comparison of bevantolol and atenolol in chronic stable angina

Comparison of Bevantolol and Atenolol in Chronic Stable Angina

ERWIN A. RODRIGUES, MB, ChB, MRCP, JOHN D. LAWRENCE, MB, MRCP, PRABIR DASGUPTA, MB, BS, ANGAS D. B. HAINS, MB, BS, FRACP,

AVIJIT LAHIRI, MB, BS, MSc, PETER R. WILKINSON, MD, MRCP, and EDWARD B. RAFTERY, MD, FRCP

A randomized, double-blind, parallel-group study design was used to compare the antiangtnal effka- cy of bevantold (200 to 400 mg) and atenolol (50 to 100 mg) each administrated once daily for 8 weeks in 39 patients with chronk stable angina. U were made using 24-hour ambulatory monttorkg and treadmill exercise testing performed 22 to 24 hours after the last dose of medictkn. Both groups were comparable at the end of the placebo phase. In the bevantotol group, exercise time increased from 7.9 f 0.7 minutes wtth placebo to 9.3 f 0.7 minutes with bevantokl (mean f standard error of the mean) (p <0.05). Time to 1 mm ST depression was unaltered. Rest and exercise heart rate decreased (p <O.OOOl and <0.0005, respectively) as did exercise double product (p <O.OOOl). In the atenolot group exercise time in-

creased from 7.1 f 0.7 minutes with placebo to 8.2 f 0.8 minutes with atenoki (p X0.02). Time to 1 mm ST depression kcreased (p <O.OOS) and rest and exercise heart rate and double product decreased (p <O.OOOl and x0.05, respectively). When within-group dtfferences between placebo and active drug were compared for bevantolol and atenolol, no signifkant differences were detected. Both drugs were well tolerated and reduced ambulatory heart rate throughout the 24 hours. This study confirms that both bevantokl and atenokI are effective antianginal agents. Bevantotot compares well with atenokl in the treatment of patients with chronic angina, and there was a similar reqxmse to exercise testhlg with the 2 chugs.

(Am J Cardiol 1988;81:1204-1209)

B evantolol hydrochloride (l-[(3,&dimethoxyphen- ethyl)amino]-3-(m-tolyloxy)-2-propanol monohydro- chloride) is a new cardioselective ,B-adrenergic blocking agent with a unique pharmacologic profile,l giving it theoretical advantages for the treatment of patients with angina pectoris. It has been shown, in animal models, to possess a-adrenergic agonist activity result- ing in a direct positive inotropic effect on the ischemic myocardium.2 In contrast to propranolol, bevantolol increases subendocardial blood flow and has been shown to produce redistribution of blood flow in is-

From the Cardiology Department and Division of Clinical Sci- ences, Northwick Park Hospital and Clinical Research Center and Ashford Hospital, Middlesex, England. This study was sup- ported by a grant from Warner-Lambert International. Manu- script received November 9, 1987; revised manuscript received March 1,1988, and accepted March 2.

Address for reprints: E. B. Raftery, MD, FRCP, Department of Cardiology, Northwick Park Hospital, Watford Road, Har- row, Middlesex, HA13LJJ England.

chemic myocardium, 3,4 thereby reducing myocardial oxygen demand and limiting the size of experimental- ly induced myocardial infarction.5 In vitro studies sug gest that the drug possesses class I and class III antiar- rhythmic activity.” It has salutory effects on serum high density lipoprotein cholesterol7 and may be suitable for once-daily administration. Clinical studies in man have confirmed its efficacy as an antianginal agent.7-9 We compared the efficacy of bevantolol with atenolol in patients with chronic stable angina to assess the clinical relevance of this unique @ blocker. Assess- ments were performed 22 to 24 hours after the last dose of medication to confirm suitability for once-daily administration,

Methods Patients: Thirty-nine patients (35 men, 4 women]

aged between 39 and 74 years (mean 60) were recruit- ed for the study. All had stable reproducible exertional angina of at least 3-month duration. All developed angina1 pain on treadmill exercise associated with re-

1204

June 1,1988 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 81 1205

producible horizontal or downsloping ST-segment depression of >O.l mV at the J point, in 1 or both of the bipolar leads CM5 and CC5. Qnly those patients phys- ically capable and mentally motivated for repeated treadmill exercise and Holter monitoring were en- tered into the trial.

Patients with a history of angina at rest or unstable angina were excluded as were those who had had an acute myocardial infarction in the preceding 3 months. Women of reproductive age were excluded as were patients with overt cardiac failure, obstructive airways disease, resting blood pressure >170/110 mm Hg, dia- betes mellitus, valvular heart disease or cardiac ar- rhythmias. Patients receiving diuretic drugs, digitalis or other cardiovascular drugs were not eligible for study. Those showing >O.5 mm ST-segment depres: sion on standing, hyperventilation or during the Val- salva maneuver were also excluded, as were patients with left ventricular hypertrophy or bundle branch block on the 12ilead electrocardiogram.

Study design: A randomized, double-blind, paral: lel-group study design was used. After an initial screening visit to confirm eligibility, patients com- menced a 2-week placebo phase, receiving 2 placebo tablets each morning. At the end of this period the patients were randomized to receive either bevantolol (Warner-Lambert International) 200 mg once daily or atenolol50 mg once daily for 4 weeks. An exercise test was performed at the end of this 4-week period. Those patients whose ‘exercise time had not improved by >2O% had their dose of medication doubled. If exercise time had improved the dose of medication was not altered. Active treatment was continued for a further 4 weeks. Twenty-four hour ambulatory electrocardiographic monitoring and maximal graded, treadmill exercise tests were performed at the end of the placebo phase andwere repeated at the end of the study. Clini- cal assessments were also performed at these visits but in addition, patients underwent a further clinical visit 2 weeks into the active treatment period to ensure acceptability of control of angina1 symptoms and lack of serious side effects.

Clinical asgessment: Patients underwent a physical examination at the end of the placebo phase and after 2,4 and 8 weeks of active treatment. Laboratory tests including hematology and clinical chemistry assays were performed before and after the active treatment phases. Angina1 diary cards were kept and the frequency of angina1 attacks and number of sublingual nitroglycerin tablets consumed were recorded. Com- pliance with the study medication was assessed by performing a pill count on the tablets returned at the end of each treatment phase.

Exercise testing: All exercise tests were performed in the morning, at least 2 hours after a light breakfast and 22 to .24 hours after the last dose of medication. Patients rested for at least 30 minutes before the test. They were instructed not to smoke or to take nitroglycerin tablets on the morning of the test.

Maximal, graded symptom-limited exercise tests were performed using a microcomputer-based system (CASE 1, Marquette Electronics) linked to a motor

TABLE I Exercise Test Variables In the Two Groups at End of Placebo Phase

Bevantolol Atenolol Group Group p Value

Exercise time (min) 7.9 f 0.7 7.07 f 0.7 NS 1 mm time, CM5 (min) 4.8 f 0.5 4.8 i 0.7 NS 1 mm time, CC5 (min) 4.6 f 0.6 4.8 f 0.7 NS Peak ST depression, CM5 (mm) 1.7 * 0.2 1.8 i 0.2 NS Peak ST depression, CC5 (mm) 1.7 f 0.2 1.6 f 0.2 NS Resting HR (beats/min) 83 f 4 87 f 4 NS Exercise HR gain (beatslmin) 44 f 4 43 i 2 NS Resting SBP (mm Hg) 142 f 5 145f6 NS Peak exercise SBP (mm Hg) 176 f 4 167 f 5 NS Peak exercise rate pressure 224 f 10 217 f 9 NS

product7100

Data are mean f standard error of the mean. HR = heart rate; NS = difference not significant; SBP = systolic blood

pressure. Abbreviations as in Table I.

driven treadmill (Quinton) in a temperature-controlled laboratory. A modified Chung exercise proto- col was used.10 Treadmill speed and gradient were automatically controlled by the computer. Standard safety procedures and legal requirements as recom- mended by the American Heart Associationll were observed. Two bipolar electrocardiographic leads (CM5 and CC5) were monitored continuously at rest, during exercise and for a minimum of 5 minutes during recovery from exercise. Systolic blood pressure was measured at rest and every 3 minutes during exercise using a mercury sphygmomanometer.

Computerized analysis of the data was performed as previously described.s Digital values of exercise time, ST-segment change, heart rate and blood pressure were stored on a cassette tape and later played back into a PDP 11/23 minicomputer (MINC Digital) from which time taken to develop 1 mm ST-segment depression, heart rate gain during exercise and rate- pressure product were derived using methods previously described.lz

Ambulatory monitoring: Ambultory electrocardiographic monitoring was carried out for 24 hours using a frequency modulated tape recorder (Oxford Medilog II) with a quartz controlled time channel, using methods previously described and validated.13t14 The same leads as used for exercise testing were monitored (CM5 and CC5). The recorded tape signal was recalled using an Oxford PB4 replay unit and displayed on a Pathfinder playback system [Reynolds Medical). Visu- al analysis of the tapes was performed to identify any prolongation of the PR interval or other conduction defects. Mean, maximum and minimum hourly heart rates were derived using a computer program.15 De- tailed quantitative ST-segment analysis was carried out using a digital system connected to the Reynolds Medical trend system.13s14

The number of episodes of ST-segment depression were printed out, together with the duration of each episode and the total duration and timing of ST-segment depression in the 24-hour recording. Using this technique the spontaneous variability of ST-segment

1206 BEVANTOLOL AND ATENOLOL IN ANGINA

depression has been shown to be 1ow.l” The duration of ST-segment depression was determined from the time the ST segment reached 1 mm below the baseline to the time it returned to within 0.5 mm of the baseline. A minimum period of 20 seconds was used to separate

9-

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E ‘- 5 w ‘U !s 4- I.5

3-

2-

1

0

r*

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lm

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Placebo

Active drug

Bevantolol Atenolol

FIGURE 1. Exercise time at the end of each phase In both groups (mean’f standard error of the mean).

Bevailtolol Atenolol BW.3nt0l0

CM5 cc5

* p<o.w5 **p<o.DK

q Placebo

q Acllve drug

FIGURE 2. Time to ‘I mm ST segment depression a! the end of each phase in both groups (mean f standard error of the mean).

150-

140-

130-

120-

E 110-

; lco-

; 90-

$ 80-

70-

60- * p<o.o5 ** p<o.o005 *** p<0.0001

FIGURE 3. Rest and exercise heart rate at the end of each phase In both groups (mean f standard error of the mean). bpm = beats/ min.

each episode. A significant episode was defined as >l mm ST-segment depression, 60 ms from the J point, lasting 3 minutes or more.

Statistical analysis: The 2 treatment groups were compared at the end of the placebo phase using Stu- dent’s unpaired t tests to ensure similarity of the 2 arms of the study. The effects of drug therapy were assessed using Student’s unpaired t tests on the within-group differences between the final assessment and placebo phases. Subjective data and ambulatory ST-segment data were analyzed using the &tailed Mann-Whitney U test and Wilcoxon signed ranks tests, respectively. The study was approved by the Hospital Ethical Com- mittee and patients gave informed written consent before participating.

Results All patients completed the placebo phase and then

began the active therapy. Nineteen men and 1 woman [mean age 60 years, range 46 to 70) were randomized to receive bevantolol. The atenolol group consisted of 16 men and 3 women [mean age 61 years, range 39 to 74). Thirty-six patients completed the full study.

Comparability of the patient groups: The results of exercise testing at the end of the placebo phase are listed in Table I. Mean f standard error of the mean exercise time was 7.9 f 0.7 minutes in the bevantolol group and 7.1 f 0.7 minutes in the atenolol group. This difference was not statistically significant. The groups were similar in terms of heart rate, systolic blood pressure, ST-segment indexes and peak exercise double product. Angina attack frequency and nitroglycerin consumption were also similar in the 2 groups during the placebo phase.

Response to bevantolol therapy: Eight of the 19 patients receiving bevantolol(42%) had the dose titrated up to 400 mg daily after 4 weeks because of an inadequate initial response. Mean f standard error of the mean exercise time increased from 7.9 f 0.7 minutes with placebo to 9.3 f 0.7 minutes after 8 weeks (p X0.05) (Figure 1). Time to 1 mm ST depression in both leads CM5 and CC5 increased significantly from placebo to the end of treatment (p <O.OOl and <O.OOl, respectively) (Figure 2). Rest and peak exercise heart rate were significantly lower after 8 weeks of treatment with bevantolol compared with placebo (p < 0.0001 and <0.0005, respectively] (Figure 3). Heart rate

zo-

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evantolol AtKiOlOl B~VXWOI Atenolol

CM5 cc5

FIGURE 4. Peak exercise ST-segment depression at the end of each phase fn both groups (mean f standard error-of the mean).

June 1, 1988 THE AMERICAN JOURNAL OF CXtDIOLOGY Volume 61 1207

gain on exercise was unaltered as was peak ST-segment depression (Figure 4). There was no significant change in resting systolic blood pressure between placebo and bevantolol therapy but peak exercise systolic blood pressure was significantly lower with bevantolol (p <O.Ol) (Figure 5). Exercise rate-pressure product decreased from 225 f 10 with placebo to 186 f 9 with bevantolol (p <O.OOOl) [Figure 6).

Response to atenolol therapy: In the atenolol group 7 of the 17 patients (41%) had their dose titrated up from 50 to 100 mg daily after 4 weeks of therapy. Mean f standard error of the mean exercise time in the atenolol group increased from 7.1 f 0.7 minutes with placebo to 8.2 f 0.8 minutes after 8 weeks of treatment (p <0.02) (Figure 1). Time to 1 mm ST depression in leads CM5 and CC5 improved significantly (p CO.005 and <O.O05, respectively) (Figure 2). Rest and exercise heart rates were lowered significantly compared with placebo (p <O.OOOl and <0.05, respectively) but heart rate gain on exercise remained the same [Figure 3). Peak exercise ST depression was similar during placebo and atenolol therapy (Figure 4) as was systolic blood pressure (Figure 5) but peak exercise rate-pressure product was significantly lower on atenolol compared with placebo (p <0.05, Figure 6).

Comparison of bevantolol and atenolol: When the within-group differences between placebo and bevantolol and between placebo and atenolol were compared, there was no statistically significant difference between the 2 drugs in exercise time, time to 1 mm ST depression, heart rate, blood pressure or peak ST depression [Table II).

Ambulatory monitoring: Holter monitoring was performed in 22 patients (Figures 7 and 8). Mean hourly heart rate throughout the 24 hours was significantly lower on bevantolol and atenolol compared with placebo. There was no significant difference between the bevantolol and atenolol treatment groups.

The number of episodes of ST-segment depression decreased from 25 on placebo to 6 on bevantolol (difference not significant). In the atenolol group the cor- responding values were 53 and 42 (difference not significant). There was no significant difference in the number of episodes or duration of ST depression between the 2 drugs when the within-group values were compared. In the bevantolol group all recorded epi-

NS NS -

Bevantolol AtenOlOl

Rest

A

* P<OOl 0 Placebo

iZ Active drug

sodes of ST depression were ,Jlent with both placebo and active drug. In the atenolrl group 26% of the episodes were symptomatic with placebo while 74% were silent. Active therapy did noi alter this significantly (17% symptomatic and 83% silent with atenolol).

Clinical assessment: Mean f standard error of the mean weekly angina1 attack frequency decreased from 4.8 f 2.2 with placebo to 2.2 f 0.9 with bevantolol [difference not significant) and from 3.2 f 1.0 on placebo to 1.6 f 0.7 on atenolol (difference not significant]. Mean weekly nitroglycerin consumption likewise decreased from 3.2 f 1.0 tablets with placebo to 2.4 f 1.2 tablets with bevantolol (difference not significant) and from 1.9 f 0.7 with placebo to 1.5 f 0.7 tablets with atenolol [difference not significant].

Compliance with drug medication, as assessed by pill counts, was good (>85%). Full blood count, serum urea, electrolytes and liver function tests did not change during the study.

Adverse effects and withdrawals: Three patients were withdrawn during the study: 1 taking bevantolol, because of lethargy, malaise and diarrhea; another taking atenolol, following a transient cerebral ischemic attack (this patient had had a previous myocardial infarction and subsequent cross-sectional echocardi- ography demonstrated the presence of a left ventricular aneurysm containing mural thrombus); the third patient was withdrawn because she developed a short, self-terminating burst of ventricular tachycardia during exercise while taking atenolol.

The study medications were otherwise well tolerated. Four patients reported adverse effects from bevantolol; 2 had fatigue, 1 headache and 1 patient complained of both headache and fatigue. On atenolol the adverse effects were headaches, insomnia, palpitation and fatigue, and 4 patients reported these side effects. Two patients complained of tiredness while taking placebo.

Discussion Bevantolol is a highly cardioselective /3 blocker,17

which has salutory effects on the ischemic myocardi- urna3s4 In a total daily dose of 200 mg it has been shown,

2401

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150-

od Bevantolol Atenolol

* I

* p<o.os ** p<0.0001

[1 Placebo t’2 Active drug

Exercise

FIGURE 5. Rest and exercise systolic blood pressure at the end of FIGURE 6. Exercise double product at the end of each phase in both each phase In both groups (mean f standard error of the mean). groups (mean f standard error of the mean).

1208 BEVANTOLCL AND ATENDLOL IN ANGINA

TABLE II Comparison of the Within-Group Differences

Placebo- Placebo- Atenolol Beva&lpl

Difference Difference p Value

Exercise time (min) +1.1 f 0.4 +I.4 i 0.6 NS 1 mm time, CM5 (min) +1.7 f 0.4 +1.4 f 0.4 NS 1 mm time. CC5 (min) +I.6 f 0.5 +1.3 * 0.3 NS Peak ST depression, CM5 (mm) +0.2 f 0.1 +O.l f 0.2 NS Peak ST depression, CC5 (mm) +0.04 f 0.1 +0.06 h 0.2 NS Resting HR (beatshnin) -19f3 -19f2 NS Peak exercise fjR (beatslmin) -11 f5 -15*3 NS Exercise HR gain (beats/min) +8f6 +2f3 NS Resting SBP (mm Hg) -8f6 -3f6 NS Peak exercise SBP (mm Hg) -9f6 -12f4 NS Peak exercise rate pressure -28 f 12 -4Of8 NS

product1100

Data are mean h standard error of the mean. Abbreviations as in Table I.

SO J,,,,,, 111111111111111 I

9 12 15 18 21 24 3 6 Time of day

FIGURE 7. Mean hourly rate on placebo and on beva~olol. bpm = beats/mln.

50-1,,,,,,,,,I,I,,,,,,,,,,,,

9 ‘12 15 18 21 24 3 6

Time of day FIGURE 8. Mean hourly rate on placebo and on atenolol. bpm = beats/mln.

in placebo-controlled studies,8 to be an effective anti- angina1 agent when administered once or twice daily. This study was designed to assess whether the theoretical advantages of bevantolol confer clinical superiori- ty over the established cardioselective ,&blocker aten- 0101, in the management of patients with chronic stable angina. Furthermore, since previous studies have assessed efficacy 2 to 4 hours after dose,8 a secondary aim of this study was to assess the antianginal efficacy of bevantolol on exercise capacity 22 to 24 hours after the last dose of medication.

Optimal doses of atenolol and bevantolol were compared by titrating the dose upward if an adequate response was not seen after 4 weeks of active therapy. Since a once-daily regime was being assessed, exercise testing was performed 22 to 24 hours after the last dose of medication but the effect of medication throughout the 24 hours was also monitored using ambulatory electrocardiographic recording. Emphasis was placed on objective measurement of exercise-induced ischemia by using a computerized exercise testing system and subsequent computer analysis of the data.

Both the bevantolol and atenolol groups were comparable at the end of the placebo phase, in terms of age, exercise time and indexes of ischemia on exercise testing. Exercise time increased in both groups and indexes of exercise-induced myocardial ischemia improved compared with placebo.

Twenty-four hour ambulatory heart rate data indi- cate that the B-blocking action of once-daily bevanto- 101 is apparent for the entire 24 hours. Although ambu- latqry heart rate was significantly lower than it was with placebo, minimum hourly heart rate, with either drug, was not low enough to cause any untoward effect. Both drugs reduced the number and duration of episodes of ST-segment depression on ambulatory monitoring and they appeared to affect symptomatic and silent episodes in a similar way. The changes not- ed were not, however, statistically significant, which probably reflects the wide individtial variation in these parameters in a small group of patients.

Both drugs were well tolerated. Neither of the com- plications seen with atenolol is likely to be related to drug therapy. Only 1 patient given bevantolol developed serious side effects, which were probably related to the drug.

Acknowledgment: We thank Gill Clarke for tech: nical assistance, Dr. Heather Pelling for statistical help and Karen Bell for typing the manuscript.

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June 1.1968 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 61 1209

Cardiol 1979:44:657-66X 5. Wadtier DC, Gross GJ. Jesmok GJ, Brooks HC, Hardman HF. Protection of ischaemic myocardium comparison of effects of propranolol, bevantolol and N-dimethvl nronmnolol on infarct size followins coronarv arterv occlusion in anaesthet&I dogs. Cardiology 1960;68:133-146: ’ ’ 6. Dukes ID, Vaughan Williams EM. Cardiovascular effects of bevantolol. a selective Et-adrenoceptor antagonist with a novel pharmacological profile. Br J Pharmacol 1965;64:365-380. 7. Salonen JT. Taskinen E, Salonen R, Sappanen K. Venalainen J. Rauramaa R. Effects of bevantolol and atenolol on symptoms, exercise tolerance and metabolic risk factors in angina pectoris. Am J Cardiol 1966;56:35E-40E. 8. Bowles MJ. Khurmi NS, O’Hara MJ. Raftery EB. Bevantolol in chronic stable angina: a placebo-controlled. double-blind crossover study of once- daily and twice-daily regimens. Am J Cardiol 1986;58:28E-34E. 9. Steen SN, Smith RL, Ginston LE, Cdley JM. Preliminary report on the use of bevantolol in patients with angino pectoris of effort. Int Res Comm Med Sci 1979:7:339. 10. Bala Subramanian V, Bowles MJ. Lahiri A. Davies AB. Raftery EB. Long- term anti-angina] action of verapamil assessed using quantitated serial tread- miII stress testing. Am J Cardiol 1981;48:529-535. 11. Ellestad MH, Blomquist CA, Naughton JP. Standards for adult exercise

testing laboratories. Circulation 1979;58:421A-430A. 12. Bala Subramanian V, Lahiri A, Paremasivan R, Raftery EB. Verapamil in chronic stable angina a controlled study with computerised multistage tread- miII exercise. Lancet 1980:1:841-644. 13. Bala Subramanian V, Lahiri A. Green HC, Stott FD. Raftery EB. AmbuIa- tory ST-segment monitoring. Problems, pitfalls, solutions and clinical applica- tions. Br Heart I 1960:44:419-425. 14. Cashman PMM, Kohli RS, Khurmi NS. Bowles MJ, Raftery EB. Semi- automated ST-segment analysis: validation. results, problems and lessons learned. In: Dal PaIu C. Pessina AC, eds. Proceedings of the Fifth Internation- al Symposium on Ambulatory Monitoring, Pedua. Italy: CLEUP. 1985:413- 427. 15. Khurmi NS. CYHara MJ, Bowles MJ, Bala Subramanian V, Raftery EB. Randomized double-blind comparison of gallopamil and propranolol in stable angina pectoris. Am J Cardioi 1964;53:6814-686. 16. Kohli RS, Cashmann PMM. Lahirl A, Raftery EB. The ST segment of the ambulatory electrocardiogram in a normal population. Br Heart J. in press. 17. Hoefle ML, Hastings SG, Meyer RF, Corey RM. Holmes A. Stratton CD. Cardioselective beta-adrenergic blocking agents l.l-[(3,4-dimethoxyphen- ethyl) amino-3-aryIoxy-2-propranoIoI. J Med Chem 1975;18:148-152.

comparison of bevantolol and atenolol in chronic stable angina

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