Long-term effectiveness of verapamil in stable and unstable angina pectoris

Long-Term Effectiveness of Verapamil in Stable and Unstable Angina Pectoris One-Year Follow-Up of PatientsTreated in Placebo-Controlled Double-BlindRandomizedClinicalTrials STEPHEN SCHEIDT, MD, WILLIAM H. FRISHMAN, MD, MILTON PACKER, MD, JAWAHAR

MEHTA, MD, OBERDAN PARODI, MD, and V. BALA SUBRAMANIAN,

MD

The clinical responses to 12 months’ treatment with ver&Qamll were evaluated in 63 patients with stable and unstable angina pectoris in whom the effectiveness of verapamil had been established in short-term double-blind placebo-controlled randomized clinical trials. In 41 patients with effort-related angtna, k)ng-term responses were sustained for periods exceeding 1 year. Twenty patients were evaluated by clinical history and showed a sustained reduction in frequency of angina1 attacks and consumption of nitroglycerin with verapamil compared with the initial placebo control periods; the magnitude of this benefit was similar to that observed durtng doubleblind treatment with the drug. Twenty-one patients were evaluated by serial treadmill exercise testing and showed a sustained improvement in exercise

duration after 4, 6, 16, 24, and 52 weeks of verapamil treatment; withdrawal of the drug resulted in a deterioration of exercise performance to levels similar to those seen before initiation of therapy. In 22 patients with unstable angina at rest, verapamil produced an ameltorat&n of anglnal symptoms that was sustained in most patients for longer than 1 year. However, these patients continued to have a high incidence of death and myocardial infarction in a frequency similar to that prevtously reported in large clinical studies ustng elther combinations of verapamil and nitrates, nifedipine and proptanolol, or propranolol and nitrates. Calciumchannel antagonists may decrease the number of patients requiring coronary artery bypass surgery for relief of refractory angina, but they do not appear to alter the natural hlstory of the disease.

Verapamil has proved useful in the treatment of supraventricular tachyarrhythmias,‘a hypertrophic cardiomyopathy,4-s vasospastic or variant angina,7 and chronic, stable, effort-induced angina.s-13 Although several trials have confirmed the effectiveness of oral verapamil in patients with chronic stable angina pec-

toris, most trials have been of short duration, usually less than 4 to 6 weeks long. As a result, the long-term antianginal effects of verapamil and other calcium antagonists have not been well documented. To evaluate the long-term value of verapamil in patients with ischemic heart disease, we conducted subjective and objective clinical follow-up examinations in 63 patients with stable and unstable angina pectoris, all of whom had been entered into short-term double-blind clinical trials comparing the effectiveness of verapamil with placebo or with propranolol; all were subsequently treated with verapamil for at least 1 year. Our results indicate that the beneficial effects of short-term therapy with verapamil are sustained during long-term treatment with the drug.

From the Divisions of Cardiology, Departments of Medicine, The New York HcepltalComell Medical Center, New York, New York; Tha Albert Einstein College of Medicine, Bronx, New York; The Mount Sinai School of Medicine and Medical Center, New York, New York; The University of Florida College of Medicine and tha Veteran’s Administration Medical Center, Gainesville, Florida; the C.N.R. Institute of Clinical Physiology, Piss, ltaty; and the Depamnent of Cardiology and the Division of Clinical Sciences, Northwick Park Hospital, London, England. This study was supported in part by Grant HL 00653-2 from the National Institutes of Health, Bethesda, Maryland, and by a grant-in-aid from the Knoll Pharmaceutical Company, Whippany. New Jersey, Dr. Frishman is a Teaching Scholar of the American Heart Association, Dallas, Texas. Dr. Packer is the recipient of a Young Investigator’s Research Award (R23-HL 25055) from the Natlonal Heart, Lung, and Blood Institute, the Nattonal lnstttutesof Health, Bethesda, Maryland. Dr. Bala Subramanian is supported by the British Heart Foundation, London, England. Address for reprints: Stephen Scheidt, MD, The New York Hospital-Cornell Medical Center, 525 East 68th Street, New York, New York 10021.

Long-Term Therapy of Stable Angina Pectoris Methods Patient population: The patient population was chosen from 66 patients with stable angina of effort who had participated in 3 randomized clinical trials. All patients had anginal pain on exertion relieved by rest or sublingual nitroglycerin, or both, occurring at least twice weekly for at least 4 weeks;

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LONG-TERM EFFICACY OF VERAPAMIL-SCHEIDT

TABLE I

ET AL.

Long-Term Effects of Verapamil on Angina1Attack Frequency, Nitroglycerin Consumption,Heart Rate, and Blood Pressure

Angina1 attacks (per week) Nitroglycerin tablets consumed (per week) Heart rate (beats/min) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg)

Baseline Placebo

DoubleBlind Verapamil

DoubleBlind Placebo

11.75 f1.5 10.58 f1.8 75.8 f3.5 138.89 f5.6 87.45 f2.7

6.9’+ f1.7 7.1++ fl.a 70.8 f2.5 122.9*+ f3.6 75.2.t f2.6

19.44 f5.7 16.25 f5.4 73.5 f2.a 133.45 f4.0 83.85 f2.9

Long-Term Follow-Up (Months After Conclusion of Double-Blind Phase) 1

2

4

6

a

7.2*+ f2.6 6.7’+ f2.6 70.9 f2.3 1265;;

7.9*+ f3.2 7.6’+ f3.2 70.9 f2.1 i24.4*+ f3.9

7.2*+ f2.9 7.0*+ f2.9 69.9’+§ f2.7 i27.8*+ f3.4

7520’6 .

7%+

7.6’+ f2.a 7.5*+ f2.8 65.0’+* f2.5 133.64 f3.a 76.8’+ f2.2

$.“,i! f3.7 65.4’+§ f2.7 131.35 f3.5 75.6*+ f2.9

‘%+

9.3*+

10

12

7.4*+ f2.9 7.1*+ f3.0 66.2’+§ f2.3 127.8’ f3.9

9.8++ f4.0 10.7 f4.0 67.4’+ f2.5 128.9** f2.8

7%+ .

7::;+

p <0.05 from baseline placebo: + p <0.05 from double-blind placebo; 9 p <0.05 from double-blind verapamil. All values are means f SEM. l

all patients demonstrated at least 1 mm S-T depression on two successive standardized treadmill exercise tests performed while receiving no treatment. No patient had severe hypertension or S-T segment changes while standing or during hyperventilation or during the Valsalva maneuver; none had unstable angina pectoris, acute myocardial infarction within 3 months, previous cardiac surgery, or congestive heart failure. No patient was taking digitalis, beta-adrenergic blocking drugs, long-acting nitrates, or antiarrhythmic agents before evaluation. Trial protocol: All patients entered a randomized clinical trial comparing verapamil with either placebo or propranolol. Scheidt et al. (unpublished observations) entered 18 patients into a double-blind crossover trial comparing placebo with verapamil, given as either 320 or 480 mg daily depending on the results of an earlier single-blind dose titration phase; each drug was administered for 4 weeks. Frishman et ali4 entered 20 patients into a double-blind crossover trial comparing verapamil(240 to 480 mg daily) with propranolol(60 to 320 mg daily); each drug was administered for 3 weeks. Bala Su-

c-

a

28 i

2 1

O-J,

I

I

I

1

I

I

P

2

4

8

16

24

52

Weeksof treatment FIGURE 1. Effect of long-term treatment with verapamil on exercise time to the development of angina and to tha appearance of 1 and 2 mm 3-T segment depression. All values are mean values f BEM. Asterisks indicate significant difference (p
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bramanian et a1.15 entered 28 patients into a double-blind crossover trial comparing verapamil360 mg daily with placebo, each administered for 2 weeks. At the end of the double-blind trial, each patient was considered for entry into a long-term verapamil follow-up protocol. Scheidt et al. entered 17 of their 18 patients into the long-term protocol; 1 patient died during the double-blind phase. Of these 17 patients, 2 failed to complete 1 year’s treatment with verapamil for reasons unrelated to drug therapy: 1 because of compliance problems and 1 because of financial difficulties. Four patients received verapamil for 10 months with good results but did not complete 1 year’s therapy at the time of termination of the long-term follow-up protocol. Of the 20 patients evaluated by Frishman et al., 8 patients chose to receive other therapy and 2 were considered unsuitable for long-term follow-up because of problems with compliance. The remaining 10 patients received verapamil for 12 months, but long-term data were obtained in only 9 patients; 1 patient who moved out of the state was lost to follow-up. As a result, Scheidt and Frishman followed up 20 patients on verapamil therapy for at least 1 year. There were 17 men and 3 women (age range 49 to 71 years). The doses administered (480 mg daily in 18 patients and 320 mg daily in 2 patients) were identical in each patient to those utilized during the double-blind studies. All 28 patients evaluated by Bala Subramanian et al. were continued on long-term verapamil therapy. There were 25 men and 3 women (age range 43 to 69 years). The dose administered was 360 mg daily in each patient, identical to that utilized during the double-blind phase. All completed 4 weeks’ treatment with verapamil; 4 patients were withdrawn before the 8 week evaluation because a dose of 360 mg daily of the drug could not be maintained: 1 because of first-degree heart block (0.28 second), 2 because of worsening angina (responsive to an increased dose of verapamil in 1 and to the addition of a beta-blocking drug in the other), and 1 because of an acute inferior myocardial infarction. Four patients were lost to follow-up study after 6 months of treatment; 21 patients completed 1 year’s treatment with verapamil. During the long-term follow-up period, verapamil was the only antianginal medication used. Long-acting nitrates and beta-blocking drugs were not added. Sublingual nitroglycerin was permitted during the study for relief of angina1 attacks but was not used prophylactically. In addition, no patient was taking digitalis, diuretics, or antiarrhythmic agents. Subjective and objective evaluations: All 41 patients were evaluated monthly for the first 2 months after completion of the double-blind phase, every second month until the

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LONGTERM

end of the first year, and every third month thereafter. The frequency of anginal attacks and consumption of nitroglycerin were determined from patient diaries, and heart rate and blood pressure were assessed at each return visit. Adverse effects were evaluated from a standardized questionnaire and by routine hematologic and biochemical laboratory tests. In addition, the patients studied by Bala Subramanian et a1.15underwent serial treadmill exercise testing after 4,8,16, 24, and 52 weeks of verapamil therapy. After completion of 1 year of treatment in these patients, verapamil was withdrawn; the dose was gradually reduced over 1 week and was replaced by placebo therapy for an additional 4 weeks. Treadmill testing was repeated at the end of the placebo period, and its results were compared with the exercise test during placebo treatment performed 1 year earlier. All tests were performed according to a protocol described previously15 and were conducted 90 to 150 minutes after administration of the last dose of verapamil or placebo. Variables evaluated included the total duration of exercise and the duration of exercise until the appearance of 1 and 2 mm S-T depression. Data analysis: The frequency of angina1 attacks and nitroglycerin consumption were analyzed in the patients of Scheidt and Frishman only for the 20 patients who completed all evaluations during the entire 12 month follow-up period. Significance was determined by Wilcoxon signed rank t tests with each period compared with the baseline placebo, dou-

ble-blind placebo, and double-blind verapamil phases. Exercise duration was assessed by Bala Subramanian et al. for 28 patients followed up for 4 weeks, 24 patients followed up to 6 months, and 21 patients followed up to 1 year; statistical analysis was performed by Student’s paired t test. Group data

are expressed as mean f standard error of the mean @EM). Results Angina1 attack frequency consumption: In the 20 patients

and

nitroglycerin

evaluated by Scheidt and Frishman, during the double-blind phases of the trial, verapamil reduced the number of angina1 attacks from 19.4 f 5.7 episodes per week on placebo to 6.9 f 1.7 per week after 3 to 4 weeks on the drug (p <0.05). During open-label verapamil therapy for 1 year, this improvement was sustained; the number of attacks throughout the follow-up period remained significantly smaller than observed during either the single- or double-blind placebo period (Table I). During the double-blind phases of the trial, verapamil reduced the number of nitroglycerin tablets consumed from 16.2 f 5.4 tablets per week on placebo to 7.1 f 1.8 per week after 3 to 4 weeks of the drug (p <0.05). During long-term open-label verapamil therapy, the number of nitroglycerin tablets consumed remained significantly smaller than that of either the single- or double-blind placebo period for the first 10 months (Table I). However, at 12 months nitroglycerin consumption was no longer significantly lower than the placebo baseline, but it was also not significantly higher than that observed during the first 4 months of verapamil therapy. These unusual findings at the 12 month follow-up visit are the result of enormous interindividual variation. Seventeen patients continued to have sustained responses; the number of angina1 attacks and tablets of nitroglycerin consumed at 12 months remained similar to or below the mean of the preceding

EFFICACY

OF VERAPAMIL-SCHEIDT

ET AL,

6 observation periods. However, 3 patients had an increase in the frequency of angina1 attacks between the 10th and 12th months of verapamil treatment (from 8.3 episodes per week on double-blind verapamil to 9.5 episodes per week during the initial 10 months’ therapy and to 22.7 episodes per week at 12 months). One of these 3 patients had relief of angina after coronary artery bypass surgery; in the other 2, nifedipine was substituted for verapamil but without alteration in angina1 frequency or nitroglycerin consumption. Hemodynamic variables: In the 20 patients evaluated by Scheidt and Frishman, verapamil reduced systolic and diastolic blood pressure during doubleblind therapy with the drug, and this reduction was sustained over the 12 month period in most patients. Diastolic blood pressure was more consistently reduced than was systolic pressure (Table I); diastolic pressure decreased from 83.8 f 2.9 to 75.2 f 2.6 mm Hg on verapamil (double-blind), and this reduction was sustained (73.7 f 2.2 mm Hg) at 12 months. Heart rate was unchanged by verapamil therapy initially, but long-term treatment produced a progressive sustained modest decrease (from 76 to 67 beats/min) after 12 months. Two of the 3 patients who had an abrupt increase in the frequency of angina1 attacks between 10 and 12 months also had an unexpected increase in blood pressure and heart rate at the time of this evaluation. Treadmill exercise performance (Fig. 1): In the 28 patients evaluated by Bala Subramanian et al., the duration of exercise increased from 6.6 to 0.5 minutes on placebo to 9.2 f 0.8 minutes after 2 weeks and to 11.4 f 0.8 minutes after 4 weeks of verapamil therapy. This improvement was maintained during the 1 year follow-up period: 11.6, 11.8, 12.8, and 11.7 minutes after 8, 16, 24, and 52 weeks, respectively. The duration of exercise until the appearance of 1 and 2 mm S-T depression was prolonged after 2 weeks’ treatment with verapamil, and this was sustained at repeat evaluation after 4 to 52 weeks. All 28 patients had angina during the placebo period, but angina limited exercise in only 13 of the 28 verapamil-treated patients after 2 weeks and in only 8 of 24 treated patients after 4 weeks. No patient who became angina-free at 4 weeks had angina at 8, 16, 24, or 52 weeks of long-term verapamil therapy. Seventeen of the 21 patients completing 1 year’s treatment with verapamil agreed to have the drug withdrawn in order to assess its continued efficacy. Six of these 17 patients could not undergo repeat exercise testing; 3 had angina at rest, 1 had a marked increase in the frequency of angina1 attacks, and 2 could not tolerate the recurrence of effort-related angina after 1 year. The mean exercise time in the 11 patients who underwent repeat treadmill evaluation was 6.9 f 0.8 minutes, which was not significantly different from the values obtained in these patients during placebo therapy 1 year earlier (6.7 f 0.5 minutes). Adverse reactions: Of the 48 patients followed on verapamil for longer than 4 weeks, constipation was the most commonly noted adverse reaction, occurring in one third to one half of the patients evaluated. This was controlled by dietary adjustment or by laxatives in most

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patients and resolved despite unchanged doses of verapamil and without any intervention in the others. Four patients had leg edema (bilateral in 2 and unilateral in 1) without signs of heart failure; edema was controlled by intermittent small doses of diuretic agents in all cases. Seven patients exhibited cardiac rhythm disturbances. Two patients had junctional rhythms, accompanied by slight dizziness in 1 of them. Two patients had asymptomatic sinus bradycardia. One patient had atrial fibrillation with a slow ventricular response accompanied by mild dizziness; 2 patients had asymptomatic first-degree heart block. All symptoms and conduction disturbances disappeared when the dose of verapamil was reduced without a loss of antianginal efficacy. One patient had acute urinary retention requiring bladder catheterization and subsequent transurethral prostatectomy; after surgery, he continued on verapamil therapy without further problems. Two patients reported occasional urinary frequency, which disappeared without dose adjustment. No significant hematologic or biochemical abnormalities were noted. Verapamil therapy was not discontinued in any patient because of the development of adverse reactions. Long-Term Therapy of Unstable Angina Pectoris Methods Patient population: The patient population consisted of 27 patients with unstable angina at rest who had participated

in two randomized clinical trials. All patients had anginal pain at rest associated with electrocardiographic S-T segment elevation, depression, or both. Parodi et a1.16evaluated 12 patients, aged 34 to 70 years; 7 had both exertional and rest angina, whereas the remaining 5 had only rest angina with preserved exercise tolerance. Obstructive coronary artery disease was confirmed in 8 of the 9 patients who underwent coronary arteriography. Mehta et al.l’Js evaluated 15 patients, aged 42 to 80 years; 13 patients had both exertional and rest angina, whereas the remaining 2 had only angina at rest. All 12 patients who had coronary arteriography had significant obstructive coronary artery disease. No patient was taking beta-adrenergic blocking drugs during the period of evaluation. Trial protocol: All patients entered a randomized clinical trial comparing verapamil with placebo. The study protocol of Parodi et al. consisted of a 2 day run-in period followed by four 2 day treatment periods alternating verapamil(480 mg daily) and placebo. The protocol of Mehta et al. employed a 24 hour placebo run-in period followed by randomization to either placebo or verapamil (320 mg daily); individual responses were determined at the end of each 24 hour period, with responders continuing on their effective regimen and nonresponders advancing from placebo to low-dose verapamil (320 mg daily) and from low-dose to high-dose verapamil(480 mg daily). At the end of the double-blind trial, all patients were considered for long-term therapy with verapamil. All 12 patients evaluated by Parodi et al. were begun on long-term treatment, but only 10 patients were followed for a mean of 47 weeks; 2 were lost to follow-up. Only 12 of the 15 patients evaluated by Mehta et al. were started on long-term verapamil therapy: 1

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had had a myocardial infarction during the double-blind trial, and 1 had failed to respond to verapamil therapy. Follow-up data are available for at least 12 months in all 12 patients and for up to 21 months in 6 patients. During the long-term 1 year follow-up period, verapamil therapy was administered in doses identical to those found effective during the double-blind phase of the trial; these doses were altered only if patients had increasing angina (1 patient in whom the dose was increased from 480 to 640 mg daily) or notable side effects (constipation in 2 patients in whom the dose was decreased from 320 to 240 mg daily). Long-acting nitrates were utilized in 15 patients, but the doses utilized were similar to those administered in each patient before treatment with verapamil and remained unchanged during the period of follow-up. Concomitant therapy with beta-adrenergic blocking drugs was not employed. Sublingual nitroglycerin was permitted during the study for relief of angina1 attacks but was not used prophylactically. Long-term evaluation: All patients were evaluated periodically in terms of symptomatic status, specifically frequency of angina1 attacks and number of nitroglycerin tablets consumed per week. Medical therapy was considered to have failed if patients had a myocardial infarction or angina unresponsive to increasing doses of verapamil, or died suddenly. Adverse effects of verapamil therapy were assessed at each clinical evaluation.

Results Short- and long-term clinical results: In the 12 patients evaluated by Parodi et a1.,16verapamil markedly reduced the number of symptomatic and asymptomatic episodes of S-T segment depression compared with placebo treatment. After completion of the short-term trial, 1 patient had a myocardial infarction while in the hospital, 8 were discharged from the hospital free of symptoms, and 3 others had occasional (1 to 3 episodes/week) attacks of angina on effort. Of the 10 patients who were followed up on long-term verapamil therapy, 7 remained free of pain and 3 continued to show a reduction in the number of ischemic episodes (averaging 2 per week). Twelve of the 15 patients treated by Mehta et a1.17 had at least a 50% reduction in angina1 attacks during short-term verapamil therapy, but these patients subsequently had a highly variable course.18 Two of the 12 patients died within 1 week of discharge from the hospital, 1 with a myocardial infarction and another with sudden death. A third patient had an inferior wall myocardial infarction 2 weeks after discharge. Anginal frequency increased in 1 patient 1 month into follow-up despite increasing doses of verapamil (up to 640 mg daily), and therapy with the drug was discontinued. One patient was found to have left main coronary artery disease 6 months after discharge and underwent coronary artery bypass surgery, although he remained asymptomatic on verapamil. In general, symptomatic responses to verapamil were excellent, and the magnitude of effect seen after 1 week of therapy was maintained in most patients for the 12 month follow-up period (Fig. 2). Seven patients were followed up by Mehta et al. for more than 1 year (up to 21 months). One patient had an

Volume 50

LONG-TERM EFFICACY

40

30

20 10

6

4

FIGURE 2. Weekly frequency (4~ SEM) of angina1 episodes and nitroglycerin (NTG) conswnption in12pathts treated witfl varapam4l on an ambulatory outpfltk3ntbasis for12monlhs.All12patkntshadrespor&dtovempamil during the inltlal hospitalization. At the end of 12 months, 7 patients wexe still taking verapamil with good clinical responses.

2

1

I

I_.

OIN: _

OF VERAPAMIL-SCHEIDT

0

Chest

n

NTG tablets

ET AL

pain episodes/week consumed/week

II

Before Verapamil

Day 7

Oay 14

e

uncomplicated inferior wall myocardial infarction at the end of 12 months’ therapy with verapamil. The other 6 patients, however, continued to exhibit excellent symptomatic responses to verapamil therapy. Mean chest pain frequency in these 6 patients after 21 months’ follow-up was 1.0 f 0.6 episodes per week, and mean nitroglycerin consumption was 1.1 f 0.5 tablets per week. Adverse effects: Adverse reactions during long-term verapamil therapy were not reported in the patients treated by Parodi et al. Of the 12 patients followed up by Mehta et al., 7 had constipation, which was mild in 6 cases. P-R interval prolongation was observed in 4 patients, but only 1 of these had first-degree heart block, which was asymptomatic. The cardiothoracic ratio in all 12 patients remained unchanged during long-term verapamil therapy (47 f 2% before and 46 f 2% after verapamil). In 1 patient who failed to respond to verapamil, facial erythema developed at a dose of 640 mg daily; upon discontinuation of the drug, the erythema disappeared over 2 weeks. Discussion Verapamil is a calcium channel blocking agent which has been used for the treatment of stable and unstable angina pectoris for over a decade. Initial studies failed to demonstrate its efficacy in chronic stable anginad but this was likely related to the small doses of verapamil administered (240 mg daily or less). Subsequent placebo-controlled double-blind studies using 320 to 480 mg daily demonstrated the short-term effectiveness of verapamil in stable angina pectoris for 4 to 8 week&-l” and in unstable angina pectoris for 48 to 96 hours,1sJ7 but few investigations have been conducted to show that these short-term benefits are sustained during long periods of drug administration. The present report attempts to provide information concerning the long-term usefulness of verapamil

Norolnbw

Day 28

Day 60

VERAPAMIL

Day

120

Day

160

Day 360

THERAPY

therapy by reporting the follow-up results in patients who entered randomized clinical trials. Although such long-term data are not placebo-controlled, documentation of drug efficacy was confirmed initially by comparison with placebo-treated periods; therefore, maintenance of improvement during long-term verapamil treatment at levels similar to those achieved with verapamil during double-blind therapy can more confidently be attributed to the beneficial effects of the drug than if such long-term evaluations had not been preceded by a placebo-controlled drug response. Long-term effectiveness in chronic stable angina: In patients with effort-related angina, verapamil reduced angina1 attack frequency and nitroglycerin consumption when compared with treatment with placebo, and the magnitude of improvement seen during shortterm treatment was sustained in most patients during long-term verapamil therapy. Only 3 of 41 patients followed up for at least 1 year exhibited an increase in angina1 frequency on therapy, and these clinical exacerbations also failed to respond to therapy with alternative calcium channel blocking drugs. This sustained improvement was confirmed by standardized exercise testing; the prolongation of exercise time seen during short-term therapy was maintained after 1 year of verapamil treatment, and these benefits disappeared rapidly when the drug was withdrawn. The duration of exercise after withdrawal of verapamil for 1 year was similar to that seen during exercise testing before in\ stitution of the drug; this observation indicates that the sustained benefits of verapamil therapy were the result of drug treatment and were not due to an alteration in the national history of the disease. Long-term effectiveness in unstable angina: Although a number of therapeutic modalities have been proposed for the treatment of patients with unstable angina associated with obstructive coronary artery disease, any short-term therapy may appear worthwhile

1982

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voknn

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LONGTERM

EFFICACY OF VERAPAMIL-SCHEIDT

ET AL.

if placebo controls are not used, since many patients with unstable angina have a spontaneous remission of symptoms.19 On other hand, uncontrolled observations during long-term therapy often prove inconclusive since the ambulatory course of the disease varies from the in-hospital course, and a large number of patients continue to have ischemic episodes despite optimal medical therapy and often require coronary bypass surgery for relief of symptoms; myocardial infarction and sudden death also occur with a variable frequency.20 In the 22 patients followed up long-term in the present study, verapamil proved effective compared with placebo in the short-term relief of symptoms in each patient. Although this clinical improvement was generally well maintained, myocardial infarction and sudden death continued to occur; coronary artery bypass surgery, however, was not performed for relief of symptoms in any patient. These results are similar to the more extensive but uncontrolled observations of Severi et al.,21 who treated 120 patients with angina at rest accompanied by S-T segment elevation with verapamil and nitrates for 2 to 8 years. The improvement in angina1 symptoms observed in most patients was sustained during the follow-up period; only 12% of patients had an exacerbation of angina1 symptoms during long-term verapamil therapy, and 50% of patients became completely painfree by the fourth year of follow-up. Despite these symptomatic benefits, however, these patients had a high incidence of myocardial infarction and death (22% and 5%, respectively, within 1 year). These results are remarkably similar to those obtained in a double-blind trial reported by Gerstenblith et a1.,22who found that nifedipine reduced the number of patients who required coronary artery bypass surgery for relief of angina1 symptoms, but failed to alter the number of patients who had myocardial infarction or died (16 and 7%, respectively, within 4 months); furthermore, benefits were limited to those patients with S-T segment elevation during episodes of pain. The incidence of myocardial infarction and death in the series of Severi et al. and the study by Gerstenblith et al. are similar to those described in the National Cooperative Study Group comparison of medical (propranolol and nitrates) and surgical therapy.20 However, in contrast to the experience with calcium antagonists, a large proportion (40%) of patients treated with propranolol and nitrates subsequently had severe angina poorly responsive to medical therapy. Therefore, calcium antagonists appear to reduce the number of patients who require bypass surgery for relief of angina but do not appear to alter the the frequency of myocardial infarction and death. Safety of long-term verapamil therapy: Verapamil was very well tolerated in the 63 patients we followed up for longer than 1 year. The most common adverse reaction was constipation; this was usually readily responsive to change in diet or mild laxatives. Conduction system disturbances were occasionally seen, but these were usually asymptomatic and responded to a reduction in the dose of verapamil. The peripheral edema

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noted in a few patients was relieved by the intermittent use of diuretics. We did not observe potentially serious adverse reactions of verapamil therapy (hypotension, congestive heart failure, or hepatotoxicity) in any of our patients, even though rare instances have been reported by other investigators.2”-25 The incidence of these reactions appears very low and should not deter clinicians from using verapamil as a safe and effective long-term antiangina1 drug. References 1. Heng MK, Singh BN, Roche AHG, et al. Effects of intravenous verapamil on cardiac arrhythmias and on the electrocardiogram. Am Heart J 1975; 90:487-498. 2. Rlnkenberger RI., Prystowsky EN, Heger JJ, Treup PT, Jackman WM, Zlpes DP. Effects of intravenous and chronic oral verapamll administration in patients with supraventrlcular tachyarrhythmias. Circulation 1980;62: 996-1010. 3. Sung RJ, Elser B, McAllister RG. Intravenous verapamil for termination of reentrant supraventricular tachycardias: intracardiac studies correlated with plasma verapamil concentrations. Ann Intern Med 1980;93:682689. 4. Roslng DR, Kent KM, Borer JS, Seldes SF, Maron BJ, Epstein SE. Varapamil therapy: a new approach to the pharmacologic treatment of hypertrophic cardiomyopathy. I. Hemodynamic effects. Circulation 1979;60: 1201-1207. 5. Rosing DR, Kent KM, Maron BJ, Epaieln SE. Verapamil therapy: a new approach to thepharmacologic treatment of hypartrophic cardiomyopathy. Il. Effects on exercise capacity and symptomatic status. Circulation 1979;60:1208-1213. 6. Rosfng DR, Condll JR, Memn BJ, et al. Verapamil tharapy: a new approach to the pharmacologic treatment of hypertrophic cardiomyopathy. III. Effects of long-term administration. Am J Cardiol 1981;48:545-553. 7. Jolmson S, Mawlleon DR, C&etl JR, Wl8erson JT, HItIfs LD. Double-blind, randomized placebo-controlled comparison of propranolol and verapamil in the treatment of patients with stable angina pectoris. Am J Med 1981; 71:433-451. 8. Phear DN. Verapamil in angina. Br Med J 1968;2:740-741. 9. Neumann M, Lfsuada AA. Double-blind evaluation of orally administered iproveratrll in patients with angina pectoris. Am J Mad Sci 1966;251: 552-556. 10. Sandier G, Clayton GA, Thornicrolt SO. Clinical evaluation of verapamil in angina pectoris. Br Med J 1968;3:224-227. 11. Llvesley B, Cattley PF, Campbell RC, Oram S. Double blind evaluation of verapamil, propranolol and isosorbida dinitrate against a placebo in the treatment of angina pectoris. Br Mad J 1973;2:375-378. 12. Andreasen F, Boye E, Chrlstofferson E, et al. Assessment of verapamil in the treatment of angina pectoris. Eur J Cardiol 1975;2:443-452. 13. Bala Subramanian V, Paramaslvan R, Lahfrl A, Raftery EB. 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Am Heart J, in press. 1% Blaglnf A, a azzel MO, CarPeggiani C, et al. Vasospastic ischemic mechanism of frequent asymptomatic transient ST-T changes during continuous electrocardiographic monitoring in selected unstable angina pectoris. Am Hearl J 1982;103:13-20. 20. Russell RD, Moraekl RE, Kouchoukos N, et al. Unstable angina pectoris: national vative study group to compare medical and surgical therapy. II. In-hospital experience and initial follow-up results in patients with one, two and three vessel disease. Am J Cardiol 1978;42:839-848. 21. Seyerl S, Dfvlee Q, Maser1 A, Marsulk P, L’Abbete A. Long-term prmis ;L2yt angtna with madlcal treatment. Am J Cardiol 1980:46:22822. Gerslenbllih0, GuyangP, Aschuti SC, et al. Nifedipina in unstable angina. A double-blind randomized trial. N Engl J Med 1982;308:8985-889. 23. Chew CYC, He&i HS, CoIlelI JT. McAlll8ier RG, Sk@ SS. 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