hemodynamic measurements were made at rest, during submaximal exercise and during angina-limited exercise before and 30 minutes after oral administration of 0.1 mg/kg of felodipine. Angina pectoris was always prevented after the drug was given and the exercise intensity was increased until recurrence of angina (5 patients) or exhaustion (3 patients). Hemodynamic data were also recorded at this higher exercise capacity. At rest and during submaximal exercise, felodipine increased heart rate and decreased arterial blood pressure and systemic vascular resistance. The prevention of angina pectoris was accompanied by lower mean pulmonary capillary wedge pressure, systemic vascular resistance and ST-segment depression; the pressure-rate product was unchanged. The 20% greater exercise capacity after felodipine was attended by a 20% increase in maximal cardiac output, a 17% increase in maximal heart rate and a 13% increase in maximal pressure-rate product; the maximal arterial blood pressure and ST-segment abnormalities were unchanged and the systemic vascular resistance was lower. The relation between ST-segment depression and the pressure-rate product during exercise was favorably influenced by felodipine. Thus, felodipine is an active antianginal drug; its major mechanism of action is to lower the systemic vascular resistance. The data also suggest that it improves coronary blood flow during exercise.     

Hemodynamic and clinical effects of combined verapamil and propranolol therapy in angina pectoris

Because of their common negative chronotropic and inotropic effects, combined therapy of beta-adrenergic blocking drugs and calcium channel antagonists has long been feared to produce synergistic cardiodepressant effects. To evaluate whether such fears are justified when such therapy is used in patients with angina pectoris, five hemodynamic and clinical studies were reviewed. These studies indicated that in patients with preserved ventricular function treated with low or moderate doses of propranolol, verapamil produced little change in cardiac performance; this finding was not significantly different from the effects of verapamil in the absence of beta-blockade. In patients receiving large doses of propranolol, verapamil produced modest but significant cardiodepressant effects; these could be avoided by withdrawal of propranolol for 24 hours. Adverse reactions, when they occurred, were primarily hemodynamic rather than electrophysiologic.Short-term (48 hours) and long-term (4 weeks) randomized controlled trials, which objectively evaluated exercise tolerance in patients with angina pectoris, demonstrated that combined therapy of verapamil and propranolol was superior not only to placebo but also to either drug alone. In patients with preserved left ventricular function, the incidence of adverse effects with combined therapy was small (less than 10%) but increased to 25% in patients with poor left ventricular performance (ejection fraction less than 30%). Combined therapy of nifedipine and propranolol also produced adverse hemodynamic and clinical reactions.Combined therapy of beta-adrenergic and calcium channel antagonists can provide substantial clinical benefits for patients with angina pectoris who remain symptomatic with either agent used alone. Because adverse effects can occur, however, patients being considered for such treatment need to be carefully selected and observed.     

Left ventricular function in patients with coronary heart disease in the presence or absence of angina pectoris during exercise radionuclide ventriculography

This study compares left ventricular (LV) performance during exercise in patients with angiographically documented coronary artery disease (CAD) based on the presence or absence of angina pectoris during the index exercise tests. The patients were divided into 2 groups: Group I included 31 patients who had angina pectoris during the test and Group II included 43 who did not. Multivessel CAD was present in 21 patients (68%) in Group I and 26 patients (60%) in Group II (difference not significant [NS]). There were no significant differences between the 2 groups in age, sex, history of diabetes mellitus, history of myocardial infarction and in the exercise duration, work load, heart rate and systolic blood pressure. Exercise-induced ST-segment depression was present in 48% of the patients in Group I and in 40% in Group II (NS). The mean LV ejection fraction at rest was 52 ± 12% in Group I and 50 ± 17% in Group II (NS). There were significant differences in the 2 groups in the change from rest to exercise in ejection fraction (?4.5 ± 7.6% in Group I vs 1 ± 9.4% in Group II, p < 0.01), end-systolic volume (29 ± 38 ml in Group I vs 9 ± 23 ml in Group II, p < 0.005), the change in systolic blood pressure-to-end-systolic volume ratio (?0.1 ± 0.5 mm Hg/ml in Group I vs 0.3 ± 1.1 mm Hg/ml in Group II, p < 0.05), and wall motion score (?0.4 ± 0.6 in Group I vs 0.09 ± 0.7 in Group II, p < 0.05).Thus, asymptomatic myocardial ischemia may occur in patients with extensive CAD and be associated with abnormal exercise LV function; however, patients with symptomatic CAD have worse exercise LV function than those with asymptomatic CAD.     

Long-term efficacy of diltiazem assessed with multistage graded exercise tests in patients with chronic stable angina pectoris

The long-term efficacy of diltiazem, 360 mg/day, in patients with grade II or III stable exertional angina pectoris (Canadian Cardiovascular Society criteria) was assessed by multistage graded exercise tests. Seventeen patients undertook a placebo-controlled, double-blind, dose-titration protocol and all received long-term therapy. Exercise tests were performed at the end of 2 weeks of placebo treatment and after 6, 18, 26, 40 and 52 weeks of diltiazem, 360 mg/day. All patients had angina during treadmill testing with placebo and the mean (+/- standard error of the mean) exercise time was 5.8 +/- 0.7 minutes. This increased to 10.8 +/- 1.0 minutes after 6 weeks, 11.3 +/- 1.1 minutes after 18 weeks, 11.4 +/- 1.1 minutes after 26 weeks, 12.9 +/- 1.2 minutes after 40 weeks and 11.6 +/- 1.3 minutes after 52 weeks of continuous diltiazem therapy (p less than 0.001 vs placebo at all stages). Four patients were withdrawn after 26 weeks of treatment; one patient underwent coronary artery bypass surgery and 3 patients required the addition of beta-adrenoreceptor blocking agents. In 1 patient an irritant rash developed on the torso, legs and arms after 39 weeks of diltiazem and disappeared after discontinuing the drug. One patient complained of swelling and stiffness of the fingers and 3 patients complained of shoulder and elbow pain. Another patient had a myocardial infarction after 8 weeks of diltiazem treatment and died. No other adverse effects were observed during this study.(ABSTRACT TRUNCATED AT 250 WORDS)