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Verapamil therapy for stable exertional angina pectoris
SYMPOSIUM ON VERAPAMIL THERAPY PART Ill: STUDIES IN EFFORT-RELATED MILTON PACKER, MD, Guest Ed&r,
FOR ANGINA ANGINA
PECTORIS
and WILLIAM H. FRISHMAN, MD, Guest Co-Edttw
Verapamil Therapy for Stable Exertional Angina Pectoris DONALD A. WEINER, MD, and MICHAEL D. KLEIN, MD
Clinical and exercise responses to therapy with the calcium-channel blocking agent verapamil were asseswd in 26 patients wlth stable exertional angina pectorls using a double-bilnd, placebo-controlled, randomized crossover study design. Verapamii, 480 mg daily, reduced the frequency of angina attacks (5.6 f 7.3 to 2.2 f 3.0 attacks per week, p
fects of verapamil were related to significant reduction in the heart rate-systolic blood pressure product during submaximal exercise. Adverse effects from verapamil were few and consisted prlmarity of’constlpatlon in 6 patients. A total of 193 patients had been entered in 8 Independent clinical trials, whkh have compared verapamil wlth placebo for the treatment of stable exertional angina pectoris, using a similar study design. The combined evidence from all these studies indicates that verapamll Is a highly effective and safe drug for the treatment of stable effort-related angina pectoris.
Conventional drug therapy for the treatment of exertional angina pectoris has relied on the use of nitrate preparations1s2 and beta-adrenergic blocking agents.sq4 These medications reduce the major determinants of myocardial oxygen demand at rest and during any level of exercise.5*s In some patients, however, troublesome side effects can occur.‘I Other patients fail to achieve satisfactory remission of symptoms, even with combinations of these drugs. A new class of antianginal drugs which inhibit the influx of calcium ions across myocardial and vascular smooth muscle and reduce automaticity in sinoatrial cardiac pacemaker cell8 has been developed. These pharmacologic actions serve to reduce heart rate and systolic blood pressure, which might benefit patients with exercise-induced angina pectoris.g-l l
This study reports the subjective and objective improvement in 26 patients with stable angina of effort treated with the calcium entry blocker drug verapamil. The results of this trial, published previously,lz are reviewed together with the results of 6 other studies, all of which utilized a double-blind, placebo-controlled, crossover study design.
From The Evans Memorial Department of Clinical Research and The Departmnrt Of Medicine, Ulhwsily HOspital, Boston University Medical Center, Boston, Massachusetts. Address for reprints: Michael D. Klein, MD, Cardiology Department, University Hospital. 75 East Newton Street, Boston, Massachusetts 02118.
November
Methods Patient population: Twenty-six men with a mean age of 55 years (range 30 to 72) were enrolled in the protocol during a 17 month period. The selection criteria included a minimum of 5 episodes of angina pectoris per week in a stable pattern and an abnormal control treadmill test with both ischemic (1 mm or greater1 S-T segment depression and angina during exercise testing. All patients had either a radionuclide or angiographic left ventricular ejection fraction greater than 40%.
Study design: The precise details of the protocol have been reported elsewhere.” In brief, it consisted of the following phases: an initial 2 week, placebo stabilization phase; a single-blind phase in which 2 doses of verapamil, 320 and 480 mg per day in 4 divided doses, were tested sequentially for 1 week
1992
The Amwkan
Journal of CAROtOLOCY
Volume 50
1153
VERAPAMIL
FOR ANGINA-WEINER
AND KLEIN
periods; and a double-blind, randomized phase in which the patients received either placebo or verapamil, 480 mg per day, for 2 week periods, followed by a 1 week drug tapering period. A 1 week buffer period separated the two randomized phases. Data collection: Subjective evaluation consisted of analyzing a diary in which the patients recorded the number of angina1 attacks and nitroglycerin tablets consumed. Objective evaluation included data recorded during performance of 8 treadmill exercise tests using the Bruce protocol’s during the 12 week protocol. The heart rates and blood pressures were recorded at rest, during submaximal exercise (defined as the end of stage 1 of exercise), and at maximal exercise. The peak S-T segment depression, the time from the start of exercise to the onset of 1 mm of S-T segment depression, and the total duration of exercise were also analyzed. Statistics: One-way analysis of variance was used to determine whether there was significant difference in the group mean values. If the analysis of variance indicated a significant difference in the mean values for a parameter, a two-tailed Student’s t test was applied. Probabilities were considered significant at the 0.05 level. All values are expressed as means f standard deviation.
1
SINGLE BLIND -ppco.o57
$ 24 b &
r~~O@br-NSl
20
Placebo
Single-blind phase: In the single-blind phase, the 26 patients reported subjective improvement during therapy with verapamil. The mean frequency of anginaI attacks decreased from 11.7 f 8.7 attacks per week on placebo to 3.7 f 6.0 attacks per week on verapamil, 320 mg daily, and to 3.7 f 5.8 attacks per week on verapamil, 480 mg daily (placebo versus both dose levels of verapamil, p <0.05) (Fig. 1). Nitroglycerin consumption was also significantly reduced during therapy with both doses of verapamil compared with placebo: from 4.5 f 5.7 tablets per week with placebo to 1.9 f 3.1 tablets per
Placebo
480
FIGURE 1. Effect of verapamil therapy compared with placebo in the number of anginai attacks and nitroglycerin tablets ingested per week in the single-blind and double-blind phases. Values are expressed as mean f standard deviation.
minutes). The exercise duration with the higher dose of verapamil was significantly greater than that seen with the lower dose (Fig. 2). The peak S-T segment depression during exercise was significantly reduced with verapamil compared with placebo only at the higher dose of verapamil (Fig. 3). Double-blind phase: Since, during the single-blind phase, no patient had major adverse effects with the higher dose of verapamil and many showed increased exercise tolerance with higher compared with lower doses of the drug, every patient was treated with either 480 mg of verapamil or identical placebo capsules during
week with verapamil, 320 mg, and 2.1 f 4.0 tablets per week with veraparnil, 480 mg (p <0.05). The differences observed between the lower and higher doses of verapamil were not significant. Objective improvement was also documented by a significant (p
Previous Double-Blind Placebo-Controlled
Patients (n) Males (n) Mean age or age range (yr) Daily dose of verapamil (mg) Evaluation period
320 480
VERAPAMIL (mg)
Results
TABLE I
1 DOUBLE BLIND
Neumann et al.14
Phear15
30
20
G
:“8
Studies Evaluating the Efficacy of Verapamil Andreasen et aLie
ii
Baia Subramanian et al.’
’
Pine et al.”
:;
fi
60
Tan et al.‘*
58
43-69
120
240
240
360
6
2
4
2
240, 360,
480 4
320 4
W)
Effects of verapamil Angina1 attacks per week Nitroglycerin tablets per week Exercise time
1154
November 1992
Not reported Decreased 27% Not reported
No improvement Not reported Not performed
The American Journal of CARMOLOGY
Decreased 25% Decreased 25% increased 20% (n = 17)
Volume 50
De%Yd __.~ Decreased
Decreased 46%
70% Increased 70%
DegcF?sed 0 Increased 70% (n = 16)
0
Decreased 78% Not increased 20%
VERAPAMIL
> I
FOR ANGINA-WEINER
AND KLEIN
7
1 SINGLE 7
BLIND
p
IOUBLE BLIN[
1
7 Qz
150
pco.05
rNS1
rNS1
EXERCISE
SUBMAXIMAL
rp-0.057
rp<00017
~P~O.0011 I-
d-)
T
1.0
_
p~0.001
pa05
r-p~oool~
Placebo
320 480
Placebo
480
1
FIGURE 2. Effect of verapamil therapy compared with placebo on treadmill time, peak S-T segment depression, and time to onset of S-T segment depression in the single-blind and double-blind phases. Values are expressed as mean f standard deviation.
the randomized double-blind crossover phase. During the double-blind phase, patients obtained benefits from verapamil that were similar to those seen during the single-blind trial. Verapamil reduced mean angina1 frequency (from 5.6 f 7.3 to 2.2 f 3.0 attacks per week, p
Placebo
320
480
Placebo
VEffAPAMIL
480
/mgl
FIGURE 3. Effect of verapamil therapy compared with placebo on the product of the heart rate and systolic blood pressure at rest, and submaximal and maximal exercise in the single-blind and double-blind phases. Values are expressed as mean f standard deviation.
One patient had abnormal liver function at the end of the double-blind phase and was withdrawn from a long-term follow-up study. In 6 of the patients (22%) constipation developed approximately 1 week after starting verapamil, but only 3 of them required treatment with stool softeners. Five patients had a prolongation of the P-R interval by 20 to 40 ms with verapamil, but did not exhibit first-degree heart block. One patient with preexisting first-degree block had no further lengthening of the P-R interval while receiving verapamil. One patient manifested a junctional rhythm, which subsided during treadmill exercise, while taking verapamil. Discussion Present study: The results of this study document both subjective and objective improvement in patients with stable angina of effort receiving verapamil, 480 mg per day. Mean angina1 attack frequency was decreased 61% and nitroglycerin consumption was reduced 65% compared with the placebo responses during the double-blind phase; the duration of time on a treadmill increased 17%. Verapamil produced few adverse effects; these consisted primarily of constipation, which was remedied by stool softeners or dietary adjustment. Previous studies (Table I): Six other double-blind, randomized, crossover, placebo-controlled clinical trials have evaluated verapamil therapy in patients with
November 1982
The American Journal of CARDIOLOGY
Volume 50
1155
VERAPAML FOR ANGINA-WEINER AND KLEiN
stable angina of effort. Trials not using such a study design are not considered in this report. Neumann et a1.14evaluated verapamil, 120 mg daily for 6 weeks, in 30 nursing home patients (15 men and 15 women) averaging more than 75 years of age. Verapamil significantly decreased the number of nitroglycerin tablets consumed, as compared with a 6 week placebo period. Phear15 compared verapamil, 240 mg daily, with placebo in 20 patients (13 men and 17 women, mean age 58 years) with each agent given for 2 weeks. No reduction in the frequency of angina1 attacks or nitroglycerin consumption was noted. No buffer period was present between randomization phases, however, and the possibility of lingering verapamil action in some patients subsequently randomized to placebo was not considered. Andreasen et a1.16assessed subjective and objective variables in a multicenter Danish study involving 47 patients (38 men and 19 women, aged 48 to 71 years) which compared verapamil, 240 mg daily, with placebo, each given for 4 weeks. Verapamil significantly reduced the frequency of angina1 attacks and nitroglycerin tablets consumed. Exercise capacity, assessed from the amount of time required to produce ischemic S-T depression during bicycle ergometry, was significantly enhanced. Adverse effects from verapamil were minimal; only 3 patients reported constipation. More recent studies have validated the subjective and objective benefits of verapamil in the treatment of effort-induced angina. Bala Subramanian et al.ll administered verapamil, 360 mg daily, or placebo to 28 patients, 25 men and 3 women, for 2 weeks each, and then treated each patient with open-label verapamil for 4 weeks. Compared with placebo, verapamil significantly increased mean treadmill tolerance by 38% during the double-blind phase, and then by an additional 21% during open-label therapy. Verapamil therapy resulted in a significant reduction in angina1 attacks (47%) and nitroglycerin consumption (45%) during the double-blind phase of the study, Seven patients had constipation requiring laxative therapy. Two patients had mild first-degree heart block. Pine et al.‘7 compared verapamil with placebo in 30 patients with effort-related angina pectoris who underwent a more detailed evaluation of response. Each patient received verapamil, 240, 360, and 480 mg per day, for 1 week in a single-blind fashion; this was followed by a double-blind placebo-controlled randomized phase in which placebo was compared with verapamil, administered in the dose which produced the greatest improvement in exercise tolerance during the singleblind phase. During the double-blind phase, verapamil significantly reduced the mean anginal attack frequency 47% and nitroglycerin consumption 55%, and significantly increased exercise capacity on the treadmill 42%. Seven patients had adverse reactions (rhythm disturbances in 3 patients, pulmonary edema in 1, and noncardiac symptoms in 3) with 480 mg daily of verapamil, all of which disappeared with a reduction in the dose to 360 mg daily. In these 7 patients the improvement in exercise duration on the lower dose of the drug (360 mg 1156
November 1962
The American Journal of CARDIOLOGY
daily) was similar to that observed with the higher dose (480 mg daily). Tan et al.,‘* in their evaluation of 12 men aged 45 to 73 years, found that verapamil, 320 mg daily for 4 weeks, produced a 78% reduction in angina1 attacks and a 20% improvement in exercise duration on a treadmill, when compared with placebo therapy for 4 weeks. The ejection fraction declined from 40 f 9% (at rest) to 35 f 11% (at peak effort) during placebo therapy, whereas during verapamil therapy the ejection fraction did not decrease during exercise (44 f 8% at rest and 45 f 12% at peak effort). These 6 studies,11J4-l8 combined with ours,12 comprise 193 patients treated with verapamil in doubleblind, placebo-controlled, randomized protocols; all but 1 studyi showed significant improvement during treatment with verapamil. The dose of verapamil ranged from 120 to 480 mg daily; adverse effects were infrequent and minor in all but 1 study,17 in which more frequent adverse reactions were observed when a dose of 480 mg daily was employed. Since 82% of the patients studied were men, it is unclear whether verapamil has similar antianginal effects in women. In evaluating the efficacy of new antianginal medications, careful attention must be given to the recruitment of patients with stable mechanical and electrical heart function who will be reliable in taking both active drug and placebo pills. Subjective (angina1 attack frequency and nitroglycerin consumption) and objective (treadmill performance) measures of drug effect should be evaluated concurrently. Patients selected should have reproducible exercise-induced angina, preferably within 3 to 6 minutes,lg on a standard exercise protocol in order to avoid distress from leg fatigue or hyperventilation at higher intensities of exercise. In analyzing group patient exercise data, consideration should be given to placebo effects, to training effects during sequential exercise tests,20,21 and to interpatient variability during control or placebo exercise tests. In the present protocol, comparison of single and subsequent double-blind placebo tests revealed that the treadmill time increased and the submaximal exercise heart rate and rate-systolic blood pressure product decreased significantly after the patients had completed a minimum of 5 treadmill tests. These changes might have been due to a training effect, since blood verapamil and norverapamil levels measured at the time of the double-blind placebo test were 0 to 18 ng/ml in 24 patients. Such minute amounts of blood verapamil would have been unlikely to reflect lingering drug action on the heart. A further significant increase in treadmill performance induced by verapamil, as compared with placebo, occurred during the double-blind phase of the study. Since training effects, if present, would probably have been completed before the initiation of the double-blind study phase, these results confirmed the exercise-enhancing capacity of verapamil. In most studies on new antianginal therapy, some patients will respond better than others. Comparison of individual responses may elucidate mechanisms involved in a greater therapeutic response. In our study, 12 patients showed minimal (less than 10%) or no imVolume 50
VERAPAMIL
provement in exercise duration while receiving verapamil, compared with placebo, in the double-blind study phase. These 12 patients did not differ from the other 14 patients with respect to baseline angina1 frequency or nitroglycerin consumption. However, the mean exercise duration on the initial baseline exercise test before entry into the study was 23% less (p <0.05) in the 14 patients with a therapeutic response to verapamil during the double-blind phase than in patients with minimal responses. These findings indicate that verapamil may confer its greatest benefit on patients whose exercise capacity is most restricted by angina before entry into the study. Mechanism of verapamil action: In the present study verapamil, compared with placebo, significantly decreased both the resting and submaximal heart rate, the submaximal systolic blood pressure, and the resting and submaximal rate-pressure product during the double-blind phase. We observed a greater effect on heart rate than on systolic blood pressure; other investigators have noted just the opposite.22 Regardless of which effect predominates, these responses can be explained by the negative chronotropic actions of verapami1,2”J4 as well as its dilating effects on systemic arterioles.2”*26 These findings are consistent with the hypotensive actions of verapamil during rest and bicycle ergometry in patients with essential hypertension.27 Clinical implications and perspectives: Thus, verapamil is a safe, effective drug in the treatment of patients with stable exertional angina pectoris. The effective dose ranges from 240 to 480 mg daily in 3 or 4 divided doses. Adverse effects are infrequent and mild, and consist primarily of constipation and prolongation of atrioventricular conduction. Overt congestive heart failure may occur rarely in patients with preserved left ventricular function. Abnormal hepatic function has been reported infrequently after verapamil therapy. In the treatment of angina of effort, verapamil may offer special advantages to patients who also have bronchial asthma or peripheral vascular disease. Such patients are likely to have an exacerbation of these disorders during therapy with beta-adrenergic blocking agents, when these are used in doses required to alleviate exerciseinduced angina.6,7
November
FOR ANGINA-WEINER
AND KLEIN
References 1. Rekhak N. Long-acting nitrates in the treatment of angina pectoris. JAMA 1976;236:1399-1402. 2. Abrams J. Nitroglycerin and long-acting nitrates. N Engl J Med 1979;302: 1234-1237. 3. Warren SG, Brewer DL, Orgaln ES. Long-term propranolol treatment for angina pectoris. Am J Cardiol 1976;37:420-426. 4. P&hard BNC. Propranolol in the treatment of angina: a review. Postgrad Med J 1976;52:31-41. 5. GoldsteInRE, RosingDR, Redwood DR, Beiser GD, Epstein SE. Clinical and circulatory effects of isosorbide dinitrate. Circulation 1971;43:629640. 6. Shand DG. Propranolol. N Engl J Med 1975;293:260-265. 7. McNeIII RS, Ingram CG. The effect of propranolol on ventilatory function. Am J Cardiol 1966;16:473-475. 8. Fleckansteln A. Specific pharmacology of calcium in myocardium. cardiac pacemakers, and vascular smooth muscle. Ann Rev Pharmacol Toxicol 1977;17:149-66. 9. Zsoter lT. Calcium antagonists. Am Heart J 1960;99:605-610. 10. Ellrodt G, Chew CYC, Slngh 9. Therapeutic implications of slow-channel blockade in cardiocirculatory disorders. Circulation 1980;62:669-679. 11. Bala Subramanlan V, Paramaslvan R, Lahlrl A, Raftery EB. Verapamil in chronic stable angina: a controlled study with computerized multistage treadmill exercise. Lancet 1960:1:641-644. 12. Broclsky SJ, Cutler SS, Welner DA, McCabe CH, Ryan TJ, Klein MD. Treatment of stable angina of effort with verapamil. A double-blind pla~;~o-controlled randomized crossover study. Circulation 1962;66:569“I
5.
13. Bruce AA, Hornstein TR. Exercise stress testing in evaluation of patients with ischemic heart disease. Prog Cardiovasc Dis 1969; 11:371-390. 14. Neumann y, Lulsada AA. Double-blind evaluation of orally administered iproveratril In patients with angina pectoris. Am J Med Sci 1966;251: 552-556. 15. Phear DN. Veraoamil in anaina: a double-blind trial. Br Med J 1968:2: 740-741. r 16. Andreasen F, Boye E, Chrlstofferson E, et al. Assessment of verapamil in the treatment of angina pectoris. Eur J Cardiol 1975;2:443-448. 17. Pine MB. Citron D. Baillev‘W. et al. Veraoamil versus olacebo in relievina stable angina pecioris. drcuiation 1982;‘65: 17-22. ’ 18. Tan AlH, Sadlck N, Kelley T, Harris PJ, Freedman SB, Bautovlch G. Vafapamil in stable effort angina: effect on left ventricular function evaluated with exercise ventriculography. Am J Cardiol 1962;49:425-430. 19. Redwood DR, Roslng Oq, Goldstein RE, Belser GD, Epstein SE. Importance of the desi of an exercise protocol in the evaluation of patients with angina pectoris. I?lrcutabon 1971;43:618-628. 20. Smokler PE, MacAlpln RV, Alvaro A, Kattus A. Reproducibility of a multistage mean maximal treadmill test for exercise tolerance in angina pectoris. Circulation 1973;48:346-351. 21. Blom@a! CG, Atkins JM. Repeated exercise testyg in Ftients with angina eTEt;r: reproducibility and follow-up results. Clrculabon 1971;44:Suppl
.....
,“.
22. Frlshman WH, Klein NA, Strom JA, et al. Superiority of verapamil to propranolol in stable angina pectoris: a double-blind, randomized cross&er trial. Circulation 1982;65:Suppl 1:1-51-l-59. 23. Wit AL, Cranefield PF. Effect of verapamil on the sinoatrial and atrioventricular nodes of the rabbit and the mechanism by which it arrests reentrant atrioventricular tachycardia. Circ Res 1974;35:413-425. 24. Zlpes DP, Fisher JC. Effects of agents which inhibit the slow channel on sinus node automaticity and atrioventricular conduction in the dog. Circ Res 1974:34:184-192. 25. Nay6 WG, Ffchte~ I, SwannJB, et al. Some effects of iproveratril(Isoptin) ;;,ihe cardiovascular system. J Pharmacol Exp Ther 1968;161:24726. Ferllnz J, Easthope JL, Aronow WS. Effects of verapamil on myocardial performance in coronary disease. Circulation 1979;59:313-319. 27. Gould BA, Mam S, Kies~ H, Bala. Subramanlan V, Raflary EB. The 24 hour ;~~;yry blood pressure proflle with verapamil. Circulation 1982;65:
1982
The American
Journal
of CARDIOLOGY
Volume 50
1157
FOR ANGINA ANGINA
PECTORIS
and WILLIAM H. FRISHMAN, MD, Guest Co-Edttw
Verapamil Therapy for Stable Exertional Angina Pectoris DONALD A. WEINER, MD, and MICHAEL D. KLEIN, MD
Clinical and exercise responses to therapy with the calcium-channel blocking agent verapamil were asseswd in 26 patients wlth stable exertional angina pectorls using a double-bilnd, placebo-controlled, randomized crossover study design. Verapamii, 480 mg daily, reduced the frequency of angina attacks (5.6 f 7.3 to 2.2 f 3.0 attacks per week, p
fects of verapamil were related to significant reduction in the heart rate-systolic blood pressure product during submaximal exercise. Adverse effects from verapamil were few and consisted prlmarity of’constlpatlon in 6 patients. A total of 193 patients had been entered in 8 Independent clinical trials, whkh have compared verapamil wlth placebo for the treatment of stable exertional angina pectoris, using a similar study design. The combined evidence from all these studies indicates that verapamll Is a highly effective and safe drug for the treatment of stable effort-related angina pectoris.
Conventional drug therapy for the treatment of exertional angina pectoris has relied on the use of nitrate preparations1s2 and beta-adrenergic blocking agents.sq4 These medications reduce the major determinants of myocardial oxygen demand at rest and during any level of exercise.5*s In some patients, however, troublesome side effects can occur.‘I Other patients fail to achieve satisfactory remission of symptoms, even with combinations of these drugs. A new class of antianginal drugs which inhibit the influx of calcium ions across myocardial and vascular smooth muscle and reduce automaticity in sinoatrial cardiac pacemaker cell8 has been developed. These pharmacologic actions serve to reduce heart rate and systolic blood pressure, which might benefit patients with exercise-induced angina pectoris.g-l l
This study reports the subjective and objective improvement in 26 patients with stable angina of effort treated with the calcium entry blocker drug verapamil. The results of this trial, published previously,lz are reviewed together with the results of 6 other studies, all of which utilized a double-blind, placebo-controlled, crossover study design.
From The Evans Memorial Department of Clinical Research and The Departmnrt Of Medicine, Ulhwsily HOspital, Boston University Medical Center, Boston, Massachusetts. Address for reprints: Michael D. Klein, MD, Cardiology Department, University Hospital. 75 East Newton Street, Boston, Massachusetts 02118.
November
Methods Patient population: Twenty-six men with a mean age of 55 years (range 30 to 72) were enrolled in the protocol during a 17 month period. The selection criteria included a minimum of 5 episodes of angina pectoris per week in a stable pattern and an abnormal control treadmill test with both ischemic (1 mm or greater1 S-T segment depression and angina during exercise testing. All patients had either a radionuclide or angiographic left ventricular ejection fraction greater than 40%.
Study design: The precise details of the protocol have been reported elsewhere.” In brief, it consisted of the following phases: an initial 2 week, placebo stabilization phase; a single-blind phase in which 2 doses of verapamil, 320 and 480 mg per day in 4 divided doses, were tested sequentially for 1 week
1992
The Amwkan
Journal of CAROtOLOCY
Volume 50
1153
VERAPAMIL
FOR ANGINA-WEINER
AND KLEIN
periods; and a double-blind, randomized phase in which the patients received either placebo or verapamil, 480 mg per day, for 2 week periods, followed by a 1 week drug tapering period. A 1 week buffer period separated the two randomized phases. Data collection: Subjective evaluation consisted of analyzing a diary in which the patients recorded the number of angina1 attacks and nitroglycerin tablets consumed. Objective evaluation included data recorded during performance of 8 treadmill exercise tests using the Bruce protocol’s during the 12 week protocol. The heart rates and blood pressures were recorded at rest, during submaximal exercise (defined as the end of stage 1 of exercise), and at maximal exercise. The peak S-T segment depression, the time from the start of exercise to the onset of 1 mm of S-T segment depression, and the total duration of exercise were also analyzed. Statistics: One-way analysis of variance was used to determine whether there was significant difference in the group mean values. If the analysis of variance indicated a significant difference in the mean values for a parameter, a two-tailed Student’s t test was applied. Probabilities were considered significant at the 0.05 level. All values are expressed as means f standard deviation.
1
SINGLE BLIND -ppco.o57
$ 24 b &
r~~O@br-NSl
20
Placebo
Single-blind phase: In the single-blind phase, the 26 patients reported subjective improvement during therapy with verapamil. The mean frequency of anginaI attacks decreased from 11.7 f 8.7 attacks per week on placebo to 3.7 f 6.0 attacks per week on verapamil, 320 mg daily, and to 3.7 f 5.8 attacks per week on verapamil, 480 mg daily (placebo versus both dose levels of verapamil, p <0.05) (Fig. 1). Nitroglycerin consumption was also significantly reduced during therapy with both doses of verapamil compared with placebo: from 4.5 f 5.7 tablets per week with placebo to 1.9 f 3.1 tablets per
Placebo
480
FIGURE 1. Effect of verapamil therapy compared with placebo in the number of anginai attacks and nitroglycerin tablets ingested per week in the single-blind and double-blind phases. Values are expressed as mean f standard deviation.
minutes). The exercise duration with the higher dose of verapamil was significantly greater than that seen with the lower dose (Fig. 2). The peak S-T segment depression during exercise was significantly reduced with verapamil compared with placebo only at the higher dose of verapamil (Fig. 3). Double-blind phase: Since, during the single-blind phase, no patient had major adverse effects with the higher dose of verapamil and many showed increased exercise tolerance with higher compared with lower doses of the drug, every patient was treated with either 480 mg of verapamil or identical placebo capsules during
week with verapamil, 320 mg, and 2.1 f 4.0 tablets per week with veraparnil, 480 mg (p <0.05). The differences observed between the lower and higher doses of verapamil were not significant. Objective improvement was also documented by a significant (p
Previous Double-Blind Placebo-Controlled
Patients (n) Males (n) Mean age or age range (yr) Daily dose of verapamil (mg) Evaluation period
320 480
VERAPAMIL (mg)
Results
TABLE I
1 DOUBLE BLIND
Neumann et al.14
Phear15
30
20
G
:“8
Studies Evaluating the Efficacy of Verapamil Andreasen et aLie
ii
Baia Subramanian et al.’
’
Pine et al.”
:;
fi
60
Tan et al.‘*
58
43-69
120
240
240
360
6
2
4
2
240, 360,
480 4
320 4
W)
Effects of verapamil Angina1 attacks per week Nitroglycerin tablets per week Exercise time
1154
November 1992
Not reported Decreased 27% Not reported
No improvement Not reported Not performed
The American Journal of CARMOLOGY
Decreased 25% Decreased 25% increased 20% (n = 17)
Volume 50
De%Yd __.~ Decreased
Decreased 46%
70% Increased 70%
DegcF?sed 0 Increased 70% (n = 16)
0
Decreased 78% Not increased 20%
VERAPAMIL
> I
FOR ANGINA-WEINER
AND KLEIN
7
1 SINGLE 7
BLIND
p
IOUBLE BLIN[
1
7 Qz
150
pco.05
rNS1
rNS1
EXERCISE
SUBMAXIMAL
rp-0.057
rp<00017
~P~O.0011 I-
d-)
T
1.0
_
p~0.001
pa05
r-p~oool~
Placebo
320 480
Placebo
480
1
FIGURE 2. Effect of verapamil therapy compared with placebo on treadmill time, peak S-T segment depression, and time to onset of S-T segment depression in the single-blind and double-blind phases. Values are expressed as mean f standard deviation.
the randomized double-blind crossover phase. During the double-blind phase, patients obtained benefits from verapamil that were similar to those seen during the single-blind trial. Verapamil reduced mean angina1 frequency (from 5.6 f 7.3 to 2.2 f 3.0 attacks per week, p
Placebo
320
480
Placebo
VEffAPAMIL
480
/mgl
FIGURE 3. Effect of verapamil therapy compared with placebo on the product of the heart rate and systolic blood pressure at rest, and submaximal and maximal exercise in the single-blind and double-blind phases. Values are expressed as mean f standard deviation.
One patient had abnormal liver function at the end of the double-blind phase and was withdrawn from a long-term follow-up study. In 6 of the patients (22%) constipation developed approximately 1 week after starting verapamil, but only 3 of them required treatment with stool softeners. Five patients had a prolongation of the P-R interval by 20 to 40 ms with verapamil, but did not exhibit first-degree heart block. One patient with preexisting first-degree block had no further lengthening of the P-R interval while receiving verapamil. One patient manifested a junctional rhythm, which subsided during treadmill exercise, while taking verapamil. Discussion Present study: The results of this study document both subjective and objective improvement in patients with stable angina of effort receiving verapamil, 480 mg per day. Mean angina1 attack frequency was decreased 61% and nitroglycerin consumption was reduced 65% compared with the placebo responses during the double-blind phase; the duration of time on a treadmill increased 17%. Verapamil produced few adverse effects; these consisted primarily of constipation, which was remedied by stool softeners or dietary adjustment. Previous studies (Table I): Six other double-blind, randomized, crossover, placebo-controlled clinical trials have evaluated verapamil therapy in patients with
November 1982
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stable angina of effort. Trials not using such a study design are not considered in this report. Neumann et a1.14evaluated verapamil, 120 mg daily for 6 weeks, in 30 nursing home patients (15 men and 15 women) averaging more than 75 years of age. Verapamil significantly decreased the number of nitroglycerin tablets consumed, as compared with a 6 week placebo period. Phear15 compared verapamil, 240 mg daily, with placebo in 20 patients (13 men and 17 women, mean age 58 years) with each agent given for 2 weeks. No reduction in the frequency of angina1 attacks or nitroglycerin consumption was noted. No buffer period was present between randomization phases, however, and the possibility of lingering verapamil action in some patients subsequently randomized to placebo was not considered. Andreasen et a1.16assessed subjective and objective variables in a multicenter Danish study involving 47 patients (38 men and 19 women, aged 48 to 71 years) which compared verapamil, 240 mg daily, with placebo, each given for 4 weeks. Verapamil significantly reduced the frequency of angina1 attacks and nitroglycerin tablets consumed. Exercise capacity, assessed from the amount of time required to produce ischemic S-T depression during bicycle ergometry, was significantly enhanced. Adverse effects from verapamil were minimal; only 3 patients reported constipation. More recent studies have validated the subjective and objective benefits of verapamil in the treatment of effort-induced angina. Bala Subramanian et al.ll administered verapamil, 360 mg daily, or placebo to 28 patients, 25 men and 3 women, for 2 weeks each, and then treated each patient with open-label verapamil for 4 weeks. Compared with placebo, verapamil significantly increased mean treadmill tolerance by 38% during the double-blind phase, and then by an additional 21% during open-label therapy. Verapamil therapy resulted in a significant reduction in angina1 attacks (47%) and nitroglycerin consumption (45%) during the double-blind phase of the study, Seven patients had constipation requiring laxative therapy. Two patients had mild first-degree heart block. Pine et al.‘7 compared verapamil with placebo in 30 patients with effort-related angina pectoris who underwent a more detailed evaluation of response. Each patient received verapamil, 240, 360, and 480 mg per day, for 1 week in a single-blind fashion; this was followed by a double-blind placebo-controlled randomized phase in which placebo was compared with verapamil, administered in the dose which produced the greatest improvement in exercise tolerance during the singleblind phase. During the double-blind phase, verapamil significantly reduced the mean anginal attack frequency 47% and nitroglycerin consumption 55%, and significantly increased exercise capacity on the treadmill 42%. Seven patients had adverse reactions (rhythm disturbances in 3 patients, pulmonary edema in 1, and noncardiac symptoms in 3) with 480 mg daily of verapamil, all of which disappeared with a reduction in the dose to 360 mg daily. In these 7 patients the improvement in exercise duration on the lower dose of the drug (360 mg 1156
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daily) was similar to that observed with the higher dose (480 mg daily). Tan et al.,‘* in their evaluation of 12 men aged 45 to 73 years, found that verapamil, 320 mg daily for 4 weeks, produced a 78% reduction in angina1 attacks and a 20% improvement in exercise duration on a treadmill, when compared with placebo therapy for 4 weeks. The ejection fraction declined from 40 f 9% (at rest) to 35 f 11% (at peak effort) during placebo therapy, whereas during verapamil therapy the ejection fraction did not decrease during exercise (44 f 8% at rest and 45 f 12% at peak effort). These 6 studies,11J4-l8 combined with ours,12 comprise 193 patients treated with verapamil in doubleblind, placebo-controlled, randomized protocols; all but 1 studyi showed significant improvement during treatment with verapamil. The dose of verapamil ranged from 120 to 480 mg daily; adverse effects were infrequent and minor in all but 1 study,17 in which more frequent adverse reactions were observed when a dose of 480 mg daily was employed. Since 82% of the patients studied were men, it is unclear whether verapamil has similar antianginal effects in women. In evaluating the efficacy of new antianginal medications, careful attention must be given to the recruitment of patients with stable mechanical and electrical heart function who will be reliable in taking both active drug and placebo pills. Subjective (angina1 attack frequency and nitroglycerin consumption) and objective (treadmill performance) measures of drug effect should be evaluated concurrently. Patients selected should have reproducible exercise-induced angina, preferably within 3 to 6 minutes,lg on a standard exercise protocol in order to avoid distress from leg fatigue or hyperventilation at higher intensities of exercise. In analyzing group patient exercise data, consideration should be given to placebo effects, to training effects during sequential exercise tests,20,21 and to interpatient variability during control or placebo exercise tests. In the present protocol, comparison of single and subsequent double-blind placebo tests revealed that the treadmill time increased and the submaximal exercise heart rate and rate-systolic blood pressure product decreased significantly after the patients had completed a minimum of 5 treadmill tests. These changes might have been due to a training effect, since blood verapamil and norverapamil levels measured at the time of the double-blind placebo test were 0 to 18 ng/ml in 24 patients. Such minute amounts of blood verapamil would have been unlikely to reflect lingering drug action on the heart. A further significant increase in treadmill performance induced by verapamil, as compared with placebo, occurred during the double-blind phase of the study. Since training effects, if present, would probably have been completed before the initiation of the double-blind study phase, these results confirmed the exercise-enhancing capacity of verapamil. In most studies on new antianginal therapy, some patients will respond better than others. Comparison of individual responses may elucidate mechanisms involved in a greater therapeutic response. In our study, 12 patients showed minimal (less than 10%) or no imVolume 50
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provement in exercise duration while receiving verapamil, compared with placebo, in the double-blind study phase. These 12 patients did not differ from the other 14 patients with respect to baseline angina1 frequency or nitroglycerin consumption. However, the mean exercise duration on the initial baseline exercise test before entry into the study was 23% less (p <0.05) in the 14 patients with a therapeutic response to verapamil during the double-blind phase than in patients with minimal responses. These findings indicate that verapamil may confer its greatest benefit on patients whose exercise capacity is most restricted by angina before entry into the study. Mechanism of verapamil action: In the present study verapamil, compared with placebo, significantly decreased both the resting and submaximal heart rate, the submaximal systolic blood pressure, and the resting and submaximal rate-pressure product during the double-blind phase. We observed a greater effect on heart rate than on systolic blood pressure; other investigators have noted just the opposite.22 Regardless of which effect predominates, these responses can be explained by the negative chronotropic actions of verapami1,2”J4 as well as its dilating effects on systemic arterioles.2”*26 These findings are consistent with the hypotensive actions of verapamil during rest and bicycle ergometry in patients with essential hypertension.27 Clinical implications and perspectives: Thus, verapamil is a safe, effective drug in the treatment of patients with stable exertional angina pectoris. The effective dose ranges from 240 to 480 mg daily in 3 or 4 divided doses. Adverse effects are infrequent and mild, and consist primarily of constipation and prolongation of atrioventricular conduction. Overt congestive heart failure may occur rarely in patients with preserved left ventricular function. Abnormal hepatic function has been reported infrequently after verapamil therapy. In the treatment of angina of effort, verapamil may offer special advantages to patients who also have bronchial asthma or peripheral vascular disease. Such patients are likely to have an exacerbation of these disorders during therapy with beta-adrenergic blocking agents, when these are used in doses required to alleviate exerciseinduced angina.6,7
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References 1. Rekhak N. Long-acting nitrates in the treatment of angina pectoris. JAMA 1976;236:1399-1402. 2. Abrams J. Nitroglycerin and long-acting nitrates. N Engl J Med 1979;302: 1234-1237. 3. Warren SG, Brewer DL, Orgaln ES. Long-term propranolol treatment for angina pectoris. Am J Cardiol 1976;37:420-426. 4. P&hard BNC. Propranolol in the treatment of angina: a review. Postgrad Med J 1976;52:31-41. 5. GoldsteInRE, RosingDR, Redwood DR, Beiser GD, Epstein SE. Clinical and circulatory effects of isosorbide dinitrate. Circulation 1971;43:629640. 6. Shand DG. Propranolol. N Engl J Med 1975;293:260-265. 7. McNeIII RS, Ingram CG. The effect of propranolol on ventilatory function. Am J Cardiol 1966;16:473-475. 8. Fleckansteln A. Specific pharmacology of calcium in myocardium. cardiac pacemakers, and vascular smooth muscle. Ann Rev Pharmacol Toxicol 1977;17:149-66. 9. Zsoter lT. Calcium antagonists. Am Heart J 1960;99:605-610. 10. Ellrodt G, Chew CYC, Slngh 9. Therapeutic implications of slow-channel blockade in cardiocirculatory disorders. Circulation 1980;62:669-679. 11. Bala Subramanlan V, Paramaslvan R, Lahlrl A, Raftery EB. Verapamil in chronic stable angina: a controlled study with computerized multistage treadmill exercise. Lancet 1960:1:641-644. 12. Broclsky SJ, Cutler SS, Welner DA, McCabe CH, Ryan TJ, Klein MD. Treatment of stable angina of effort with verapamil. A double-blind pla~;~o-controlled randomized crossover study. Circulation 1962;66:569“I
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13. Bruce AA, Hornstein TR. Exercise stress testing in evaluation of patients with ischemic heart disease. Prog Cardiovasc Dis 1969; 11:371-390. 14. Neumann y, Lulsada AA. Double-blind evaluation of orally administered iproveratril In patients with angina pectoris. Am J Med Sci 1966;251: 552-556. 15. Phear DN. Veraoamil in anaina: a double-blind trial. Br Med J 1968:2: 740-741. r 16. Andreasen F, Boye E, Chrlstofferson E, et al. Assessment of verapamil in the treatment of angina pectoris. Eur J Cardiol 1975;2:443-448. 17. Pine MB. Citron D. Baillev‘W. et al. Veraoamil versus olacebo in relievina stable angina pecioris. drcuiation 1982;‘65: 17-22. ’ 18. Tan AlH, Sadlck N, Kelley T, Harris PJ, Freedman SB, Bautovlch G. Vafapamil in stable effort angina: effect on left ventricular function evaluated with exercise ventriculography. Am J Cardiol 1962;49:425-430. 19. Redwood DR, Roslng Oq, Goldstein RE, Belser GD, Epstein SE. Importance of the desi of an exercise protocol in the evaluation of patients with angina pectoris. I?lrcutabon 1971;43:618-628. 20. Smokler PE, MacAlpln RV, Alvaro A, Kattus A. Reproducibility of a multistage mean maximal treadmill test for exercise tolerance in angina pectoris. Circulation 1973;48:346-351. 21. Blom@a! CG, Atkins JM. Repeated exercise testyg in Ftients with angina eTEt;r: reproducibility and follow-up results. Clrculabon 1971;44:Suppl
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22. Frlshman WH, Klein NA, Strom JA, et al. Superiority of verapamil to propranolol in stable angina pectoris: a double-blind, randomized cross&er trial. Circulation 1982;65:Suppl 1:1-51-l-59. 23. Wit AL, Cranefield PF. Effect of verapamil on the sinoatrial and atrioventricular nodes of the rabbit and the mechanism by which it arrests reentrant atrioventricular tachycardia. Circ Res 1974;35:413-425. 24. Zlpes DP, Fisher JC. Effects of agents which inhibit the slow channel on sinus node automaticity and atrioventricular conduction in the dog. Circ Res 1974:34:184-192. 25. Nay6 WG, Ffchte~ I, SwannJB, et al. Some effects of iproveratril(Isoptin) ;;,ihe cardiovascular system. J Pharmacol Exp Ther 1968;161:24726. Ferllnz J, Easthope JL, Aronow WS. Effects of verapamil on myocardial performance in coronary disease. Circulation 1979;59:313-319. 27. Gould BA, Mam S, Kies~ H, Bala. Subramanlan V, Raflary EB. The 24 hour ;~~;yry blood pressure proflle with verapamil. Circulation 1982;65:
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