General Cardiology
Cardiology 1992:80:324-331
L. Zanolla E. Carbonieri L. Rossi P. Marino P. Zardini
Gallopamil in Chronic Stable Angina: Antianginal Effect and Mechanism of Action
Institute of Cardiology, University of Verona, Italy
A Randomized, Placebo-Controlled, Double-Blind, Cross-Over Trial
Abstract
double-blind, placebo-controlled, cross-over trial of oral gallopamil was performed in 10 patients with stable angina. Gallopamil significantly increased mean exercise time and 1-mm ST time. The rate-pressure product was increased at 1-mm ST time, but unmodified at the highest comparable work load and at peak exercise. The ST segment depression was significantly reduced both at the highest comparable work load and at peak exercise. Gallopamil proves safe and effective; the mechanism of its anti-ischemic effect seems to be due both to an increase in myocardial oxygen supply and to a reduction in myocardial oxygen demand. A
Introduction
Methods and Patients
The calcium antagonist gallopamil was de veloped late in the 1960s as a methoxy deriva tive of the chemical substance verapamil. Only more recently, however, it has been introduced into clinical practice. Few studies investigating the effectiveness and the mecha nism of action of the drug during chronic oral administration are available at present [1-4]. This study was therefore undertaken in order to evaluate the anti-ischemic effect of chronic administration of gallopamil in pa tients with chronic stable effort angina.
Received: February 5. 1992 Accepted after revision: Fcbruar>' 25. 1992
Patients Inclusion criteria were: (1) a clear history of stable exertional angina: (2) no history or ECG signs of pre vious myocardial infarction; (3) no clinical evidence of left ventricular heart failure: (4) normal left ventricular volume and function at two-dimensional échocardio graphie examination and absence of regional wall mo tion abnormalities; (5) age less than 70 years, and (6) an ischemic response to exercise tests, performed while receiving no treatment, defined as > 1 mm horizontal or downsloping ST segment depression on ECG, with development of angina. Exclusion criteria were: ( 1) congestive heart failure: (2) uncontrolled severe hypertension; (3) conduction
Luisa Zanolla. MD Institute of Cardiology Ospedalc Maggiorc Piazzale Stefani I 1-Vcrona (Italy)
© 1992 S. Kargcr AG. Basel 0008-6312/92/ 0806-0324$2.75/0
Downloaded by: Nagoya University 133.6.82.173 - 1/14/2019 3:20:38 PM
Keyw ords Gallopamil Stable angina
system disease, and (4) a previous myocardial infarc tion. Informed consent was obtained from each pa tient.
corded at a paper speed of 50 mm/s. Peak E- and Awave velocities were measured on five consecutive car diac cycles, and the measurements were averaged.
Study Design The protocol consisted of an initial l()-day single blind placebo run-in phase. During this period, each patient received a placebo tablet every 8 h (identical to gallopamil tablets). Patients were then randomized to a double-blind placebo or gallopamil treatment for 2 weeks, then crossed to the other medication regimen for 2 weeks. No washout period was incorporated. Exercise tests and echocardiographic examinations were performed before entry, after placebo run-in and after each 2-week treatment period. The data from the examinations performed after the two treatment peri ods were used for comparison. During the study, patients were permitted only sublingual nitroglycerin tablets for anginal attacks.
Statistical A nalvsis Data are expressed as means ± 1 SD. Differences between mean values during placebo and during gallo pamil treatment were assessed by Student's t lest for paired data, according to the cross-over design [7]. A probability level < 0 .0 5 was considered significant in assessing treatment and period effects; a level < 0 .1 0 was considered significant when assessing interac tions.
Echocardiographic Measurements M-mode echocardiograms were obtained by using an Irex System II echocardiograph with a 2.25-MHz transducer. The patient was in a 30° left lateral decubi tus; the position of the transducer (intercostal space and distance from the midsternal line) was recorded at the first examination and kept constant. During an unforced held expiration, the left ventri cle was visualized at the chordae tendineae level and recorded at a paper speed of 50 mm/s. Left ventricular diameters were measured on five consecutive cardiac cycles, and the measurements were averaged. The echo-Doppler examination was performed by using a Toshiba SSH-65 echocardiograph with a 2.5MHz transducer. The recordings were made in the api cal four-chamber view; the sample volume was placed about I cm from the middle of the annulus of the mitral valve in diastole; the Doppler signal was re
Patients Ten consecutive male patients with effortinduced stable angina were entered into the study after informed consent was obtained. The average age was 60.8 ± 4.6 years (range 55-67). Exercise Tests
No interaction between treatment and pe riod was documented for any parameter con sidered. The mean exercise time was 9.1 ± 2.5 min on placebo; it was significantly in creased to 10.3 ± 1.9 min on gallopamil (t = 3.15. p = 0.006; table 1). The 1-mm ST time (time to develop a 1-mm ST alteration on ECG) was 6.7 ± 2.6 min on placebo; it was significantly increased to 9.1 ± 2.4 min on gallopamil (t = 5.66. p = 0.0001). The 1-mm ST time was the only parameter to present a significant period effect; the treatment effect was however highly statistically significant (table 1). Circulatory Changes at Rest The resting heart rate (HR) was 69.8 ± 12.1 beats/min on placebo and 70.4 ± 11.5 on gallopamil (t = 0.19, NS). Both systolic and diastolic standing blood pressures at rest were unaffected by treatment (139.5 ± 16.6 vs.
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Exercise Protocol Exercise tests [5] were performed on a bicycle ergometer in the upright position; the work load was increased by 25 W every 2 min. The ECG was moni tored countinuously and analyzed on-line by a com puter system [6] during exercise and during a 6-min recovery period; a 12-lead ECG was recorded, and aus cultatory blood pressure was measured before exercise, every' 2 min during exercise and during the recovery period. The tests were limited only by symptoms suffi cient to preclude further exercise (anginal pain, dys pnea. fatigue, pain in the legs) or by severe ECG altera tions (ST depression > 3 mm).
Results
Table 1. Effect of gallopamil on exercise tests
Exercise time, s
l-mrn ST time
p value
Treatment order
Parameters
P-G
G-P
P G d(;-p
9.4 ±2.9 10.6 ± 1.9 1.2± 1.3
8.8 ±2.3 10.0 ±2.0 l.2 ± 1.1
0.006
P G do-p
7.4 ±3.4 8.8 ±3.0 1.4 ± 1.3
6.0 ±1.4 9.4 ±1.9 3.4± 1.3
0.0001
P = Placebo: G = gallopamil; dG.p = difference between gallopamil and placebo.
p = 0.00001
2251
-
20-
326
RPP
X 1.000
Zanolla/Carbonieri/Rossi/Marino/ Zardini
ST mm
Gallopamil in Chronic Stable Angina
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Fig. 1 . ST = ST segment depres sion. □ = Placebo; ^ = gallopamil. a Circulatory changes at the I-mm ST time, b Circulatory changes at the highest comparable work load.
Table 2.
Circulatory changes during exercise
Treatment order p value p_G G_p _______________________________________________________________________________ l-mm ST time
HR
SBP
RPP
P G do-p P G 4g p P G 4
Highest comparable work load
HR
SBP
RPP
ST
Maximum exercise
HR
SBP
RPP
ST
g
-p
P G dc;p P G do-p P G dc-p P G do-p P G do-p P G do-p P G do-p P G dc-p
I24.6± 17.1 129.0 ± 14.6 4.4 ±9.9 194 ± 11.4 205 ±25.5 11.0± 16.7 24.304 ±4.629 26.701 ±6.389 2,397 ±3,540
112.0 ± 22.0 128.0 ±20.8 16.0± 16.6 189.2 ±29.7 199.4 ±33.3 10.2 ± 25.5 2 1.570 ± 7.535 25,941 ±8.313 4,371 ±5,649
133.6 ± 15.3 126.4 ±24.1 - 7 .2 ± 16.7 199 ± 15.1 202 ±26.6 3 ±20.8 26.730±4,983 25.941 ±7,517 - 8,080 ± 1,975 1.94 ± 1.1 0.62 ±0.65 -0 .9 0 ±2.4
134.0 ± 19.4 119.0± 21.6 - 1 5.0±8.2 191 ±49.4 187 ±37.0 -4 ± 2 7 .7 25,052 ± 11.038 22,790 ±7.692 -2,261 ±6.390 1.82 ± 0.80 0.30 ±0.45 - 1.52 ± 0.58
138.4 ± 15.9 136.2 ± 14.0 -2 .2 ±6.7 202 ±17.9 209 ±25.1 7 ±13.9 28.160 ±5,597 28.702 ±6.185 -5 4 2 ±2,838 1.94 ± 1.1 1.04 ± 1.0 -0 .9 0 ±0.40
133.3 ±4.0 140.8 ± 16.2 -7 .5 ±14.4 210 ± 38.5 200 ±36.5 -1 0 ± 9.1 30.112± 9.722 27.085 ±8.965 -3,027± 2.013 1.82 ± 0.80 0.66 ±0.55 -1 .1 6 + 0 .6 3
0.0225
NS
0.0220
0.019
NS
NS
0.00001
NS
NS
NS
0.00008
139 ± 23.7 mm Hg, t = 0.10. NS, and 80.5 ± 8.6 vs. 75 ± 9.4 mm Hg. t = 2.08. NS. respec tively). Circulatory Changes during Exercise
At the 1-mm ST time, the HR was signifi cantly increased (118.3 ± 19.9 vs. 128.5 ±
16.9 beats/min: t = 2.326. p = 0.0225), systolic blood pressure (SBP) was unmodified (191.6 ± 212.3 vs. 202.2 ± 28.1 mm Hg; t = 1.55. NS), and the rate-pressure product (RPP) was significantly increased (22,937 ± 6.069 vs. 26.321 ± 7,001; t = 2.34, p = 0.0220; table 2, fig. la).
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ST = ST segment depression: P = placebo: G = gallopamil: dG-p = difference between gallopamil and placebo.
Fig. 2. Circulatory changes at peak exercise. Abbreviations and symbols as in the legend to figure I.
Table 3. Echocardiographie measurements
Treatment order P-G Enddiastolic diameter
Endsystolic diameter
Fractional shortening
Doppler E wave
Doppler A wave
E/A ratio
P G do-p P G ¿G-P P G dc-p P G do-p P G do-p P G do-p
p value
G-P
48.4 ± 1.52 50.0 ±5.1 50.8 ±1.92 52.0 ±5.8 2.4 ±2.1 2.0± 1.6 29.4 ±3.3 31.2 ±5.3 30.4± l.l 31.0 ±5.4 1.0 ± 2.8 -0 .2 0 ± 1.1 39.3± 5.5 37.5 ±9.2 40.2 ± 1.2 40.3 ±8.6 0.81 ±5.9 2.78 ±2.1 0.42 ±0.10 0.44 ±0.05 0.39 ±0.03 0.48 ±0.19 -0 .0 5 ±0.04 0.05 ±0.15 0.50±0.10 0.50 ±0.11 0.49 ±0.12 0.44 ±0.05 -0 .0 6 ±0.10 -0.02±0.11 0.90 ±0.20 0.85 ±0.23 0.89 ± 0.1 1 0.97 ±0.28 0.12 ± 0.12 -0.01 ±0.23
0.0022
NS
NS
NS
NS
NS
328
Zanolla/Carbonieri/Rossi/Marino/ Zardini
Gallopamil in Chronic Stable Angina
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P = Placebo: G = gallopamil: dc¡.p = difference between gallopamil and placebo.
Echocardiographic Measurements
At the M-mode echocardiographic exami nation, the enddiastolic diameter evidenced a significant, but slight increase with gallopamil (49.2 ± 3.6 vs. 51.4 ± 4.1 mm. t = 3.77. p = 0.0022): the endsystolic diameter (30.3 ± 4.2 vs. 30.7 ± 3.7 mm. t = 0.61. NS) and frac tional shortening (38.4 ± 7.2 vs. 40.2 ± 5.8. t = 1.27, NS: table 3) were unmodified. At the Doppler examination, no variation was evident in peak E-wave velocities (0.43 ± 0.08 vs. 0.44 ± 0 .1 4 m/s. t = 0.11. NS), in peak A-wave velocities (0.50 ± 0 .1 0 vs. 0.47 ± 0.09 m/s. t = 1.07. NS) and in their ratio (0.97 ± 0.21 vs. 0.93 ± 0.21. t = 0.93, NS). Side Effects
No patient complained of side effects dur ing gallopamil treatment.
Discussion
It has been demonstrated that gallopamil is three to five times as potent as verapamil on a weight-for-weight basis [8], The drug, in fact, significantly increased the exercise tolerance in patients with stable exertional angina [14], When considering the mechanism by which gallopamil exerts its antianginal effect, most authors concluded that the drug could improve exercise tolerance by reducing the myocardial oxygen demand. Rettig and Sen [9] reported that the RPP. an indirect index of myocardial oxygen con sumption [10], was reduced by gallopamil at the highest comparable work load, while at peak exercise it was unaffected by treatment: moreover, ST segment depression was re duced at the highest comparable work load, but not at peak exercise. Scrutinio et al. [3], 2 h after administration of the drug, observed a reduction in the RPP at the highest comparable work load and a reduction in ST segment depression; at 1-mm ST time and at peak exercise, both the RPP and the ST segment depression were unmod ified. De Scrvi ct al. [ 11] provided further infor mation for the importance of the reduction in the myocardial oxygen demand: during atrial pacing, after acute gallopamil administration, pacing tolerance was increased, but no varia tions were observed in mean blood flow in the great cardiac vein or in regional coronary resistance. Khurmi et al. [1], on the contrary', ob served an increase in the RPP al peak exercise on gallopamil, when the ST segment depres sion was unmodified: they therefore suggested that gallopamil could improve the myocardial oxygen supply. Our patients had a significantly prolonged exercise time with gallopamil treatment, but at peak exercise the RPP was unmodified: this
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At the highest comparable work load (i.e. at the placebo test work load), the mean HR was 133.8 ± 16 beats/min on placebo; it was reduced to 123.1 ± 20.6 on gallopamil (t = 2.41. p = 0.019). SBP was unaffected by gallo pamil (195 ± 34.7 vs. 194.5 ± 31.4 mm Hg: t = 0.06. NS). The RPP was 25.891 ± 8.122 on placebo. 24.365 ± 7.360 on gallopamil; the difference was not significant (t = 0.78, NS). The ST segment depression was signifi cantly reduced (1.8 ± 0.9 vs. 0.46 ± 0.5 mm, t = 7.49. p = 0.00001: table 2. fig. lb). At the maximum exercise, gallopamil treatment did not affect the HR (138 ± 16.3 vs. 133.6 ± 16.1 beats/min, t = 1.46, NS), the SBP (198 ± 34.9 vs. 200.5 ± 30.8 mm Hg. t = 0.47. NS) and the RPP (27,750 ± 7.918 vs. 27,137 ± 7.187. t = 0.60. NS). The ST segment depres sion was significantly reduced (1.8 ± 0.9 vs. 0.8 ± 0.7 mm. I = 6.14. p = 0.00008, table 2, fig. 2).
observation suggests a reduction in the myo cardial oxygen demand, similar to that ob tained with verapamil [12]. It should however be noted that the RPP was significantly increased at 1-mm ST time; moreover, the ST segment depression was sig nificantly reduced by gallopamil treatment both at the highest comparable work load and at peak exercise. These variations are not jus tified by a mere reduction in the myocardial oxygen demand. In fact, only an increase in the myocardial oxygen supply could explain the observation that the patients performed a higher work load with reduced electrocardiographical signs of ischemia. In isolated cardiac muscle, gallopamil ex erts a profound negative inotropic effect [ 13]. In vivo, after acute intravenous administra tion. Sesto et al. [14] observed an increase in enddiastolic volumes and a reduction in ejec tion fractions, though the differences were not statistically significant. Stauch et al. [15], by using radionuclide ventriculography, after acute oral administration, observed no varia tions in enddiastolic volume, a reduction in ejection fractions at rest and an increase in
ejection fractions during exercise. During chronic treatment, echocardiography is a use ful tool for assessing the drug influence on the left ventricular function, and the technique has been used for evaluating calcium antago nist drugs [ 16, 17], During chronic treatment with gallopamil, Scrutinio et al. [3] and Fisman et al. [ 18] found no variations in ejection fractions and ventricular volumes in patients with a normal left ventricular function; the same result was obtained by Tartagni et al. [19] using nuclear ventriculography. In our patients, though statistically significant, only a minimal variation in the enddiastolic diam eter was evident. Moreover, no variation was observed in Doppler indexes of left ventricu lar filling. In conclusion, gallopamil appears effective in improving exercise tolerance in patients with chronic stable angina, both through an increase in the myocardial oxygen supply and by a reduction in the myocardial oxygen con sumption; the drug has also proved to be safe, without relevant effects on the left ventricular function.
1 Khurmi NS. O'Hara MJ. Bowles MJ. Bala Subramanian V, Raftcry EB: Randomized double-blind com parison of gallopamil and proprano lol in stable angina pectoris. Am J Cardiol 1984:53:684-689. 2 Rettig G. Sen S, Vogel W. Hcisel A. SchiefTer H. Bette L: Antianginal ef ficacy of gallopamil in comparison to nifedipine, lnt J Cardiol 1988:19: 315-325.
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3 Scrutinio D, Lagioia R. Mangini SG, Mastropasqua F, Ricci A, Chiddo A. Rizzon P: Objective eval uation of gallopamil in patients with chronic stable angina. Exercise test ing, Holter monitoring, cross-sec tional echocardiography and plasma levels. Eur J Cardiol 1989:10:168176. 4 Sangiorgio P. Rubboli A. Brunelli D. Bracchetti D: II gallopamil nell’angina stabile da sforzo. Effetti di due diversi dosaggi. G Ital Car diol 1989;19:40-45.
Zanolla/Carbonieri/Rossi/Marino/ Zardini
5 Schlant RC. Blomqvisl CG, Brandeburg RO. et al: Guidelines for exer cise testing: A report of the Ameri can College of Cardiology/Amcrican Heart Association Task Force on Assessment of Cardiovascular Pro cedures (Subcommittee on exercise testing). J Am Coll Cardiol 1986:8: 725-738. 6 Rossi L. Carbonieri E. Castello C. Rossi R. Sciarretta G. Zardini P: Description and evaluation of a method for computer analysis of the exercise electrocardiogram. J Electrocardiol 1987;20:312-320. 7 Hills M. Armitage P: The two-pe riod cross-over clinical trial. Br J Clin Pharmacol 1979:8:7-20.
Gallopamil in Chronic Stable Angina
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References
12 Zanolla L, Trevi GP. Rizzo A. et al: Long-term persistence of antianginal effect of oral verapamil in chronic stable angina. J Cardiovasc Pharmacol 1984;6:423-428. 13 Fleckenstein A: Specific pharmacol ogy of calcium in myocardium, car diac pacemakers, and vascular smooth muscle. Annu Rev Pharma col Toxicol 1977;17:149-166. 14 Sesto M. Ivancic R. Custovic F: The effect of gallopamil on the hemody namics of patients with coronary ar tery disease; in Kaltenbach M. Hop!' R (eds): Gallopamil. Pharmacologi cal and Clinical Profile of a Calcium Antagonist. Berlin. Springer. 1984 pp. 96-98 15 Stauch M. Grossmann G. Schmidt A, Richter P. Waitzingcr J. Wanjura D. Adam WE. König W: Effect of gallopamil on left ventricular func tion in regions with and without ischemia. Eur Heart J. 1987;8(suppl G):77-83.
16 Lindvall K. Cocco G. Wendt G. Chu D. Hcizmann P: Serial M-mode echocardiography in evaluation of the cardiovascular effects of tiapamil and their relationship to plasma levels in patients with coro nary artery disease. Int J Cardiol 1981;1:15-24. 17 Zanolla L. Marino P. G oliaG . Prioli MA. Padrini R, Zardini P: Variazioni della funzione ventricolare sinistra durante terapia cronica con verapamil in pazienti anginosi. In fluenza delle concentrazioni plasmatiche del farmaco. Analisi quantitativa M-mode. G Ital Cardiol 1989:19:591-597. 18 Fisman EZ. Pines A. Ben-Ari E. Shiner RJ. Drory Y. Friedman BA. Kellerman JJ: Echocardiographie evaluation of the effects o f gallo pamil on left ventricular function. Clin Pharmacol Ther 1988:44:100106. 19 Tartagni F. Maiello L. Marchetti G. Dondi M. Franchi R. Monetti N, Magnani B: Clinical and hemody namic effects of long-term adminis tration of gallopamil in patients with coronary artery disease and normal or impaired left ventricular function. Am J Cardiol 1989:63: 291-296.
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8 Fleckenstcin A: Fleckcnstein B. Spall F. Byon YK: Gallopamil (D600) - A calcium antagonist of high potency and specificity. Effects on the myocardium and pacemakers: in Kaltenbach M. Hopf R (eds): Gallo pamil. Pharmacological and Clini cal Profile of a Calcium Antagonist. Berlin. Springer. 1984 pp 1-32. 9 Reuig G. Sen S: Acute and long term effect of gallopamil in patients with stable angina pectoris; in Kal tenbach M. Hopf R (eds): Gallo pamil. Pharmacological and Clini cal Profile of a Calcium Antagonist. Berlin. Springer, 1984 pp. 136-142. 10 Gobel FL, Nordstrom LA. Nelson RR, Jorgesen CR, Wang Y: The rate-pressure product as an index of myocardial oxygen consumption during exercise in patients with an gina pectoris. Circulation 1978:57: 549-556. 11 De Servi S. Ferrario M. Ghio S. et al: Coronary haemodynamic effects of short term intravenous adminis tration of gallopamil in patients with stable exertional angina. Br Heart J 1987:57:226-231.
Cardiology 1992:80:324-331
L. Zanolla E. Carbonieri L. Rossi P. Marino P. Zardini
Gallopamil in Chronic Stable Angina: Antianginal Effect and Mechanism of Action
Institute of Cardiology, University of Verona, Italy
A Randomized, Placebo-Controlled, Double-Blind, Cross-Over Trial
Abstract
double-blind, placebo-controlled, cross-over trial of oral gallopamil was performed in 10 patients with stable angina. Gallopamil significantly increased mean exercise time and 1-mm ST time. The rate-pressure product was increased at 1-mm ST time, but unmodified at the highest comparable work load and at peak exercise. The ST segment depression was significantly reduced both at the highest comparable work load and at peak exercise. Gallopamil proves safe and effective; the mechanism of its anti-ischemic effect seems to be due both to an increase in myocardial oxygen supply and to a reduction in myocardial oxygen demand. A
Introduction
Methods and Patients
The calcium antagonist gallopamil was de veloped late in the 1960s as a methoxy deriva tive of the chemical substance verapamil. Only more recently, however, it has been introduced into clinical practice. Few studies investigating the effectiveness and the mecha nism of action of the drug during chronic oral administration are available at present [1-4]. This study was therefore undertaken in order to evaluate the anti-ischemic effect of chronic administration of gallopamil in pa tients with chronic stable effort angina.
Received: February 5. 1992 Accepted after revision: Fcbruar>' 25. 1992
Patients Inclusion criteria were: (1) a clear history of stable exertional angina: (2) no history or ECG signs of pre vious myocardial infarction; (3) no clinical evidence of left ventricular heart failure: (4) normal left ventricular volume and function at two-dimensional échocardio graphie examination and absence of regional wall mo tion abnormalities; (5) age less than 70 years, and (6) an ischemic response to exercise tests, performed while receiving no treatment, defined as > 1 mm horizontal or downsloping ST segment depression on ECG, with development of angina. Exclusion criteria were: ( 1) congestive heart failure: (2) uncontrolled severe hypertension; (3) conduction
Luisa Zanolla. MD Institute of Cardiology Ospedalc Maggiorc Piazzale Stefani I 1-Vcrona (Italy)
© 1992 S. Kargcr AG. Basel 0008-6312/92/ 0806-0324$2.75/0
Downloaded by: Nagoya University 133.6.82.173 - 1/14/2019 3:20:38 PM
Keyw ords Gallopamil Stable angina
system disease, and (4) a previous myocardial infarc tion. Informed consent was obtained from each pa tient.
corded at a paper speed of 50 mm/s. Peak E- and Awave velocities were measured on five consecutive car diac cycles, and the measurements were averaged.
Study Design The protocol consisted of an initial l()-day single blind placebo run-in phase. During this period, each patient received a placebo tablet every 8 h (identical to gallopamil tablets). Patients were then randomized to a double-blind placebo or gallopamil treatment for 2 weeks, then crossed to the other medication regimen for 2 weeks. No washout period was incorporated. Exercise tests and echocardiographic examinations were performed before entry, after placebo run-in and after each 2-week treatment period. The data from the examinations performed after the two treatment peri ods were used for comparison. During the study, patients were permitted only sublingual nitroglycerin tablets for anginal attacks.
Statistical A nalvsis Data are expressed as means ± 1 SD. Differences between mean values during placebo and during gallo pamil treatment were assessed by Student's t lest for paired data, according to the cross-over design [7]. A probability level < 0 .0 5 was considered significant in assessing treatment and period effects; a level < 0 .1 0 was considered significant when assessing interac tions.
Echocardiographic Measurements M-mode echocardiograms were obtained by using an Irex System II echocardiograph with a 2.25-MHz transducer. The patient was in a 30° left lateral decubi tus; the position of the transducer (intercostal space and distance from the midsternal line) was recorded at the first examination and kept constant. During an unforced held expiration, the left ventri cle was visualized at the chordae tendineae level and recorded at a paper speed of 50 mm/s. Left ventricular diameters were measured on five consecutive cardiac cycles, and the measurements were averaged. The echo-Doppler examination was performed by using a Toshiba SSH-65 echocardiograph with a 2.5MHz transducer. The recordings were made in the api cal four-chamber view; the sample volume was placed about I cm from the middle of the annulus of the mitral valve in diastole; the Doppler signal was re
Patients Ten consecutive male patients with effortinduced stable angina were entered into the study after informed consent was obtained. The average age was 60.8 ± 4.6 years (range 55-67). Exercise Tests
No interaction between treatment and pe riod was documented for any parameter con sidered. The mean exercise time was 9.1 ± 2.5 min on placebo; it was significantly in creased to 10.3 ± 1.9 min on gallopamil (t = 3.15. p = 0.006; table 1). The 1-mm ST time (time to develop a 1-mm ST alteration on ECG) was 6.7 ± 2.6 min on placebo; it was significantly increased to 9.1 ± 2.4 min on gallopamil (t = 5.66. p = 0.0001). The 1-mm ST time was the only parameter to present a significant period effect; the treatment effect was however highly statistically significant (table 1). Circulatory Changes at Rest The resting heart rate (HR) was 69.8 ± 12.1 beats/min on placebo and 70.4 ± 11.5 on gallopamil (t = 0.19, NS). Both systolic and diastolic standing blood pressures at rest were unaffected by treatment (139.5 ± 16.6 vs.
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Exercise Protocol Exercise tests [5] were performed on a bicycle ergometer in the upright position; the work load was increased by 25 W every 2 min. The ECG was moni tored countinuously and analyzed on-line by a com puter system [6] during exercise and during a 6-min recovery period; a 12-lead ECG was recorded, and aus cultatory blood pressure was measured before exercise, every' 2 min during exercise and during the recovery period. The tests were limited only by symptoms suffi cient to preclude further exercise (anginal pain, dys pnea. fatigue, pain in the legs) or by severe ECG altera tions (ST depression > 3 mm).
Results
Table 1. Effect of gallopamil on exercise tests
Exercise time, s
l-mrn ST time
p value
Treatment order
Parameters
P-G
G-P
P G d(;-p
9.4 ±2.9 10.6 ± 1.9 1.2± 1.3
8.8 ±2.3 10.0 ±2.0 l.2 ± 1.1
0.006
P G do-p
7.4 ±3.4 8.8 ±3.0 1.4 ± 1.3
6.0 ±1.4 9.4 ±1.9 3.4± 1.3
0.0001
P = Placebo: G = gallopamil; dG.p = difference between gallopamil and placebo.
p = 0.00001
2251
-
20-
326
RPP
X 1.000
Zanolla/Carbonieri/Rossi/Marino/ Zardini
ST mm
Gallopamil in Chronic Stable Angina
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Fig. 1 . ST = ST segment depres sion. □ = Placebo; ^ = gallopamil. a Circulatory changes at the I-mm ST time, b Circulatory changes at the highest comparable work load.
Table 2.
Circulatory changes during exercise
Treatment order p value p_G G_p _______________________________________________________________________________ l-mm ST time
HR
SBP
RPP
P G do-p P G 4g p P G 4
Highest comparable work load
HR
SBP
RPP
ST
Maximum exercise
HR
SBP
RPP
ST
g
-p
P G dc;p P G do-p P G dc-p P G do-p P G do-p P G do-p P G do-p P G dc-p
I24.6± 17.1 129.0 ± 14.6 4.4 ±9.9 194 ± 11.4 205 ±25.5 11.0± 16.7 24.304 ±4.629 26.701 ±6.389 2,397 ±3,540
112.0 ± 22.0 128.0 ±20.8 16.0± 16.6 189.2 ±29.7 199.4 ±33.3 10.2 ± 25.5 2 1.570 ± 7.535 25,941 ±8.313 4,371 ±5,649
133.6 ± 15.3 126.4 ±24.1 - 7 .2 ± 16.7 199 ± 15.1 202 ±26.6 3 ±20.8 26.730±4,983 25.941 ±7,517 - 8,080 ± 1,975 1.94 ± 1.1 0.62 ±0.65 -0 .9 0 ±2.4
134.0 ± 19.4 119.0± 21.6 - 1 5.0±8.2 191 ±49.4 187 ±37.0 -4 ± 2 7 .7 25,052 ± 11.038 22,790 ±7.692 -2,261 ±6.390 1.82 ± 0.80 0.30 ±0.45 - 1.52 ± 0.58
138.4 ± 15.9 136.2 ± 14.0 -2 .2 ±6.7 202 ±17.9 209 ±25.1 7 ±13.9 28.160 ±5,597 28.702 ±6.185 -5 4 2 ±2,838 1.94 ± 1.1 1.04 ± 1.0 -0 .9 0 ±0.40
133.3 ±4.0 140.8 ± 16.2 -7 .5 ±14.4 210 ± 38.5 200 ±36.5 -1 0 ± 9.1 30.112± 9.722 27.085 ±8.965 -3,027± 2.013 1.82 ± 0.80 0.66 ±0.55 -1 .1 6 + 0 .6 3
0.0225
NS
0.0220
0.019
NS
NS
0.00001
NS
NS
NS
0.00008
139 ± 23.7 mm Hg, t = 0.10. NS, and 80.5 ± 8.6 vs. 75 ± 9.4 mm Hg. t = 2.08. NS. respec tively). Circulatory Changes during Exercise
At the 1-mm ST time, the HR was signifi cantly increased (118.3 ± 19.9 vs. 128.5 ±
16.9 beats/min: t = 2.326. p = 0.0225), systolic blood pressure (SBP) was unmodified (191.6 ± 212.3 vs. 202.2 ± 28.1 mm Hg; t = 1.55. NS), and the rate-pressure product (RPP) was significantly increased (22,937 ± 6.069 vs. 26.321 ± 7,001; t = 2.34, p = 0.0220; table 2, fig. la).
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ST = ST segment depression: P = placebo: G = gallopamil: dG-p = difference between gallopamil and placebo.
Fig. 2. Circulatory changes at peak exercise. Abbreviations and symbols as in the legend to figure I.
Table 3. Echocardiographie measurements
Treatment order P-G Enddiastolic diameter
Endsystolic diameter
Fractional shortening
Doppler E wave
Doppler A wave
E/A ratio
P G do-p P G ¿G-P P G dc-p P G do-p P G do-p P G do-p
p value
G-P
48.4 ± 1.52 50.0 ±5.1 50.8 ±1.92 52.0 ±5.8 2.4 ±2.1 2.0± 1.6 29.4 ±3.3 31.2 ±5.3 30.4± l.l 31.0 ±5.4 1.0 ± 2.8 -0 .2 0 ± 1.1 39.3± 5.5 37.5 ±9.2 40.2 ± 1.2 40.3 ±8.6 0.81 ±5.9 2.78 ±2.1 0.42 ±0.10 0.44 ±0.05 0.39 ±0.03 0.48 ±0.19 -0 .0 5 ±0.04 0.05 ±0.15 0.50±0.10 0.50 ±0.11 0.49 ±0.12 0.44 ±0.05 -0 .0 6 ±0.10 -0.02±0.11 0.90 ±0.20 0.85 ±0.23 0.89 ± 0.1 1 0.97 ±0.28 0.12 ± 0.12 -0.01 ±0.23
0.0022
NS
NS
NS
NS
NS
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Gallopamil in Chronic Stable Angina
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P = Placebo: G = gallopamil: dc¡.p = difference between gallopamil and placebo.
Echocardiographic Measurements
At the M-mode echocardiographic exami nation, the enddiastolic diameter evidenced a significant, but slight increase with gallopamil (49.2 ± 3.6 vs. 51.4 ± 4.1 mm. t = 3.77. p = 0.0022): the endsystolic diameter (30.3 ± 4.2 vs. 30.7 ± 3.7 mm. t = 0.61. NS) and frac tional shortening (38.4 ± 7.2 vs. 40.2 ± 5.8. t = 1.27, NS: table 3) were unmodified. At the Doppler examination, no variation was evident in peak E-wave velocities (0.43 ± 0.08 vs. 0.44 ± 0 .1 4 m/s. t = 0.11. NS), in peak A-wave velocities (0.50 ± 0 .1 0 vs. 0.47 ± 0.09 m/s. t = 1.07. NS) and in their ratio (0.97 ± 0.21 vs. 0.93 ± 0.21. t = 0.93, NS). Side Effects
No patient complained of side effects dur ing gallopamil treatment.
Discussion
It has been demonstrated that gallopamil is three to five times as potent as verapamil on a weight-for-weight basis [8], The drug, in fact, significantly increased the exercise tolerance in patients with stable exertional angina [14], When considering the mechanism by which gallopamil exerts its antianginal effect, most authors concluded that the drug could improve exercise tolerance by reducing the myocardial oxygen demand. Rettig and Sen [9] reported that the RPP. an indirect index of myocardial oxygen con sumption [10], was reduced by gallopamil at the highest comparable work load, while at peak exercise it was unaffected by treatment: moreover, ST segment depression was re duced at the highest comparable work load, but not at peak exercise. Scrutinio et al. [3], 2 h after administration of the drug, observed a reduction in the RPP at the highest comparable work load and a reduction in ST segment depression; at 1-mm ST time and at peak exercise, both the RPP and the ST segment depression were unmod ified. De Scrvi ct al. [ 11] provided further infor mation for the importance of the reduction in the myocardial oxygen demand: during atrial pacing, after acute gallopamil administration, pacing tolerance was increased, but no varia tions were observed in mean blood flow in the great cardiac vein or in regional coronary resistance. Khurmi et al. [1], on the contrary', ob served an increase in the RPP al peak exercise on gallopamil, when the ST segment depres sion was unmodified: they therefore suggested that gallopamil could improve the myocardial oxygen supply. Our patients had a significantly prolonged exercise time with gallopamil treatment, but at peak exercise the RPP was unmodified: this
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At the highest comparable work load (i.e. at the placebo test work load), the mean HR was 133.8 ± 16 beats/min on placebo; it was reduced to 123.1 ± 20.6 on gallopamil (t = 2.41. p = 0.019). SBP was unaffected by gallo pamil (195 ± 34.7 vs. 194.5 ± 31.4 mm Hg: t = 0.06. NS). The RPP was 25.891 ± 8.122 on placebo. 24.365 ± 7.360 on gallopamil; the difference was not significant (t = 0.78, NS). The ST segment depression was signifi cantly reduced (1.8 ± 0.9 vs. 0.46 ± 0.5 mm, t = 7.49. p = 0.00001: table 2. fig. lb). At the maximum exercise, gallopamil treatment did not affect the HR (138 ± 16.3 vs. 133.6 ± 16.1 beats/min, t = 1.46, NS), the SBP (198 ± 34.9 vs. 200.5 ± 30.8 mm Hg. t = 0.47. NS) and the RPP (27,750 ± 7.918 vs. 27,137 ± 7.187. t = 0.60. NS). The ST segment depres sion was significantly reduced (1.8 ± 0.9 vs. 0.8 ± 0.7 mm. I = 6.14. p = 0.00008, table 2, fig. 2).
observation suggests a reduction in the myo cardial oxygen demand, similar to that ob tained with verapamil [12]. It should however be noted that the RPP was significantly increased at 1-mm ST time; moreover, the ST segment depression was sig nificantly reduced by gallopamil treatment both at the highest comparable work load and at peak exercise. These variations are not jus tified by a mere reduction in the myocardial oxygen demand. In fact, only an increase in the myocardial oxygen supply could explain the observation that the patients performed a higher work load with reduced electrocardiographical signs of ischemia. In isolated cardiac muscle, gallopamil ex erts a profound negative inotropic effect [ 13]. In vivo, after acute intravenous administra tion. Sesto et al. [14] observed an increase in enddiastolic volumes and a reduction in ejec tion fractions, though the differences were not statistically significant. Stauch et al. [15], by using radionuclide ventriculography, after acute oral administration, observed no varia tions in enddiastolic volume, a reduction in ejection fractions at rest and an increase in
ejection fractions during exercise. During chronic treatment, echocardiography is a use ful tool for assessing the drug influence on the left ventricular function, and the technique has been used for evaluating calcium antago nist drugs [ 16, 17], During chronic treatment with gallopamil, Scrutinio et al. [3] and Fisman et al. [ 18] found no variations in ejection fractions and ventricular volumes in patients with a normal left ventricular function; the same result was obtained by Tartagni et al. [19] using nuclear ventriculography. In our patients, though statistically significant, only a minimal variation in the enddiastolic diam eter was evident. Moreover, no variation was observed in Doppler indexes of left ventricu lar filling. In conclusion, gallopamil appears effective in improving exercise tolerance in patients with chronic stable angina, both through an increase in the myocardial oxygen supply and by a reduction in the myocardial oxygen con sumption; the drug has also proved to be safe, without relevant effects on the left ventricular function.
1 Khurmi NS. O'Hara MJ. Bowles MJ. Bala Subramanian V, Raftcry EB: Randomized double-blind com parison of gallopamil and proprano lol in stable angina pectoris. Am J Cardiol 1984:53:684-689. 2 Rettig G. Sen S, Vogel W. Hcisel A. SchiefTer H. Bette L: Antianginal ef ficacy of gallopamil in comparison to nifedipine, lnt J Cardiol 1988:19: 315-325.
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3 Scrutinio D, Lagioia R. Mangini SG, Mastropasqua F, Ricci A, Chiddo A. Rizzon P: Objective eval uation of gallopamil in patients with chronic stable angina. Exercise test ing, Holter monitoring, cross-sec tional echocardiography and plasma levels. Eur J Cardiol 1989:10:168176. 4 Sangiorgio P. Rubboli A. Brunelli D. Bracchetti D: II gallopamil nell’angina stabile da sforzo. Effetti di due diversi dosaggi. G Ital Car diol 1989;19:40-45.
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Gallopamil in Chronic Stable Angina
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8 Fleckenstcin A: Fleckcnstein B. Spall F. Byon YK: Gallopamil (D600) - A calcium antagonist of high potency and specificity. Effects on the myocardium and pacemakers: in Kaltenbach M. Hopf R (eds): Gallo pamil. Pharmacological and Clini cal Profile of a Calcium Antagonist. Berlin. Springer. 1984 pp 1-32. 9 Reuig G. Sen S: Acute and long term effect of gallopamil in patients with stable angina pectoris; in Kal tenbach M. Hopf R (eds): Gallo pamil. Pharmacological and Clini cal Profile of a Calcium Antagonist. Berlin. Springer, 1984 pp. 136-142. 10 Gobel FL, Nordstrom LA. Nelson RR, Jorgesen CR, Wang Y: The rate-pressure product as an index of myocardial oxygen consumption during exercise in patients with an gina pectoris. Circulation 1978:57: 549-556. 11 De Servi S. Ferrario M. Ghio S. et al: Coronary haemodynamic effects of short term intravenous adminis tration of gallopamil in patients with stable exertional angina. Br Heart J 1987:57:226-231.
