Randomized double-blind comparison of gallopamil and propranolol in stable angina pectoris

Randomized Double-BlindComparisonof Gallopamil and Propranololin Stable Angina Pectoris NARDEV S. KHURMI, MB, BS, MARTIN J. O’HARA, MRCP I, MICHAEL J. BOWLES, MRCP, V. BALA SUBRAMANIAN,

MD, and EDWARD B. RAFTERY, BSc, MD

A new calcium ion antagonist, gallopamil, 150 mg/day, was compared with propranolol, 240 mg/day, in 20 patients with stable chronic angina. The patients were studied in a randomized, placebo-controlled, double-blind, crossover trial. Multistage treadmill exercise with computer-assisted electrocardiographic analysis was performed after 2 weeks of placebo therapy and at the end of each 4-week active treatment period. The mean ( f standard error of the mean) exercise time to development of angina was 5.4 f 0.3 minutes with placebo; this increased to 9.4 f 0.7 minutes with propranolol (p
significant vs propranolol). Both drugs significantly prolonged the time to development of 1 mm of ST depression. Five patients became free of angina during treadmlll testing with gallopamll therapy and 2 with propranolol. Both drugs decreased the heart rate at rest; propranolol also decreased the maximal exercise heart rate, which was slightly increased with gallopamll. Wlth the exception of 1 patient in whom raised liver enzymes developed, gallopamil was well tolerated. Thus, gallopamil is an effective antianginal agent that has few of the unwanted effects associated with other calcium channelblocking drugs. (Am J Cardiol 1984;53:884-888)

The number of available slow calcium channel-blocking drugs has rapidly increased since these drugs have been shown to be effective in a wide range of cardiovascular disorders. New members of this group must be tested against tried medications if their relative effectiveness is to be clearly established. This is particularly true for angina pectoris where /3-adrenoreceptor blocking agents have been the drugs of choice for 20 years1-5; in this group, propranolol has become the standard against which all other fl-adrenoreceptor blocking agents are compared.i+16 The slow calcium channel-blocking drugs are accepted for the management of vasospastic7-I2 and chronic stable angina. 13-lg The 3 best known drugs in this group are verapamil, nifedipine and diltiazem, and all are effective in increasing exercise tolerance under standardized conditions.iPlg Gallopamil is a new slow calcium channel-blocking agent that is structurally similar to verapamil (Fig. 1). It is 3 to 8 times as potent

as verapamil on a weight-for-weight basis and may produce fewer adverse effects. In this study we have compared gallopamil with propranolol using a doubleblind, crossover trial design with fixed doses and objective methods of assessment to evaluate the relative efficacy and safety of this drug. Methods Patients: Twenty patients (17 men and,3 women) aged 49 to 75 years who fulfilled the requirements for inclusion in the study were recruited. Inclusion and exclusion criteria have been reported previously.15,i6 All had established exertional angina that was reproducible on repeated treadmill testing and associated with the appearance of ST depression of 1 mm; ST depression was both absolute and relative to the value at rest measured at the J point in at least one of the leads monitored. Before entering the study, patients were withdrawn gradually from their current antianginal treatment and received no treatment except glyceryl trinitrate for a minimum of 7 days. Trial design: All cardioactive medication was withdrawn for the duration of the study except for the trial medication and sublingual nitroglycerin as required. Patients began therapy with a 2-week placebo run-in period. After this regimen, they were randomized to propranolol(240 mg/day) or gallopamil(150 mg/day) in 3 divided doses for 4 weeks, at the end of which time each patient crossed over to the alternate regimen. No washout period was incorporated. Formal exer-

From the Department of Cardiology and Division of Clinical Sciences, Northwick Park Hospital and Clinical Research Centre, Harrow, Middlesex, United Kingdom. Manuscript received August 18, 1983; revised manuscript received November 28, 1983, accepted December 1, 1983. Address for reprints: Edward B. Raftery, MD, Cardiology Department, Northwick Park Hospital and Clinical Research Centre, Watford Road, Harrow, Middlesex, HA1 3UJ, United Kingdom. 684

March 1, 1984

THE AMERICAN JOURNAL OF CARDIOLOGY Volume 53

TABLE I

FH3 r-CH,-CH,-N-CHr-CH,

Stage

665

Treadmill Protocol Time (min)

Gradient (% incline)

Speed (mph)

CH CHI’CH,

x HCl

: 3 4

Verasamil

Gallopamil FIGURE 1. Molecular structure of gallopamil and verapamil.

cise testing was repeated at the end of the placebo period and after 4 and 8 weeks of active drug therapy. Safety procedures recommended by the American Heart Association20 were followed. During the 2 weeks of the placebo phase, the patients took 2 tablets., 1 each of gallopamil and propranolol placebo 3 times daily. This phase was single blind. In the crossover phase the 2 tablets were either active gallopamil and placebo propranolol or active propranolol and placebo gallopamil (double-dummy

L.D. d 50 yrs

3 3

3 3

8 12

technique). This phase was double blind. All the active and placebo tablets were identical in appearance. The patients were instructed in the use of a diary card to document the frequency of angina1 episodes and glyceryl trinitrate consumption. The importance of not using prophylactic trinitrate tablets during the trial period was emphasized to each patient. Exercise evaluation: At the end of the placebo period and each 4-week active treatment period the patients were exercised on a treadmill with a marquette computer-assisted system for exercise. A modified Balke’s protocolis was used for every test (Table I) and the patients stopped the test because of angina or, if that had been controlled by treatment, dyspnea or fatigue. All tests were performed in a temperature-controlled laboratory in the morning between 90 and 150 minutes after the last dose of the drug and after 30 minutes of rest. The ECG was monitored during exercise and for 5 minutes thereafter in the supine posture using bipolar leads CMs and CC&and was analyzed on-line by a microprocessor

ST

HEART RATE

Exercise Placebo

time

4.0 mins Angina

9.4 mins

Gallopamil

Angina

50mg t.i.d. x 4wks

8.7 mins

Propranolol

Angina 80mg t.i.d. x 4wks

Time FIGURE 2. Continuous ST-segment and heart rate plots of the same patient (a 50-year-old man) during placebo, gallopamil and propranolol treatment. Time is on the horizontal axis, with 2-minute intervals marked. The ST level is on the vertical axis, with lines at l-mm intervals marked. The end of exercise is denoted by a vertical line in the middle of each panel. The improvement in exercise tolerance and ST depression is evident.

GALLOPAMIL

666

AND PROPRANOLOL

12

IN ANGINA

P=NS

1

P=NS l

P

G PR

Ex. time

P

G

PR

lmm time CM5

FIGURE 3. Left, duration of exercise (Ex.) during treatment with placebo (P), gallopamil (G) and propranolol (FR). Right, time on treadmill exercise test to the development of 1 mm ST-depression during treatment with placebo, gallopamil and propranolol. Data are mean f standard error of the mean. p
that provided a continuous display of heart rate, ectopic counts and ST-segment level. At the completion of each test, the computer produced a plot of these variables against time (Fig. 2). The digital values of ST-segment change, heart rate and blood pressure were stored on a tape cassette and later played back into a PDP 11/23 minicomputer. A program calculated and stored all the following objective variables at minute intervals during and after exercise: exercise time; l-mm time (time to develop 1 mm of ST depression relative to the resting level); heart rate at rest; maximal heart rate; heart rate gain (maximal heart rate minus heart rate at rest); heart rate recovery in 5 minutes (maximal heart rate minus heart rate 5 minutes after termination of exercise); maximal ST depression in leads CM:, and CC,; maximal ST depression divided by exercise time; and ST recovery (ST level after 5 minutes recovery minus level at point of termination of exercise). At each visit a history was taken using a standard questionnaire, a physical examination was conducted and blood was drawn for hematologic and biochemical estimations. A Student paired t test (2-tailed) was used for the statistical analysis.

Results

l

160 1

P

G PR

Resting HR

P

G

PR

Maximum HR

P

G

PR

HR gain

FIGURE 4. Heart rate (HR) response with placebo (P), gallopamil (G) and propranolol (PR). Left, HR at rest; middle, maximal HR; right, HR gain. Data are mean f standard error of the mean.

Eighteen patients (15 men and 3 women) completed the trial. Two patients were withdrawn; 1 developed unstable angina and 1 had an acute myocardial infarction and died from cardiogenic shock. Both patients were in the fourth week of treatment with gallopamil at the time. Placebo: All 18 patients developed angina during exercise testing during the placebo period at times ranging between 3.2 and 9.0 minutes with a mean f standard error of the mean [SEMI value of 5.4 f 0.3 minutes (Fig. 3, Tables II and III). The heart rate at rest was 81 f 3 beats/min, maximal heart rate 117 f 2 beats/min and the heart rate gain during exercise 37 f 3 beats/min. The greatest value of ST-segment depression in lead CM5 was 1.9 f 0.2 mm and the mean l-mm ST depression time was 3.7 f 0.4 minutes. The heart rate recovered by a mean 41 f 3 beats/min and the

TABLE

Patient Data and Individual Exercise Times (min) on Placebo, Gallopamil and Propranolol Age WI

2.0

Case :

1.6

! 5 1.2

Y

a

z

9 0.8 :: :z

0.4

:5” 0

II

P M-ST

G

PR

1 CM5

P M-ST

G

PR

1 CC5

P

G

:;

PR

ST recovery CM5

FIGURE 5. Left, maximal ST-segment (M-ST) depression in lead CMs; middle, lead CC,; right, ST recovery in 5 minutes in lead CMs during treatment with placebo (P), gallopamil (G) and propranolol (PR). The data are mean f standard error of the mean.

18 :; Mpsn;ge

& Sex 53M 51M 67F 56M 67F 66M 63M 53M 49M 50M 66M 57M 6OF 53M 59M 75M 69M 55M 63M 60M 59.6 yr,

Placebo 6.4

10.5

5.; 4:9

;I;:

Free of angina on maximal exercise. SEM = standard error of the mean. l

Gallopamil

Propranolol 10.3 a.9

Withdrawn 9.7 7.5 10.5 12.9 11.5 9.5 7.3 16.3 152.80 Withdrawn 6.6’ l

‘Z 7.2 15.1’ 10.1 f0.7

k”o 714 1::: 9.3 9.8 a.7 1;:: 7.6 11.0 6.4 6.2’ 10.2 7.0 1% 9:4 f0.7

March 1,1984

ST segment by 1.7 f 0.2 mm (lead CM& over 5 minutes after exercise (Fig. 2). Gallopamil: Gallopamil treatment increased the mean exercise time to 10.1 f 0.7 minutes (p
TABLE III

THE AMERICAN JOURNAL OF CARDIOLOGY Volume 53

687

Fourteen of the 18 patients exercised longer with gallopamil than with propranolol, with a range difference of 0.2 to 3.6 minutes. Four exercised longer with propranolol than with gallopamil, with a range difference of 1.0 to 1.8 minutes. The mean difference did not attain statistical significance. Propranolol significantly reduced the resting and maximal heart rates compared with gallopamil (p
Exercise Test Values in 18 Patients During Placebo, Gallopamil and Propranolol Therapy p Values Placebo

Exercise time (min) Rest HR (beatslmin) Maximal HR (beatsimin) HR gain (beats/min) HR recovery in 5 min (beatsjmin) HR gain/ex time (beats/min) Max ST CM5 (mm) Max ST CCs (mm) ST recovery CMs in 5 min (mm) ST recovery CCs in 5 min (mm) Max STlex time CM5 (mmlmin) Max ST/ex time CCs (mm/min) 1 mm time CM5 (min) 1 mm time CCs (min) Rest systolic BP (mm Hg) Peak systolic BP (mm Hg) Rate-pressure product (peak unit)

5.4 f 0.3 81 f3 117f2 37 f 3 41 f3

Gallopamil (150 ma/day)

‘“;: : 8.’

Propranolol (240 ma/day)

?i: : 8.’ 94 f 2

37 f 2

‘Z

46 f 3

31 f2

PI vs Ga

PI vs Pr

Ga vs Pr



$I;




NS


CO.05

<0:001
7 f 0.9

5 f 0.4

4 f 0.3

1.9 f 0.2 1.7 f 0.2 1.7 f 0.2

2.0 f 0.2 1.8 f 0.2 1.7 f 0.2

:.3 $8.: 1:4 f 0:2

z NS

NS

NS

1.4 f 0.2

1.5 f 0.2

1.1 f 0.1

NS

<0.05

NS

0.4 f 0.06

0.2 f 0.03

0.2 f 0.03



NS

0.4 f 0.06

0.2 f 0.03

0.2 l 0.02



NS

3.7 f 0.4 3.9 f 0.3 124f3

6.4 f 0.4 7.1 f 0.4 119f2

7.2 f 0.5 8.0 f 0.8 118f2



;: NS

137f2

141 f 3

131 f 2

NS

NS


160 f 3

173f5

123 f 3

<0.05



NS

Data are expressed as mean f standard error of the mean. BP = blood pressure; ex = exercise; Ga = gallopamil; HR ‘= heart rate; Max = maximal; 1 mm time = time taken for developing l-mm ST depression relative to resting level; NS = not significant; PI = placebo; Pr = propranolol; Rate-pressure product = systolic blood pressure at peak multiplied by maximal heart rate divided by 100; ST = ST depression.

688

GALLOPAMIL

AND PROPRANOLOL IN ANGINA

shock. No constipation, pedal edema, flushing or prolongation of the PR interval was observed with gallopamil. No reported adverse effects with propranolol were observed in this study. Discussion Calcium channel-blocking drugs are now firmly established as effective therapy for chronic stable angina pectoris.13-lg Verapamil, diltiazem and nifedipine are in clinical use for this indication in most countries. Having established that the first generation of calcium blocking drugs are effective therapeutic agents, intensive research is underway to produce new drugs with improved efficacy, longer duration of action and fewer adverse effects. Particular problems have been associated with verapamil (i.e., constipation) and with nifedipine (i.e., headaches, flushing and palpitations in susceptible patients). l7 Molecular manipulation and slow-release formulations are some of the methods that have been used to reduce these effects. For example, nicardipine and nifedipine are both dihydropyridine derivatives and are equally effective slow calcium channel-blocking agents. 21~~ However, nicardipine appears to produce fewer adverse effects in closes up to 120 mg/day.23 Nifedipine in a slow-release formulation produces lower serum levels and has a greatly reduced incidence of headache, flushing and palpitations. Gallopamil is a verapamil analog and differs from it by the addition of a methyl radical. Dose-ranging studies have indicated an effective range of 75 to 150 mg/day, compared with 360 to 480 mglday with verapamil. We have studied gallopamil to establish its efficacy and mode of action and chosen propranolol as the standard drug for comparison. To acquire comparative data the protocol was identical to that used in all our previous clinical trials. These methods of evaluation were designed to yield objective data with a minimum of observer bias, and an opportunity to examine the mode of action of the drugs under study. Our results show gallopamil to be effective in prolonging the exercise time. In the group of 18 patients who received 150 mglday, the mean exercise time increased by 87%. These results were not significantly different from those seen with 240 mg/day of propranolol. Gallopamil clearly exerted its antianginal effect by a different mechanism from propranolol. Whereas rest and maximal heart rates were reduced by propranolol, only the rest value was reduced by gallopamil, and the maximal heart rate was increased by 6 beats/min. The peak ST-segment depression was unaltered by either drug, but the time to development of 1 mm of ST depression relative to the value at rest was significantly prolonged by both. This suggests that gallopamil directly improves the myocardial oxygen supply/demand ratio, whereas ,L3blockade exerts its action by reducing heart rate. Of 20 patients who received gallopamil, adverse reactions developed in only 3. This incidence of unwanted effects compares favorably with that reported with other calcium channel blockers. Elevation of liver enzymes have been reported with verapamil.24 Gallopamil and verapamil are similar in chemical

structure and mechanism of action. Our experience with verapamil suggests a 75% improvement in exercise tolerance23 and a 30% incidence of constipation. This trial showed an 87% improvement in exercise tolerance with gallopamil and no constipation. Compared with the previous studies, propranolol also showed a greater improvement in exercise tolerance and no reported adverse effects were observed.25s26 In this study only 18 patients were evaluated, and it is not reasonable to infer that gallopamil is superior to verapamil; however, our data indicate that it has a similar efficacy and may have fewer adverse effects. References 1. P&hard BNC. Beta-blockade in angina pectoris. Propranolol in the treatment of angina: a review. Postgrad Med J 19?6;52:suppl 4:35-41. 2. Thadani U, Davidson C, Singleton W, Taylor SH. Comparison of five beta adrenoreceptor antagonists with different ancillary properties during susy;rd twice daily therapy in angina pectoris. Am J Med 1980;68:2433. Keyrilainen 0, Vusitalo A. Effects of metoprolol in angina pectoris-a s´ study with exercise tests and a Ions term tolerability study. Acta Med Stand 19?6:199:491-497. 4. Ekelund LG, Anders G, Olsson ORO, Rossner S. Effects of the cardioselective beta adrenergic receptor blocking agent-metoprolol-in angina ~;;oris. A subacute study with exercise tests. Br Heart J 19?6;38:1555. Thadani U, Parker JO. Propranolol in angina pectoris: duration of improved exercise tolerance and circulatory effeEts after acute oral adminisiration. Am J Cardiol 19?9;44:118-125. 6. Martlns de Olivelra J. Comparative effects of verapamil and propranolol in patients with angina pectoris. Arch Bras Cardiol 19?8;31:45-50. 7. Bala titwamanlan V, Mlllar-Craig MW, Davies AB, Raflery ES. Verapamil in variant angina. Assessment by high fidelity frequency modulated ambulatory tape recording. Am Heart J 1981;101:849-850. 8. Goldberg S, Relchek N, Wilson J, Hlrshfleld JWJ, Muller J, Kastor JA. Nifedioine in the treatment of Prinzmetal’s (variant) .I anaina. Am J Cardiol 19?9;~4:804-810. 9. Severi S, Davies GJ, Yaseri A, Marzullo P, L’Abbate A. Long-term pro nosis of ‘variant’ angina with medical treatment. Am J Cardlol 1980;4 8:

3%_3R3

w-v

h-b.

IO. Freeman WR, Peter T, Mandel WJ. Verapamil therapy in variant angina pectoris refractory to nitrates. Am Heart J 1981;102:358-362. 11. Peplne CJ. Felman RL, Whittle J. Curry RC. Contl CR. Effects of the calcium anta$onist diltiaiem in paiients-with.variant angina. Am Heart J 1981:101:?19-725. 12. Zells R. Calcium blocker therapy for unstable angina pectoris. N Engl J Med 1982;306:926-928. 13. MoscowlIz RM, Plcclni PA, Nacarelll GV, Zells R. Nifedipine therapy for stable angina pectoris: preliminary results on angina frequency and treadmill exercise res onse. Am J Cardiol 19?9;44:81 l-816. 14. Corbalan R, & nzalez R, Chatnono G, Munoz M, Roblquez JA, Casanegra P. Effects of a calcium inhibitw, nifedipine, on exercise tolerance in patients with angina pectoris. Chest 1981;?9:302-305. 15. Bala Subramanlan V, Paramaslvan R, Lahlrl A, Raftery EB. Verapamil in chronic stable angina: a controlled study with computerised treadmill exercise. Lancet 1980;1:841-844. 16. Bala SubramanlanV, Bowles Y, Lahlrl A, Davies AB, Raftery ES. Longterm antianginal action of verapamil assessed with quantitated serial treadmill stress testing. Am J Cardiol 1981;48:529-535. I?. Bala Subramanlan V, Bowles MJ, Khurml NS, Davies AB, Raftery EB. A randomized double-blind comparison of verapamil and nifedipine in chronic stable angina. Am J Cardiol 1982;50:696-703. 18. Bala Subramanlan V, Khurml NS, Bowles YJ, O’Hara hl, Raftery ES. Objective evaluation of three dose levels of diltiazem in patients with chronic stable angina. J Am Coll Cardiol 1983;1:1144-1153. 19. Krlkler DM, Rowland E. Clinical value of calcium antagonists in treatment of cardiovascular disorders. J Am Coll Cardiol 1983;1:355-384. 20. Ellestad MH, Blomqulsl CG, Naughton JP. Standards for adult exercise testing laboratories. Circulation 1979;58:421A-430A. 21. Bowles MJ, Subramanlan VB, Khurmi NS, Davies AB, Raftery ES. Efficacy of a new calcium blocking agent nicardipine in chronic stable angina (abstr). Br J Clin Pharmacol 1982;13:590. 22. Jones RI, Hornung RS, Sonecha TS, Raflery ES. The effect of a new calcium channel blocker nicardipine on 24hour ambulatory blood oressure and the pressor response to i&metric and dynamic exercise. Hyp&tension 1983;1:85-89. 23. Bala Subramanian V, Bowles MJ, Khurml NS, Raftery ES. Comparative evaluation of four slow channel blockers with propranolol in stable angina pectoris (abstr). Circulation 1982;66:72. 24. Brodsky SJ? Cutler SST Weiner DA, Klein MD. Hepatotoxicity due to treatment with verapamll. Ann Intern Med 1981;94:490-491. 25. D’Hara MJ, Subramanlan VB, Khurml NS, Bowles MJ, Raftery EB. Diltiazem compared with propranolol for the treatment of stable angina pectoris using serial quantitated treadmill tests (abstr). J Am Coll Cardiol 1983;l. 680. 26. Subramanlan VB, Bowles MJ, Davles AS, Raftery ES. Calcium channel blockade as orimarv theraov for stable anaina oectoris. A double-blind placebo-contiolled &omparistin of verapamiland dropranolol. Am J Cardiol 1982:50:1158-1163.