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Randomized, placebo-controlled study of the effect of verapamil on exercise hemodynamics in coronary artery disease
Randomized, Placebo-ControlledStudy of the Effect of Verapamil on Exercise Hemodynamics in Coronary Artery Disease J. NORMAN PATTON, MD, RONALD E. VLIETSTRA, MB, ChB, and ROBERT L. FRYE, MD
At cardiac catheterization, 16 patients with coronary artery disease (14 men and 2 women) were allocated by a random, double-blind method to intervention with placebo (saline solution) or verapamil (0.2 mg/kg total by bolus and by lo-minute infusion). In all patients, resting and exercise (3 minutes with a bicycle at 150 kgbm/min) hemodynamic values were obtained during a control period and after intervention. Subsequent lefl ventriculography and coronary arteriography revealed a mean ejection fraction of 52 and 53% and the mean number of diseased vessels (3-vessel scale) of 2.1 and 1.5
in the placebo and verapamil groups, respectively. In both groups of patients, exercise induced significant increased heart rate, mean arterial pressure, left ventricular end-diastolic pressure and cardiac index. Verapamil increased the heart rate and decreased the mean arterial pressure at rest and the arterial pressure during exercise. It did not affect exercise-induced increases in left ventricular enddiastolic pressure or cardiac index. These results support a role for peripheral mechanisms mediating the antianginal effects of verapamil. (Am J Cardiol 1964; 53:674-678)
Verapamil is effective in the treatment of rest1 and exertionaW angina pectoris. Although the drug is clearly effective in preventing coronary artery spasm4 and has significant hemodynamic effects at rest,5 data on its effect on exercise hemodynamics are limited.6 To further elucidate the mechanism of its action in exertional angina pectoris, we present hemodynamic data obtained at rest and during exercise in patients with coronary artery disease (CAD).
failure. Study patients were not taking other cardioactive medications. Specifically, none was receiving @-blocking drugs or calcium antagonists, and administration of nitrates was discontinued at least 8 hours before the study. Study protocol: All hemodynamic measurements were obtained with the patients supine before injection of contrast material. Left ventricular (LV) catheterization was carried out by the brachial approach with fluid-filled catheters attached to pressure-sensitive transducers (Statham P23D). The 0 reference was placed at the midchest level. Baseline data included heart rate, brachial artery and LV pressures, and cardiac index. The cardiac index was measured by LV injection of indocyanine green and withdrawal of blood from the brachial artery through a cuvette densitometer (model XC302, Waters Corp.). The stroke work index was calculated from the following formulas: (mean brachial artery pressure - LV end-diastolic pressure) X stroke volume index X 0.0144. All measurements were repeated after 2 minutes with the feet in the upright position attached to a bicycle ergometer and after 3 minutes of exercise at 150 kgm/min. The patients were allowed to rest and then were given either placebo or verapamil in a double-blind manner. Verapamil was given as a bolus at 0.1 mg/kg and was followed by a lo-minute infusion at 0.01 mg/kg/min for a total dose of 0.2 mg/kg. Hemodynamic measurements were then repeated at rest, after elevation of the feet for 2 minutes, and after exercise at 150 kg-m/min for 3 minutes. After the exercise protocol, biplane LV cineangiography was performed with diatrizoate meglumine (Renografin-769 at 0.6 ml/kg injected over a 3-second period. The ejection fraction was calculated by a previously described videometric tech-
Methods Serial measurements of cardiac function made in the catheterization laboratory are known to be subject to many sources of variation.7 We previously demonstrated considerable individual variation in placebo-treated control subjects.5 Therefore, a randomized, double-blind, placebo-controlled study design was used in a predetermined number of patients. Selection of patients: The study group included 16 patients. All were referred to the cardiac catheterization laboratory because of suspected CAD. They had no evidence of other heart disease, and there were no clinical signs of heart
From the Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota. Manuscript received August 15, 1983; revised manuscript received December 2, 1983, accepted December 6, 1983. Address for reprints: Ronald E. Vlietstra, MB, ChB, Mayo Clinic, Rochester, Minnesota 55905. 674
March 1, 1964
TABLE I
Outcome of Randomization Verapamil (n = 8)
Placebo (n = 8)
Age (W No. of diseased vessels (3-vessel scale) Ejection fraction (%) Heart rate at rest (beatslmin) Mean arterial pressure (mm Hg) Left ventricular end-diastolic oressure (mm Ha) Ca;diad index (lite&min/m*)
58f 11 2.1 f 0.8
56f 7 1.8 f 0.7
NS NS
52f 11 73 f 5 102 f 14 15 f 3
53 f 16 63fll 103f14 17f4
NS NS NS NS
3.1 f 0.6
2.8 f 0.6
NS
Values are mean f standard error of the mean. NS = not significant.
nique.9 Coronary angiography was carried out in standard angled views by the Sones technique.lO Statistical analysis: Statistical analysis was obtained by the Wilcoxon signed rank test. The randomization code was broken only after all studies and measurements had been completed.
Results All patients had significant CAD, with at least 70% diameter reduction of 1 major epicardial artery. The mean age, heart rate, arterial pressure, LV end-diastolic pressure, cardiac index, number of diseased vessels and LV ejection fraction in the 2 groups of patients are shown in Table I. In terms of these variables, no significant differences between the groups were evident. During the first period of exercise at 150 kgm/min, there were significant increases in mean heart rate, arterial pressure, LV end-diastolic pressure, cardiac index and LV stroke work index in both groups (Tables II and III). However, the patients in the 2 groups responded differently after receiving placebo or verapamil. In the patients who received placebo, there were minimal but significant decreases in resting LV end-diastolic pressure and cardiac index. The other hemodynamic variables at rest were unchanged (Table II, Fig. 1 to 4). During the second exercise period in the patients who received placebo, there were again significant increases in heart rate, mean arterial pressure, LV end-diastolic
Placebo
THE AMERICAN JOURNAL OF CARDIOLOGY
Volume 53
675
pressure, cardiac index and LV stroke work index. The mean values did not differ significantly from those in the first exercise period (Table II, Fig. 1 to 4). The product of mean exercise heart rate times blood pressure during exercise was 11,270 before and 11,932 after administration of the placebo. These values were not significantly different (Table II, Fig. 5). In contrast, in the group of patients who received verapamil, infusion of the drug was associated with a significant increase in mean heart rate (from 63 to 70 beats/min) and a decrease in mean arterial pressure (from 121 to 112 mm Hg) (Table III, Fig. 1 to 4). The other hemodynamic variables were unchanged. During the second period of exercise, the mean heart rate, blood pressure, LV end-diastolic pressure and cardiac index all increased significantly, as they had done during exercise before administration of the drug. The mean LV stroke work index increased from 49 to 57, but the change was not significant. The mean heart rate increased and mean arterial pressure decreased from values before the drug was given, but only the change in arterial pressure was significant (Table III, Fig. 3). The product of mean heart rate times blood pressure was not significantly different from that obtained before administration of verapamil (Table III, Fig. 5).
Placebo
Verapamil
r NS
130
t HR
Beats/ minute
--so l
110
90
h
70
A
Control
70
Intervention
11 L3e
1 _
I
Control
Intervention
FIGURE 2. Effect of intervention on heart rate (HR) during exercise. Control and intervention values are shown in placebo and verapamil groups. Bars indicate mean values. There were no significant changes (NS).
Verapamu
Placebo
Verapamil
85
=v 75
HR Beats/ minute
‘50pco.05
75
-
65
65
MAP mm Hg
-
110
I-9 55
55
45
i 45
fl
NS 35
L-
Control
130
+
90 pco.01
L 35
Intervention
Control
Intervention
FIGURE 1. Effect of intervention on heart rate (HR) at rest. Control and intervention values for heart rate are shown in placebo and verapamil groups. Bars indicate mean values. Only verapamil induced a significant change-an increase in HR. NS = not significant (p >0.05).
Control
Intervention
Control
Intervention
FIGURE 3. Effect of intervention on mean arterial pressure (MAP) at rest. Control and intervention values for MAP are shown in placebo and verapamil groups. Bars indicate mean values. There was a significant decrease in pressure in the verapamil group. NS = not significant.
Heart Rate (beats/min)
s; 58
73 f 5 72 f 8
Control Intervention
::
;t 62 75
Control Intervention
107 133 93
77 83 71
Control Intervention Control Intervention Control Intervention Control Intervention
95 f 9 96f 17
:: 84
::
101
:; 75
Control Intervention
Ex 105 103 tX
73 75 77
Control Intervention Control Intervention
Rest
Placebo Group
102 f 101 f
14 15
95 89
102 90 83 84 100 111 107 122
91 95
104 97 130 121
Rest
119f 123 f
9,213 9,912
14,124 20,482 8,928 8,556 10,540 10,660 11,392 10,956
10,302 10,403
13,860 12,772 11,808 11,718
HR X MAP, Exercise (beats/min X mm Hg)
14 19 11,270 f 1,939 11.932 f 3,669
Mean f Standard Deviation
111 118
132 154 96 93 124 130 128 132
102 103
132 124 123 126
Ex
Mean Arterial Pressure (mm Hg)
3.1 f 0.4 2.8 f 0.4
2.8 2.5
3.1 x.: 3:3 3.3 3.1 2.5 2.2
t.9” 218
3.5 2.7 3.3
Rest
4.7 f 0.5 4.6 f 1.0
Control Intervention
63f 70f
:t 76
t:
70 3:
11 8’
88f 93 f
Ex
10 13
:; 89
16”
93 :z
:: G
109 117 92 103
103 f 92 f
l
14 llf
113 100
123 99 114 95 107 96
79 ;: 81
‘99 101
95
Rest
121 f 112 f
10,710 10,146
13,392 13,248 10,414 8,550 10,922 8,840
7,626 8,010 9,102 10,208
12,426 13,221 10,672 11,124
HR X MAP, Exercise (beatslmin XmmHg)
15 14’
10,658 f 1,786 10,418 f 2,009
Mean f Standard Deviation
126 114
144 138 127 114 127 104
93 128: 116
114 113 116 108
Ex
Mean Arterial Pressure (mm Hg)
Significantly different from control value, p
16
Control Intervention
Control Intervention Control Intervention Control Intervention
13 14
15
Control Intervention Control Intervention
11 12
:3 tX 61
81 85 72
10
Rest
Control Intervention Control Intervention
9
Heart Rate (beatsimin)
Verapamil. Group
Case
TABLE Ill
2::
8:; 3.9 :::
4.7 3::
1.: 411
4.0 6.5 5.1
Ex
Cardiac Index (liters/min/m*)
2.8 f 0.6 3.1 f 0.6
2.9 4.0
3.8 3.7 2.5 2.7 1.8 2.3
I.3” 2:9 3.1 3.4
3.1 3.2 2.6
Rest
4.2 f 0.6 4.3 f 0.9
4.6 4.7
4.6 5.6 3.4 3.2 4.9 4.1
z.t 3:6 3.8 3.6
4.5 5.6 4.2
Ex
Cardiac Index (liters/min/m*)
Ex = exercise: HR = heart rate: LVEDP = left ventricular end-diastolic pressure; MAP = mean arterial pressure.
Case
TABLE II
89f 68f
3; 91
5:
:3” 5: 65 73
10 16
54f 49f
64 63
:: 5”; 38 ;:
14” 33 68
‘44.
41
17 12
Rest
66 f 57 f
16 22
f2” 65
71
1:; z:
45 42 Sf
62 41
::
Ex
17 f 5 18 f 4
14 18
:‘3
:B 11 ;:
:s :3”
1.9
20
Rest
::
:5 23 11 9
:; 13
zz
z: 33
32
Ex
22 f 9 24 f 9
26 f 9 28 f 7
:Ft
:x 30 34 40 31
;!z 37 30
27 24 25 35
Ex
LVEDP (mm Hg)
15 f 3 11 f4
1:8
::
2:
:7” 1;
:8”
::
;2”
54”
13
Rest
LVEDP (mm Hg)
56
Ex
Stroke Work Index (g-m/m*)
53f 10 50 f 8
53 51
2:
z: 2: 43 Fz
41
62 48 ;:
Rest
Stroke Work Index (pm/m*)
e
March 1, 1964
The effect of verapamil on the relation between LV stroke work index and LV end-diastolic pressure was investigated by plotting the change in LV stroke work index between the first and second exercise periods against the corresponding change in LV end-diastolic pressure (Fig. 6). In both the patients who received placebo and those who received verapamil, no consistent pattern of response occurred, particularly no clear evidence of any change in overall ventricular performance after administration of verapamil. Discussion Verapamil is effective in ameliorating symptoms in exertional angina.2*3 The most important effect of antianginal drugs is to produce a favorable :relation between myocardial oxygen supply and demand. Potential antianginal actions of verapamil have been reviewed by Vanhoutte rl; they include negative chronotropicI and inotropic13 effects on the heart and arterial dilatation,14 reducing afterload. Each of these actions tends to reduce myocardial oxygen demand. In addition, myocardial oxygen supply may be increased by the drug’s coronary vasodilator actionr”r7 or by a reduction in platelet aggregation.18 In studies in which patients have exercised or pacing had been performed to the point of angina pectoris, the effect of orally administered verapamil has been to decrease the double product of heart rate and arterial pressure for any given exercise or pacing stress.2Jg Thus, by lowering myocardial oxygen demand, verapamil delays the onset of angina and ischemic LV dysfunction during a graded stress evaluation.2Jo,21 Generally, no significant effect has been observed on myocardial oxygen supply, as indicated by an unchanged double product at onset of angina.2JsT20 In this study, we demonstrated that intravenously administered verapamil produced a significant decrease in mean arterial pressure during exercise, an insignificant increase in heart rate, and no change in LV enddiastolic pressure, LV stroke work index or cardiac index. We did not observe any significant change in the product of mean heart rate times blood pressure with the protocol used. We hypothesize that transient hy-
Placebo
THE AMERICAN JOURNAL OF CARDIOLOGY Volume 53
677
potension-induced reflex tachycardia, often noted after intravenous administration of verapamil,22 prevented a significant decrease in double product at this mild exercise load. The absence of a clear effect on the relation between the change in exercise LV stroke work index and the change in LV end-diastolic pressure suggests that the drug did not depress overall cardiac performance during exercise. The LV end-diastolic pressure usually increases during supine exercise in patients with CAD.8 Marked increases probably reflect an ischemically mediated decrease in compliance that can be reversed with nitroglycerin or surgical revascularization.s,23y24 In the current study, however, acutely administered verapamil did not diminish exercise-induced increases in LV end-diastolic pressure. Verapamil is at least as effective as propranolol in patients with exertional angina.2Jt25s26 It is pertinent, then, to compare its effects on exercise hemodynamics with those of propranolol and nitroglycerin in patients who have CAD. Administration of nitroglycerin is associated with a decrease in LV end-diastolic pressure and volume and a reflex increase in heart rate.z4T27In addition, nitro-
Placebo
Veraoamil 2oow
1sooo 16000
HR x BP Beats x mm Hg/ min
16ooO
,4000 -
12ooa
l.?WO
-loo00
Iwo0
Booo
8000
Control
Intervention
R L.l -
Control
Intervention
FffiURE 5. Effect of intervention on product of exercise heart rate times mean arterial pressure (HR X BP). Control and intervention values are shown in placebo and verapamil groups. Bars indicate mean values. Changes were not significant (NS).
Verapamil
.
150
+30 ALVSWI g. m/m2
t I30 -
MAP mm Hg
--
A A
--
+20 +10
110
110
+
90
70
L Control
+5
90 t
NS
-5.
Control
.
.
--
701 Intervention
,
I -10
:'
P
_,o__
+‘:
l
l '
.
A
ALVEDP mm Hg
A
A Intervention
FffiURE 4. Effect of intervention on mean arterial pressure (MAP) during exercise. Control and intervention values are shown in placebo and verapamil groups. Bars indicate mean values. There was a significant decrease in the verapamil group. NS = not significant.
A
-20 --
At
FIGURE 6. Change in exercise left ventricular stroke work index (ALVSWI) and left ventricular enddiastolic pressure (ALVEDP) (intervention minus control) in placebo and verapamil groups.
676
EFFECT OF VERAPAMIL ON EXERCISE HEMODYNAMICS
glycerin improves some regional wall motion abnormalities and prevents the decrease in regional ejection fraction associated with exercise-induced myocardial ischemia.27 Propranolol has different hemodynamic effects. It decreases the heart rate, arterial pressure, LV stroke work index and cardiac index during exercise.29 In a dog model of ischemia, propranolol also prevents the decrease in contractility of ischemic tissue during exercise while depressing contractility in the adjacent normal tissue.30 Our results indicate that a major hemodynamic effect of intravenously administered verapamil appears to be a decrease in afterload without any major alteration in overall cardiac performance during mild supine exercise. The characteristic changes produced by nitroglycerin and propranolol did not occur with verapamil. These findings coincide with those observed by Pfisterer et al27 in which a different calcium antagonist (nifedipine) was used. This demonstration of a different antianginal effect for verapamil supports the logic of combining the drug with nitrates or &blocking drugs in selected patients with refractory angina pectoris. It also reinforces the clinical strategy of identifying specific antianginal agents best suited to the needs of individual patients. Acknowledgment: We appreciate the help of Lila R. Elveback, PhD, in designing the study and of Duane M. Ilstrup, MS, in performing the statistical analyses. We thank the Knoll Pharmaceutical Company for financial support and the supply of verapamil used in this study. References 1. Johnson SM, Maurftson DR, WilIerson JT, Hlllfs LD. A controlled trial of veraoamil for Prinzmetal’s variant anoina. N Engl J Med 1961;304:662666.’ 2. Leon MB, Roalng DR, Bonow RO, Lipson LC, Epoteln SE. Clinical efficacy of veraoamil alone and combined with wooranolol in treatina oatients with chrt&&able angina~pectoris. Am J Cardiol 1961;46:131~1’39. 3. Frlshman WH, Klein NA, Strom JA, Wlllens H, LeJemlel TH, Jentzer J, Slegel L, Klein P, Klrsohen N, Silverman R, Pollack S, Doyle R. Klraten E, Sonnenbllck EH. Superiority of verapamil to propranolol in stable angina oectoris: a double-blind, randomized crossover trial. Circulation 1962; &i:suppl 1:1-51-l-59. 4. Brown BG, Pierce CD, Petersen RB, Slngh BN, Boleon EL, Dodge HT. Verapamil, a mild epicardial coronary dilator, inhibits sympathetic and ergonovine-induced coronary constriction in humans (abstr). Circulation 1981;84:suppl IV:IV-150. 5. Vlfetetra RE. Farlas MAC, Frye RL, Smith HC, Rltman EL. Effect of verapamil on lefiventricular fbnction: a~randomized, placebo-controlled study. Am J Cardiol 1963;51:1213-1217. 6. Atterhog JH, Ekelund LG. Haemodynamic effects of intravenous verapamil at rest and during exercise in subjectively healthy middle-aged men. Eur J Clin Pharmacol 1975;8:317-322.
7. Thadanl U, Lewla JR, Manyari D, Boroomand K, Cohen J, Weaf RO, P&er JD. Are the clinial and hemodynamic events during exercise stress testing in invasive shdies in patients with angina pectoris reproducible? Circulation 1980;61:744-750. 6. McCalllater BD, Ylplntsol 7, Hallermann FJ, Wallace RB, Frye RL. Left ventricular performance during mild supine leg exercise in coronary artery disease. Circulation 1966;37:922-931. 9. Rltman EL, Sturm RE, Wood EH. Biplane roentgen videometric system for dynamic (8Olsec) studies of the shape and size of circulatory structures, particularly the left ventricle. Am J Cardiol 1973;32:160-167. 10. Sones FM Jr, Shlrey EK. Cine coronary arteriography. Mod Concepts Cardiovasc Dis 1962;31:735-738. 11. Vanhoutte PM. Calcium-entry blockers and vascular smooth muscle. Circulation 1982;65:suppl l:l-1 l-l-19. 12. Wft AL, Cranefield PF. Effect of verapamil on the sinoatrial and atrioventricular nodes of the rabbit and the mechanism by which it arrests reentrant atrioventricular nodal tachycardia. Circ Res 1974;35:413-425. 13. Nayler WG, S&o J. Effect of verapamil on contractility, oxygen utilization, and calcium exchangeability in mammalian heart muscle. Cardiovasc Res 1972;6:120-128. 14. Haeusler 0. Differential effect of verapamil on excitation-contraction coupling in smooth muscle and on excitation-secretion coupling in adrenergic nerve terminals. J Pharmacol Ex Ther 1972;160:672-682. 15. Haas H, Hartfekler G. &Isopropyl-a- P(N-methyl-N-homoveratryl)+amino-propyl]+l-dimethoxyphenyl-acetonitril, sine substanz mit coronarnfasserweiternden Eigenschaften. Arzneim Forsch 1962;12:549-556. 16. r hew CYC, Srown BG, Slngh BN, He&t HS, Sohnugg SJ, Wang M, Shah PM, Do+ HT. Mechanism of action of verapamil in ischemii heart disease: observations on changes in systemic and coronary hemodynamics and coronary vasomobility. Clin Invest Med 1980;3:151-156. 17. Chew CY, Brown BG, SInah BN, Wang MM, Pierce C, Petersen R. Effects of verapamil on coronary hmodynamic function and vasomobility relative to its mechanism of antianainal action. Am J Cardiol 1983:51:699-705. 16. Pumphrey CW, Fuater V, 6ewanjee M, Kayo M, Cheaebfo J,. Vlletatra R. Verapamil is an effective in vivo inhibitorof platelet activation In peripheral vascular grafts in dogs (abstr). Circulation 1961;64:suppl IV:IV-56. 19. Rauleau JL, ChatlerJee K, Ports TA, Doyle MB, Hlramatau B, Pwmley WW. Mechanism of relief of pacing-induced angina with oral verapamil: reduced -oxygen demand. Circulation 1963;67:94-100. 20. Pine MB, Cltron PD, Ballly DJ, Butman S, Plasencfa GO, Landa DW, Wang RK. Verapamil versus placebo in relieving stable angina pectoris. Circulation 1982;65:17-22. 21. Hecht HS, Chew CYC, Burnam YH, Hopklns J, Schnug9 S, Slngh BN. Verapamil in chronic stable angina: amelioration of pacing-induced abnormalities of left ventricular ejection fraction, regional wall motion, lactate metabolism and hemodynamics. Am J Cardiol 1981;46:536-544. 22. Klein HO, Nlnlo R, Oren V, Lang R, Sarell P, DlSegnl E, Davld D, Guerrero J, Kapllnaky E. The acute hemodynamic effects of intravenous verapamil in coronary artery disease: assessment by equilibrium-gated radionuclide ventriculography. Circulation 1983;87:101-110. 23. Vlletstra RE, Chesebro JH, Frye RL, Wallace RB. Improvement of left ventricular exercise hemodynamic function after aorta-coronary artery bypass raftin J Thorac Cardiovasc Surg 1961;61:65-91. 24. Parker g0, DI 8 lorgi S, West RO. A hemodynamic study of acute coronary insufficiency precipitated by exercise: with observations on the effects of nitroglycerin. Am J Cardiol 1988;17:470-483. 25. Sandier 0, Clayton GA, Thornlcroft SO. Clinical evaluation of verapamil in angina ectoris. Br Med J 1966;3:224-227. 26. Llvesley I! , Catley PF, Campbell RC, Oram S. Double-blind evaluation of verapamil, propranolol, and isosorbide dinitrate against a placebo in the treatment of angina pectoris. Br Med J 1973;1:375-376. 27. Pflsterer M, Glaus L, Burkart F. Comparative effects of nitroglycerin, nifedipine and metoprolol on regional left ventricular function in patients with one-vessel coronary disease. Circulation 1963;67:291-301. 26. Cheaebro JH, Rltman EL, Frye RL, Smlth HC, Rutherford BD, Fulton RE, Pluth JR, Barnhorat DA. Regional myocardial wall thickening response to nitroglycerin: a predictor of myocardial response to aortocoronary bypass surgery. Circulation 1978;57:952-957. 29. Parker JO, West RO, DlGiorgl S. Hemodynamic effects of propranolol in coronary heart disease. Am J Cardiol 1968;21:11-19. 30. Kumada T, Gallagher KP, Shlrato K, McKown D, Miller M, Kemper WS, Whfte F, Roes J Jr. Reproduction of exercise-induced regional my-dial dysfunction by propranolol: studies in a canine model of chronic coronary artery stenosis. Circ Res 1980;46: 190-200.
At cardiac catheterization, 16 patients with coronary artery disease (14 men and 2 women) were allocated by a random, double-blind method to intervention with placebo (saline solution) or verapamil (0.2 mg/kg total by bolus and by lo-minute infusion). In all patients, resting and exercise (3 minutes with a bicycle at 150 kgbm/min) hemodynamic values were obtained during a control period and after intervention. Subsequent lefl ventriculography and coronary arteriography revealed a mean ejection fraction of 52 and 53% and the mean number of diseased vessels (3-vessel scale) of 2.1 and 1.5
in the placebo and verapamil groups, respectively. In both groups of patients, exercise induced significant increased heart rate, mean arterial pressure, left ventricular end-diastolic pressure and cardiac index. Verapamil increased the heart rate and decreased the mean arterial pressure at rest and the arterial pressure during exercise. It did not affect exercise-induced increases in left ventricular enddiastolic pressure or cardiac index. These results support a role for peripheral mechanisms mediating the antianginal effects of verapamil. (Am J Cardiol 1964; 53:674-678)
Verapamil is effective in the treatment of rest1 and exertionaW angina pectoris. Although the drug is clearly effective in preventing coronary artery spasm4 and has significant hemodynamic effects at rest,5 data on its effect on exercise hemodynamics are limited.6 To further elucidate the mechanism of its action in exertional angina pectoris, we present hemodynamic data obtained at rest and during exercise in patients with coronary artery disease (CAD).
failure. Study patients were not taking other cardioactive medications. Specifically, none was receiving @-blocking drugs or calcium antagonists, and administration of nitrates was discontinued at least 8 hours before the study. Study protocol: All hemodynamic measurements were obtained with the patients supine before injection of contrast material. Left ventricular (LV) catheterization was carried out by the brachial approach with fluid-filled catheters attached to pressure-sensitive transducers (Statham P23D). The 0 reference was placed at the midchest level. Baseline data included heart rate, brachial artery and LV pressures, and cardiac index. The cardiac index was measured by LV injection of indocyanine green and withdrawal of blood from the brachial artery through a cuvette densitometer (model XC302, Waters Corp.). The stroke work index was calculated from the following formulas: (mean brachial artery pressure - LV end-diastolic pressure) X stroke volume index X 0.0144. All measurements were repeated after 2 minutes with the feet in the upright position attached to a bicycle ergometer and after 3 minutes of exercise at 150 kgm/min. The patients were allowed to rest and then were given either placebo or verapamil in a double-blind manner. Verapamil was given as a bolus at 0.1 mg/kg and was followed by a lo-minute infusion at 0.01 mg/kg/min for a total dose of 0.2 mg/kg. Hemodynamic measurements were then repeated at rest, after elevation of the feet for 2 minutes, and after exercise at 150 kg-m/min for 3 minutes. After the exercise protocol, biplane LV cineangiography was performed with diatrizoate meglumine (Renografin-769 at 0.6 ml/kg injected over a 3-second period. The ejection fraction was calculated by a previously described videometric tech-
Methods Serial measurements of cardiac function made in the catheterization laboratory are known to be subject to many sources of variation.7 We previously demonstrated considerable individual variation in placebo-treated control subjects.5 Therefore, a randomized, double-blind, placebo-controlled study design was used in a predetermined number of patients. Selection of patients: The study group included 16 patients. All were referred to the cardiac catheterization laboratory because of suspected CAD. They had no evidence of other heart disease, and there were no clinical signs of heart
From the Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota. Manuscript received August 15, 1983; revised manuscript received December 2, 1983, accepted December 6, 1983. Address for reprints: Ronald E. Vlietstra, MB, ChB, Mayo Clinic, Rochester, Minnesota 55905. 674
March 1, 1964
TABLE I
Outcome of Randomization Verapamil (n = 8)
Placebo (n = 8)
Age (W No. of diseased vessels (3-vessel scale) Ejection fraction (%) Heart rate at rest (beatslmin) Mean arterial pressure (mm Hg) Left ventricular end-diastolic oressure (mm Ha) Ca;diad index (lite&min/m*)
58f 11 2.1 f 0.8
56f 7 1.8 f 0.7
NS NS
52f 11 73 f 5 102 f 14 15 f 3
53 f 16 63fll 103f14 17f4
NS NS NS NS
3.1 f 0.6
2.8 f 0.6
NS
Values are mean f standard error of the mean. NS = not significant.
nique.9 Coronary angiography was carried out in standard angled views by the Sones technique.lO Statistical analysis: Statistical analysis was obtained by the Wilcoxon signed rank test. The randomization code was broken only after all studies and measurements had been completed.
Results All patients had significant CAD, with at least 70% diameter reduction of 1 major epicardial artery. The mean age, heart rate, arterial pressure, LV end-diastolic pressure, cardiac index, number of diseased vessels and LV ejection fraction in the 2 groups of patients are shown in Table I. In terms of these variables, no significant differences between the groups were evident. During the first period of exercise at 150 kgm/min, there were significant increases in mean heart rate, arterial pressure, LV end-diastolic pressure, cardiac index and LV stroke work index in both groups (Tables II and III). However, the patients in the 2 groups responded differently after receiving placebo or verapamil. In the patients who received placebo, there were minimal but significant decreases in resting LV end-diastolic pressure and cardiac index. The other hemodynamic variables at rest were unchanged (Table II, Fig. 1 to 4). During the second exercise period in the patients who received placebo, there were again significant increases in heart rate, mean arterial pressure, LV end-diastolic
Placebo
THE AMERICAN JOURNAL OF CARDIOLOGY
Volume 53
675
pressure, cardiac index and LV stroke work index. The mean values did not differ significantly from those in the first exercise period (Table II, Fig. 1 to 4). The product of mean exercise heart rate times blood pressure during exercise was 11,270 before and 11,932 after administration of the placebo. These values were not significantly different (Table II, Fig. 5). In contrast, in the group of patients who received verapamil, infusion of the drug was associated with a significant increase in mean heart rate (from 63 to 70 beats/min) and a decrease in mean arterial pressure (from 121 to 112 mm Hg) (Table III, Fig. 1 to 4). The other hemodynamic variables were unchanged. During the second period of exercise, the mean heart rate, blood pressure, LV end-diastolic pressure and cardiac index all increased significantly, as they had done during exercise before administration of the drug. The mean LV stroke work index increased from 49 to 57, but the change was not significant. The mean heart rate increased and mean arterial pressure decreased from values before the drug was given, but only the change in arterial pressure was significant (Table III, Fig. 3). The product of mean heart rate times blood pressure was not significantly different from that obtained before administration of verapamil (Table III, Fig. 5).
Placebo
Verapamil
r NS
130
t HR
Beats/ minute
--so l
110
90
h
70
A
Control
70
Intervention
11 L3e
1 _
I
Control
Intervention
FIGURE 2. Effect of intervention on heart rate (HR) during exercise. Control and intervention values are shown in placebo and verapamil groups. Bars indicate mean values. There were no significant changes (NS).
Verapamu
Placebo
Verapamil
85
=v 75
HR Beats/ minute
‘50pco.05
75
-
65
65
MAP mm Hg
-
110
I-9 55
55
45
i 45
fl
NS 35
L-
Control
130
+
90 pco.01
L 35
Intervention
Control
Intervention
FIGURE 1. Effect of intervention on heart rate (HR) at rest. Control and intervention values for heart rate are shown in placebo and verapamil groups. Bars indicate mean values. Only verapamil induced a significant change-an increase in HR. NS = not significant (p >0.05).
Control
Intervention
Control
Intervention
FIGURE 3. Effect of intervention on mean arterial pressure (MAP) at rest. Control and intervention values for MAP are shown in placebo and verapamil groups. Bars indicate mean values. There was a significant decrease in pressure in the verapamil group. NS = not significant.
Heart Rate (beats/min)
s; 58
73 f 5 72 f 8
Control Intervention
::
;t 62 75
Control Intervention
107 133 93
77 83 71
Control Intervention Control Intervention Control Intervention Control Intervention
95 f 9 96f 17
:: 84
::
101
:; 75
Control Intervention
Ex 105 103 tX
73 75 77
Control Intervention Control Intervention
Rest
Placebo Group
102 f 101 f
14 15
95 89
102 90 83 84 100 111 107 122
91 95
104 97 130 121
Rest
119f 123 f
9,213 9,912
14,124 20,482 8,928 8,556 10,540 10,660 11,392 10,956
10,302 10,403
13,860 12,772 11,808 11,718
HR X MAP, Exercise (beats/min X mm Hg)
14 19 11,270 f 1,939 11.932 f 3,669
Mean f Standard Deviation
111 118
132 154 96 93 124 130 128 132
102 103
132 124 123 126
Ex
Mean Arterial Pressure (mm Hg)
3.1 f 0.4 2.8 f 0.4
2.8 2.5
3.1 x.: 3:3 3.3 3.1 2.5 2.2
t.9” 218
3.5 2.7 3.3
Rest
4.7 f 0.5 4.6 f 1.0
Control Intervention
63f 70f
:t 76
t:
70 3:
11 8’
88f 93 f
Ex
10 13
:; 89
16”
93 :z
:: G
109 117 92 103
103 f 92 f
l
14 llf
113 100
123 99 114 95 107 96
79 ;: 81
‘99 101
95
Rest
121 f 112 f
10,710 10,146
13,392 13,248 10,414 8,550 10,922 8,840
7,626 8,010 9,102 10,208
12,426 13,221 10,672 11,124
HR X MAP, Exercise (beatslmin XmmHg)
15 14’
10,658 f 1,786 10,418 f 2,009
Mean f Standard Deviation
126 114
144 138 127 114 127 104
93 128: 116
114 113 116 108
Ex
Mean Arterial Pressure (mm Hg)
Significantly different from control value, p
16
Control Intervention
Control Intervention Control Intervention Control Intervention
13 14
15
Control Intervention Control Intervention
11 12
:3 tX 61
81 85 72
10
Rest
Control Intervention Control Intervention
9
Heart Rate (beatsimin)
Verapamil. Group
Case
TABLE Ill
2::
8:; 3.9 :::
4.7 3::
1.: 411
4.0 6.5 5.1
Ex
Cardiac Index (liters/min/m*)
2.8 f 0.6 3.1 f 0.6
2.9 4.0
3.8 3.7 2.5 2.7 1.8 2.3
I.3” 2:9 3.1 3.4
3.1 3.2 2.6
Rest
4.2 f 0.6 4.3 f 0.9
4.6 4.7
4.6 5.6 3.4 3.2 4.9 4.1
z.t 3:6 3.8 3.6
4.5 5.6 4.2
Ex
Cardiac Index (liters/min/m*)
Ex = exercise: HR = heart rate: LVEDP = left ventricular end-diastolic pressure; MAP = mean arterial pressure.
Case
TABLE II
89f 68f
3; 91
5:
:3” 5: 65 73
10 16
54f 49f
64 63
:: 5”; 38 ;:
14” 33 68
‘44.
41
17 12
Rest
66 f 57 f
16 22
f2” 65
71
1:; z:
45 42 Sf
62 41
::
Ex
17 f 5 18 f 4
14 18
:‘3
:B 11 ;:
:s :3”
1.9
20
Rest
::
:5 23 11 9
:; 13
zz
z: 33
32
Ex
22 f 9 24 f 9
26 f 9 28 f 7
:Ft
:x 30 34 40 31
;!z 37 30
27 24 25 35
Ex
LVEDP (mm Hg)
15 f 3 11 f4
1:8
::
2:
:7” 1;
:8”
::
;2”
54”
13
Rest
LVEDP (mm Hg)
56
Ex
Stroke Work Index (g-m/m*)
53f 10 50 f 8
53 51
2:
z: 2: 43 Fz
41
62 48 ;:
Rest
Stroke Work Index (pm/m*)
e
March 1, 1964
The effect of verapamil on the relation between LV stroke work index and LV end-diastolic pressure was investigated by plotting the change in LV stroke work index between the first and second exercise periods against the corresponding change in LV end-diastolic pressure (Fig. 6). In both the patients who received placebo and those who received verapamil, no consistent pattern of response occurred, particularly no clear evidence of any change in overall ventricular performance after administration of verapamil. Discussion Verapamil is effective in ameliorating symptoms in exertional angina.2*3 The most important effect of antianginal drugs is to produce a favorable :relation between myocardial oxygen supply and demand. Potential antianginal actions of verapamil have been reviewed by Vanhoutte rl; they include negative chronotropicI and inotropic13 effects on the heart and arterial dilatation,14 reducing afterload. Each of these actions tends to reduce myocardial oxygen demand. In addition, myocardial oxygen supply may be increased by the drug’s coronary vasodilator actionr”r7 or by a reduction in platelet aggregation.18 In studies in which patients have exercised or pacing had been performed to the point of angina pectoris, the effect of orally administered verapamil has been to decrease the double product of heart rate and arterial pressure for any given exercise or pacing stress.2Jg Thus, by lowering myocardial oxygen demand, verapamil delays the onset of angina and ischemic LV dysfunction during a graded stress evaluation.2Jo,21 Generally, no significant effect has been observed on myocardial oxygen supply, as indicated by an unchanged double product at onset of angina.2JsT20 In this study, we demonstrated that intravenously administered verapamil produced a significant decrease in mean arterial pressure during exercise, an insignificant increase in heart rate, and no change in LV enddiastolic pressure, LV stroke work index or cardiac index. We did not observe any significant change in the product of mean heart rate times blood pressure with the protocol used. We hypothesize that transient hy-
Placebo
THE AMERICAN JOURNAL OF CARDIOLOGY Volume 53
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potension-induced reflex tachycardia, often noted after intravenous administration of verapamil,22 prevented a significant decrease in double product at this mild exercise load. The absence of a clear effect on the relation between the change in exercise LV stroke work index and the change in LV end-diastolic pressure suggests that the drug did not depress overall cardiac performance during exercise. The LV end-diastolic pressure usually increases during supine exercise in patients with CAD.8 Marked increases probably reflect an ischemically mediated decrease in compliance that can be reversed with nitroglycerin or surgical revascularization.s,23y24 In the current study, however, acutely administered verapamil did not diminish exercise-induced increases in LV end-diastolic pressure. Verapamil is at least as effective as propranolol in patients with exertional angina.2Jt25s26 It is pertinent, then, to compare its effects on exercise hemodynamics with those of propranolol and nitroglycerin in patients who have CAD. Administration of nitroglycerin is associated with a decrease in LV end-diastolic pressure and volume and a reflex increase in heart rate.z4T27In addition, nitro-
Placebo
Veraoamil 2oow
1sooo 16000
HR x BP Beats x mm Hg/ min
16ooO
,4000 -
12ooa
l.?WO
-loo00
Iwo0
Booo
8000
Control
Intervention
R L.l -
Control
Intervention
FffiURE 5. Effect of intervention on product of exercise heart rate times mean arterial pressure (HR X BP). Control and intervention values are shown in placebo and verapamil groups. Bars indicate mean values. Changes were not significant (NS).
Verapamil
.
150
+30 ALVSWI g. m/m2
t I30 -
MAP mm Hg
--
A A
--
+20 +10
110
110
+
90
70
L Control
+5
90 t
NS
-5.
Control
.
.
--
701 Intervention
,
I -10
:'
P
_,o__
+‘:
l
l '
.
A
ALVEDP mm Hg
A
A Intervention
FffiURE 4. Effect of intervention on mean arterial pressure (MAP) during exercise. Control and intervention values are shown in placebo and verapamil groups. Bars indicate mean values. There was a significant decrease in the verapamil group. NS = not significant.
A
-20 --
At
FIGURE 6. Change in exercise left ventricular stroke work index (ALVSWI) and left ventricular enddiastolic pressure (ALVEDP) (intervention minus control) in placebo and verapamil groups.
676
EFFECT OF VERAPAMIL ON EXERCISE HEMODYNAMICS
glycerin improves some regional wall motion abnormalities and prevents the decrease in regional ejection fraction associated with exercise-induced myocardial ischemia.27 Propranolol has different hemodynamic effects. It decreases the heart rate, arterial pressure, LV stroke work index and cardiac index during exercise.29 In a dog model of ischemia, propranolol also prevents the decrease in contractility of ischemic tissue during exercise while depressing contractility in the adjacent normal tissue.30 Our results indicate that a major hemodynamic effect of intravenously administered verapamil appears to be a decrease in afterload without any major alteration in overall cardiac performance during mild supine exercise. The characteristic changes produced by nitroglycerin and propranolol did not occur with verapamil. These findings coincide with those observed by Pfisterer et al27 in which a different calcium antagonist (nifedipine) was used. This demonstration of a different antianginal effect for verapamil supports the logic of combining the drug with nitrates or &blocking drugs in selected patients with refractory angina pectoris. It also reinforces the clinical strategy of identifying specific antianginal agents best suited to the needs of individual patients. Acknowledgment: We appreciate the help of Lila R. Elveback, PhD, in designing the study and of Duane M. Ilstrup, MS, in performing the statistical analyses. We thank the Knoll Pharmaceutical Company for financial support and the supply of verapamil used in this study. References 1. Johnson SM, Maurftson DR, WilIerson JT, Hlllfs LD. A controlled trial of veraoamil for Prinzmetal’s variant anoina. N Engl J Med 1961;304:662666.’ 2. Leon MB, Roalng DR, Bonow RO, Lipson LC, Epoteln SE. Clinical efficacy of veraoamil alone and combined with wooranolol in treatina oatients with chrt&&able angina~pectoris. Am J Cardiol 1961;46:131~1’39. 3. Frlshman WH, Klein NA, Strom JA, Wlllens H, LeJemlel TH, Jentzer J, Slegel L, Klein P, Klrsohen N, Silverman R, Pollack S, Doyle R. Klraten E, Sonnenbllck EH. Superiority of verapamil to propranolol in stable angina oectoris: a double-blind, randomized crossover trial. Circulation 1962; &i:suppl 1:1-51-l-59. 4. Brown BG, Pierce CD, Petersen RB, Slngh BN, Boleon EL, Dodge HT. Verapamil, a mild epicardial coronary dilator, inhibits sympathetic and ergonovine-induced coronary constriction in humans (abstr). Circulation 1981;84:suppl IV:IV-150. 5. Vlfetetra RE. Farlas MAC, Frye RL, Smith HC, Rltman EL. Effect of verapamil on lefiventricular fbnction: a~randomized, placebo-controlled study. Am J Cardiol 1963;51:1213-1217. 6. Atterhog JH, Ekelund LG. Haemodynamic effects of intravenous verapamil at rest and during exercise in subjectively healthy middle-aged men. Eur J Clin Pharmacol 1975;8:317-322.
7. Thadanl U, Lewla JR, Manyari D, Boroomand K, Cohen J, Weaf RO, P&er JD. Are the clinial and hemodynamic events during exercise stress testing in invasive shdies in patients with angina pectoris reproducible? Circulation 1980;61:744-750. 6. McCalllater BD, Ylplntsol 7, Hallermann FJ, Wallace RB, Frye RL. Left ventricular performance during mild supine leg exercise in coronary artery disease. Circulation 1966;37:922-931. 9. Rltman EL, Sturm RE, Wood EH. Biplane roentgen videometric system for dynamic (8Olsec) studies of the shape and size of circulatory structures, particularly the left ventricle. Am J Cardiol 1973;32:160-167. 10. Sones FM Jr, Shlrey EK. Cine coronary arteriography. Mod Concepts Cardiovasc Dis 1962;31:735-738. 11. Vanhoutte PM. Calcium-entry blockers and vascular smooth muscle. Circulation 1982;65:suppl l:l-1 l-l-19. 12. Wft AL, Cranefield PF. Effect of verapamil on the sinoatrial and atrioventricular nodes of the rabbit and the mechanism by which it arrests reentrant atrioventricular nodal tachycardia. Circ Res 1974;35:413-425. 13. Nayler WG, S&o J. Effect of verapamil on contractility, oxygen utilization, and calcium exchangeability in mammalian heart muscle. Cardiovasc Res 1972;6:120-128. 14. Haeusler 0. Differential effect of verapamil on excitation-contraction coupling in smooth muscle and on excitation-secretion coupling in adrenergic nerve terminals. J Pharmacol Ex Ther 1972;160:672-682. 15. Haas H, Hartfekler G. &Isopropyl-a- P(N-methyl-N-homoveratryl)+amino-propyl]+l-dimethoxyphenyl-acetonitril, sine substanz mit coronarnfasserweiternden Eigenschaften. Arzneim Forsch 1962;12:549-556. 16. r hew CYC, Srown BG, Slngh BN, He&t HS, Sohnugg SJ, Wang M, Shah PM, Do+ HT. Mechanism of action of verapamil in ischemii heart disease: observations on changes in systemic and coronary hemodynamics and coronary vasomobility. Clin Invest Med 1980;3:151-156. 17. Chew CY, Brown BG, SInah BN, Wang MM, Pierce C, Petersen R. Effects of verapamil on coronary hmodynamic function and vasomobility relative to its mechanism of antianainal action. Am J Cardiol 1983:51:699-705. 16. Pumphrey CW, Fuater V, 6ewanjee M, Kayo M, Cheaebfo J,. Vlletatra R. Verapamil is an effective in vivo inhibitorof platelet activation In peripheral vascular grafts in dogs (abstr). Circulation 1961;64:suppl IV:IV-56. 19. Rauleau JL, ChatlerJee K, Ports TA, Doyle MB, Hlramatau B, Pwmley WW. Mechanism of relief of pacing-induced angina with oral verapamil: reduced -oxygen demand. Circulation 1963;67:94-100. 20. Pine MB, Cltron PD, Ballly DJ, Butman S, Plasencfa GO, Landa DW, Wang RK. Verapamil versus placebo in relieving stable angina pectoris. Circulation 1982;65:17-22. 21. Hecht HS, Chew CYC, Burnam YH, Hopklns J, Schnug9 S, Slngh BN. Verapamil in chronic stable angina: amelioration of pacing-induced abnormalities of left ventricular ejection fraction, regional wall motion, lactate metabolism and hemodynamics. Am J Cardiol 1981;46:536-544. 22. Klein HO, Nlnlo R, Oren V, Lang R, Sarell P, DlSegnl E, Davld D, Guerrero J, Kapllnaky E. The acute hemodynamic effects of intravenous verapamil in coronary artery disease: assessment by equilibrium-gated radionuclide ventriculography. Circulation 1983;87:101-110. 23. Vlletstra RE, Chesebro JH, Frye RL, Wallace RB. Improvement of left ventricular exercise hemodynamic function after aorta-coronary artery bypass raftin J Thorac Cardiovasc Surg 1961;61:65-91. 24. Parker g0, DI 8 lorgi S, West RO. A hemodynamic study of acute coronary insufficiency precipitated by exercise: with observations on the effects of nitroglycerin. Am J Cardiol 1988;17:470-483. 25. Sandier 0, Clayton GA, Thornlcroft SO. Clinical evaluation of verapamil in angina ectoris. Br Med J 1966;3:224-227. 26. Llvesley I! , Catley PF, Campbell RC, Oram S. Double-blind evaluation of verapamil, propranolol, and isosorbide dinitrate against a placebo in the treatment of angina pectoris. Br Med J 1973;1:375-376. 27. Pflsterer M, Glaus L, Burkart F. Comparative effects of nitroglycerin, nifedipine and metoprolol on regional left ventricular function in patients with one-vessel coronary disease. Circulation 1963;67:291-301. 26. Cheaebro JH, Rltman EL, Frye RL, Smlth HC, Rutherford BD, Fulton RE, Pluth JR, Barnhorat DA. Regional myocardial wall thickening response to nitroglycerin: a predictor of myocardial response to aortocoronary bypass surgery. Circulation 1978;57:952-957. 29. Parker JO, West RO, DlGiorgl S. Hemodynamic effects of propranolol in coronary heart disease. Am J Cardiol 1968;21:11-19. 30. Kumada T, Gallagher KP, Shlrato K, McKown D, Miller M, Kemper WS, Whfte F, Roes J Jr. Reproduction of exercise-induced regional my-dial dysfunction by propranolol: studies in a canine model of chronic coronary artery stenosis. Circ Res 1980;46: 190-200.