European Heart Journal (1992) 13,1129-1134

Effect of benazepril on myocardial ischaemia in patients with chronic stable angina pectoris D. TZIVONI*, S. GOTTLIEB, N. S. KHURMI, A. MEDINA, A. GAVISH AND S. STERN

The Heiden Department of Cardiology, Bikur Cholim Hospital and the Hebrew University Hadassah Medical School, Jerusalem, Israel KEY WORDS: Exercise testing, ambulatory ECG monitoring, ACE inhibitors, myocardial ischaemia, anti-ischaemic therapy. The anti-ischaemic properties of benazepril, a non-sulfhydryl inhibitor of angiotensin-converting enzyme, were assessed in 20 patients with chronic stable angina pectoris, by repeated exercise tests and repeated 72-h ambulatory electrocardiographic monitoring. The study was a double-blind, placebo-controlled cross-over; 11 patients received benazepril 10 mg b.i.d. and nine received 20 mg b.i.d. All patients had a positive treadmill stress test and at least three ischaemic episodes during 24 h of ambulatory electrocardiographic monitoring. Benazepril at a dose of 10 mg b.i.d. did not improve the exercise duration, the time taken to reach 1 mm ST depression. Similar findings were observed during treatment with 20 mg b.i.d. Benazepril at a dose of 10 mg b.i.d. was ineffective in improving ischaemic parameters during daily activities. However, among the nine patients who received 20 mg b.i.d. the number of ischaemic episodes was reducedfrom 142 to 103, and the total duration of ischaemia was reducedfrom 1099 to 531 min. The number of weekly anginal attacks was reducedfrom 58 to 33, and the weekly sublingual nitroglycerin tablets consumption was reducedfrom 31 to 14. When the two doses (10 mg and 20 mg) were combined (H = 20), the number of ischaemic episodes was reduced from 314 to 260 (P = 0074), and the duration of ischaemia was reduced from 3453 to 2514 min (P = 0-072).

Introduction Benazepril is a new, non-sulfhydryl, orally active, selective inhibitor of angiotensin-converting enzyme (ACE). Clinical studies have confirmed the antihypertensive activity of benazepril''-2' and its beneficial effect on congestive heart failure'3'. The usefulness of ACE inhibitors in coronary artery disease is uncertain and has not been well explored. A pilot investigation'4' of captopril in patients with angina pectoris and concomitant essential hypertension suggests that this class of drugs might be beneficial in this group of patients'5'6'. Angiotensin II is a potent vasoconstrictor of the systemic and coronary arteries, which increases the vascular tone of the large conductive coronary vessels. In addition, it possesses positive inotropic effects, therefore increasing the inotropic state and afterload17"9'. ACE inhibitors reduce blood pressure without inducing reflex tachycardia and thereby lower the rate-pressure product. This can be beneficial in patients with angina pectoris where the primary aim of medical therapy is to improve myocardial oxygen supply and reduce myocardial oxygen consumption. It has also been suggested that ACE inhibitors are coronary vasodilators'10"1. Therefore, in view of the suggested mechanisms of ACE inhibitors in patients with coronary artery disease, it was considered worthwhile to investigate the Submitted for publication 3 June 1991, and in revised form 16 October 1991. Correspondence' Shmucl Gottlieb, MD, The Heiden Department of Cardiology, Bilcur Cholim Hospital, P.O. Box 492, Jerusalem 91002. Israel •Present address: Dan Tzivoru, MD, Director, Department of Cardiology. Shaare Zedelc Medical Center, P.O. Box 3235, Jerusalem 91031. 0195-668X/92/081129 + 06 $03 00/0

safety and the anti-anginal and anti-ischaemic effects of benazepril in patients with chronic stable angina pectoris. Methods PATIENT POPULATION

A total of 20 patients (18 men and two women) aged 4770 years (mean 61-3 years) with established chronic stable angina pectoris were included in the study. The duration of their angina ranged from 4 to 168 months (mean 38-7 months). The diagnosis of coronary artery disease was established by the presence of previous myocardial infarction (five patients) or angiographic evidence of significant coronary artery disease (11 patients). All 20 patients had a typical history of effort-induced angina with a positive stress test. All patients gave written informed consent and were required to fulfil tjie following inclusion and exclusion criteria. Inclusion criteria Classical history of angina pectoris of at least 3 months duration, reproducible effort-induced angina pectoris occurring during treadmill exercise and associated with a horizontal or down-sloping ST-segment depression of 1-5 mm or more. Presence of at least three episodes of ST depression during 24 h of ambulatory ECG monitoring when undergoing no treatment at the beginning of the placebo run-in period. Exclusion criteria Patients above 70 years of age, and patients with evidence of myocardial infarction within the preceding 4 I 1992 The European Society of Cardiology

1130 D.Tzivoni etal.

months, coronary artery by-pass surgery within the preceding 6 months, left ventricular hypertrophy or bundle branch block in a resting 12-lead electrocardiogram, or arrhythmias sufficiently severe to interfere with the interpretation of ST-segment changes, or unstable angina pectoris were not studied. Chronic heart failure, hypotension (resting systolic blood pressure of less than 110 mmHg), hypertension with a resting blood pressure of more than 170/105 mmHg, or insulin-dependent diabetes mellitus were other exclusion criteria.

activities, or fatigue or shortness of breath, or if ST depression exceeded 3 mm. AMBULATORY ELECTROCARDIOGRAPHIC MONITORING

All patients underwent 24-h ambulatory electrocardiographic recording during the single-blind placebo run-in period, and 72 h recording during the double-blind treatment period using ACS reel-to-reel of twchchannel AM recorders, calibrated to lOmm.mV" 1 . Recorders were equipped with an 'event button' which the patient was instructed to activate when any chest pain or discomfort was experienced. Silver-silver chloride disposable skin Previous treatments electrodes were attached to a well-shaved and scrubbed Long-acting nitrates, /?-blockers and calcium antagonchest wall. The exploring electrodes were attached to the ists were withdrawn (according to manufacturer's instrucV3-like and V5-like positions'12'. The Cardiodata Prodigy tions) before the inclusion of a patient in the trial. System, combined with a PDP 11/73 computer was used Sub-lingual glyceryl trinitrate was allowed throughout for the digitalization and analysis of the Holter tapes. the trial to abort acute anginal attacks. Diuretics, Holter data were analysed by a highly experienced techdigitalis, tricyclic antidepressants, NSAIDs and other nician, using a validated computer algorithm (version investigational drugs were not permitted throughout the 7.07) for ST analysis. trial period. The ST analysis was performed in both channels in a semi-automatic-interactive method. The technician had TRIAL PROCEDURE to set the isoelectric level at the PR segment and the J Before starting the trial a general medical examination point. The system determined the ST slope by measuring was performed for each eligible patient who consented to the average level of the ST segment 60 ms after the J point take part in the trial. The personal data, medical history in consecutive 30 s samples. Any ST deviation from the and findings of the medical examination were recorded. isoelectric level was displayed on the ST trend. The ST There was a single-blind placebo run-in period of 1 changes during the whole monitoring period were plotted week's duration. During this period the patients took one in two-channel ST-trend histograms. A heart rate trend placebo tablet of benazepril in the morning and one in was plotted on the same time scale as the ST trend in order the evening: two exercise tests were performed in order to enable accurate determination of the heart rate at onset to assess the reproducibility. Ambulatory ST-segment of ischaemic episodes. Electrocardiographic samples were monitoring for 24 h was performed on the first day of the printed out in real time, 2 min before onset of ST placebo run-in period. depression, at onset of ischaemia (1 mm of ST depression), The double-blind treatment periods lasted 1 week. At at maximum ST depression, at maximum heart rate and on the end of each double-blind treatment period a symptom- return to the isoelectric line. Each episode was visually limited treadmill exercise test was performed in the morn- verified by a physician, both from the ST trend and from ing 2-3 h after administration of the trial medication, and the real-time print-outs. ambulatory ST-segment monitoring was performed for The following variables'' 3~'51 were measured and 72 h. The protocol was approved by the hospital ethics recorded at the end of each treatment period: 1. number of committee. episodes of ST-segment depression greater than 1 0 mm and of at least 1 min duration (both symptomatic and EXERCISE TEST asymptomatic), during 72 h in leads V3 and V,; 2. total The treadmill exercise tests were performed on a duration of ST-segment depression during 72 h; 3. maxiQuinton 3000 treadmill (each patient performing the test mum depth of ST-segment depression during 72 h; 4. at a specific time every day) after a light breakfast taken at mean heart rate at the onset of episodes of ST-segment least 2 h before the test. No beverages containing caffeine, depression; 5. mean heart rate at maximum depth of no smoking and no sublingual nitroglycerin tablets were ischaemic episodes. allowed in the 2 h prior to the test. . The treadmill exercise tests were performed using a STATISTICAL ANALYSIS Bruce protocol. At the end of each 3 min stage, blood All statistical analyses were performed using the pressure and a 12-lead electrocardiogram were also Statistical Analysis System (SAS), Version 5.18. For recorded. The ST-segment level and heart rate were statistical significance testing (two-tailed tests), the sigrecorded every minute during exercise and every 5 min nificance level was set at 5%. The confidence level was set thereafter. Leads V3, V5 and aVF were continuously at 95% for computing the confidence limits. monitored and recorded every minute. ST-segment The relationship between a confidence interval (CI) and depression was measured 80 ms after the J-point. a simple t-test is the following. A t-test shows a significant The exercise tests were maximum-symptom limited and treatment — placebo difference with an error of the first were terminated if the patient reported moderate to severe kind of a, if, and only if, the confidence interval with the anginal pain which would have limited his/her everyday confidence level of 1 —a does not include 0.

Benazepril in angina pectoris 1131

Table I Effect of benazepril on resting blood pressure, heart rate, number of anginal attacks and sub-lingual nitroglycerin consumption per week lOmgb.i.d.

Resting systolic blood pressure (mmHg) Resting heart rate, (beats. min~') • Resting rate-pressure product Number of anginal attacks per week Number of GTN per week

20 mg b.i.d.

Placebo

Benazepril

Placebo

Benazepril

127-7 72-9 92-9 78 18

127-7 67-3 86-9 % 35

135 71-2 96-7 58 31

128 67-4 86-3 33 14

GTN = glyceryl trinitrate.

Table 2

Exercise test results in II patients with low-(10 mg b.i.d.) and nine with high-(20 mg b.i.d.j dose benazepril Placebo

Exercise time (min) Time to 1 mm ST depression (min) Maximal ST depression (mm) Heart rate at maximal exercise (beats min"1) Systolic BP at maximal exercise (mmHg) Rate-pressure product at maximal exercise (units) x I02

8-3± 10 5-I±l-2 2-0±0-4 136±5 149 1 ± 8 6 204-9±18-6

Benazepril 10 mg b.i.d. (95% C I ) ' 8O±O-8 4-4±0-9 21 ±0-4 133±5

(-0-89to+0-43) (-1-60to +0-20) (-0-58 to +0-40) (-8-Oto2-37)

155 9 ± ll-9( —6 25 to +19-88) 211-5±22-9(-8-39to+21-52)

Benazepril 20 mg b.i.d. (95% CI)*

Placebo 6-9±0-7 4-5±0-8 2-2±0-3 125±6 163 8 ± 16-5 2O9-2±27-9

7-6±0-6 i 5-o±O-9 2-3±0-3 132±6

(-1-52to+2-70) (-1-27 to+2-66) (-0-89to+1-22) (-11-35 to+23-80)

167-8±9-8 (-34-15 to +40-82) 222-5 ± 18-5(-56-49 to+80-75)

Data are expressed as mean ± standard error of the mean. BP = Blood pressure. *95% confidence interval, both upper and lower, of the mean difference between active treatment and placebo.

Table 3

Comparison of ambulatory ECG monitoring variables per 72 h between placebo and treatment periods High dose ( N = 19)

Low dose (N = II) Placebo Number of ischaemic episodes Duration of ischaemic episodes (min) Mean maximal ST depression (mm)

172 2360 315

Benazepril lOmgb.i.d. (95% C I ) ' 157 (-4-97 to+2-25) 1983 ( - 1 2 3 1 8 to+54-63) 3-13 ( — 0-91 to +0-96)

Placebo

142 1094 3-20

Benazepril 20 mg b.i.d. (95% CI)* 103 (-10-53 to+1-86) 531 (-136-61 to+11-49) 3-50(-0-86to0-26)

*95% CI = 95% confidence interval, both upper and lower, of the mean differences between active treatment and placebo.

Results Twenty patients (18 men and two women) aged 47-70 years were recruited for the study. Eleven patients were studied on low dose benazepril (10 mg b.i.d.) and nine on high-dose benazepril (20 mg b.i.d.). Premature discontinuation One patient withdrew from the treatment prematurely at the last visit while receiving placebo in the high-dose benazepril group. This patient developed unstable angina and was hospitalized. The last exercise test was not performed. Blood pressure and heart rate The effect of benazepril on resting blood pressure and heart rate is shown in Table 1. With the low-dose

benazepril (10 mg b.i.d.) there was no change in mean systolic blood pressure, while the heart rate was reduced from 73 to 67 beats . min"1 (95% CI - 1004 to - 105). With the high dose benazepril (20 mg b.i.d.) mean systolic blood pressure and heart rate were both insignificantly reduced (135 to 128 mmHg, and 71 to 67 beats, min"1 respectively). Angina attacks and sub-lingual nitroglycerin consumption In the low-dose group during 1 week of treatment, 78 angina attacks were recorded under placebo and 96 with benazepril lOmgb.i.d. Similarly, the consumption of sublingual glyceryl trinitrate tablets was 18 under placebo and 35 under benazepril (Table 1). In the high-dose group 58 angina attacks were recorded under placebo and these were reduced to 33 under benazepril 20 mg b.i.d.

1132 D.Tzivoni etal.

-

400

4000

300-

3000-

200-

•5 2000 -

100 -

1000-

Low

High

Both

Figure I Number of ischaemic episodes during 72 h of Holter monitoring in the placebo period and during 72 h of active treatment with benazepril. Low=10mg b.i.d. (11 patients), High = 20mg b.i.d. (nine patients). Both = both groups (20 patients), 0 = benazepril, • = placebo;

Similarly, consumption of sub-lingual glyceryl trinitrate tablets was 31 under placebo and this was reduced to 14 under benazepril. EXERCISE TEST RESULTS (TABLE 2)

In the low-dose benazepril group there was no change in any of the exercise test variables. In the high-dose benazepril group an insignificant increase in exercise duration (6-9 to 7-6 min) and in the time taken to reach 1 mm ST depression (4-5 to 50 min) was observed. AMBULATORY ELECTROCARDIOGRAPHS MONITORING (TABLE 3)

Low

High

Both

Figure 2 Duration of ischaemic episodes during 72 h of Holter monitoring in the placebo period and during 72 h of active treatment with benazepril. For key see Fig. 1.

(28-8%) were symptomatic (95% CI -1-88 to +0-38) and 185 asymptomatic (95% CI -4.81 to + 0 91). The total ischaemic burden, as expressed by total duration of ST-segment depression, was 2360 min during the placebo period and was reduced to 1983 min (95% CI -123-18 to +54-63) with benazepril lOmg b.i.d. In the high-dose group the ischaemic burden was 1094 min under placebo. This was reduced to 531 min (95% CI -136-61 to +11-49) with benazepril 20 mg b.i.d. When the two groups of patients were combined (N = 20), the total ischaemic burden was 3453 min under placebo, and was reduced to 2514 min (95% CI —98-6 to +4-6, P = 0-072) during active treatment with benazepril (Fig. 2). There was no change in the maximal ST depression between the placebo and benazepril treatment. There was also no change in the mean heart rates at the onset of ischaemic episodes during benazepril therapy.

In the low-dose group, under placebo the total number of episodes of ST-segment depression was 172, of which 58 (33-7%) were symptomatic and 114 asymptomatic. TOLERABILITY AND COMPLIANCE Subjective tolerability was regarded as good to very Under benazepril lOmg b.i.d. treatment, the total number of episodes was reduced to 157(95%CI -4-97 to +2-25), good in all patients under both dosages of benazepril, of which 56 (35-7%) were symptomatic (95% CI - 1 -68 to except for one patient who reported fair tolerability under + 1 -32) and 101 asymptomatic (95% CI - 3-69 to + 1 -33). benazepril 10 mg b.i.d. and compliance to trial treatment was considered to be very good. In the high-dose benazepril group, under placebo the total number of episodes of ST-segment depression was 142, of ADVERSE EFFECTS which 32 (22-5%) were symptomatic and 110 asymptoA cough was reported by one patient while receiving matic. During treatment with benazepril 20 mg b.i.d., the benazepril 20 mg b.i.d. and one patient reported dryness total number of episodes was reduced to 103 (95% CI of the nasal mucosa while receiving benazepril lOmg - 10-53 to +1-86), of which 19 (18-4%) were sympto- b.i.d. Headaches were reported by three patients under matic (95% CI — 3-41 to +0-52) and 84 asymptomatic benazepril 10 mg b.i.d. One patient reported diarrhoea (95% CI -9-30 to +3-53). When the two groups of under benazepril 20 mg b.i.d., and another reported patients were combined (N = 20), during the placebo dizziness and giddiness under placebo. period the total number of ischaemic episodes was 314, of which 90 (28-7%) were symptomatic and 224 asymptomatic. During the active treatment period with ben- Discussion Clinical trials aimed to assess the efficacy of antianginal azepril, the total number of episodes was reduced to 260 (95% CI -5-68 to +0-28, P = 0-074) (Fig. 1), of which 75 drugs are classically designed around reduction of the

Benazepril in angina pectoris 1133

anginal attack rate and sub-lingual glyceryl trinitrate consumption. As about 80% of ischaemic episodes during daily life are silent1'4"171, changes in symptoms cannot be used as indicators of effectiveness of anti-ischaemic therapy. Therefore, more objective methods to assess ischaemic changes and anti-ischaemic therapy are needed. The results of this double-blind-placebo, controlled cross-over study suggest that benazepril in a dose of 10 mg b.i.d. and 20 mg b.i.d. is well tolerated and no clinically relevant, or biochemical abnormalities were detected. During exercise testing, benazepril, either in the lowor high-dose regime did not produce any clinically significant effects on exercise tolerance, blood pressure at rest and maximum exercise, ST-segment changes and heart rate. Similar findings have been reported with other ACE inhibitors'6'8"1. Benazepril did not alter the mean maximum exercise capacity, compared to the placebo. During 72 h of ambulatory electrocardiographs monitoring, the number of episodes of ST-segment depression and total ischaemic burden were not changed by benazepril 10 mg b.i.d. However, benazepril 20 mg b.i.d. produced a greater reduction in the number of ischaemic episodes and the duration of ischaemia, compared to the placebo. The number of ischaemic episodes was reduced from 142 to 103, and ischaemia duration was reduced from 1094 to 531 min. This effect was observed both in the silent and symptomatic ischaemic episodes. Similarly, under benazepril 20 mg b.i.d., the number of weekly anginal attacks was reduced from 58 to 33 and the number of the sub-lingual nitroglycerine tablets consumed was reduced from 31 to 14 per week. It should be mentioned that with the 10 mg b.i.d. dose there was a non-significant increase in the number of weekly angina attacks, compared to the placebo, from 78 to 96 and the number of nitroglycerine tablets consumed was increased from 18 to 35. No explanation for this non-significant increase has been formulated. When the two groups of patients, receiving benazepril, either 10 mg b.i.d. or 20 mg b.i.d., were combined for analysis (Fig. 1,2), the number of ischaemic episodes was reduced from 314 to 260 (/> = 007), and the duration of ischaemia was reduced from 3453 to 2514 min (/> = 007). These changes, that almost reached statistical significance, are clinically relevant. Similar observations were reported with benazepril 20 mg b.i.d. by Klein et a/.'201 who found that benazepril did not produce any clinical benefits in terms of exercise test variables, but reduced the number of daily ischaemic episodes and their duration. Thus, benazepril might be effective in improving spontaneous ischaemic episodes, which are induced, at least partially, by change in coronary tonus, while it may be ineffective in improving exercise test variables which are dependent mainly on the increase in myocardial oxygen demand. It is also possible that the anti-ischaemic effects of benazepril are present at doses higher than those used for hypertension or heart failure. CONCLUSIONS

The results of this study suggest that benazepril is well tolerated by patients with chronic stable angina.

Although it did not produce any clinical benefit in terms of exercise test variables in normotensive patients with stable angina pectoris, the data obtained with ambulatory electrocardiographic monitoring suggest that benazepril might be effective in improving silent myocardial ischaemia. In order to assess the anti-ischaemic properties of ACE inhibitors, further clinical studies in various subgroups of patients at different doses (probably 20 mg b.i.d. or higher) are warranted, especially in hypertensive patients or in patients with reduced left ventricular function and angina pectoris. This study was supported by a research grant from CIBA-GEIG Y, Basel, Switzerland. References [1] Guyene TT, Bellet M, Sassano P, Serrurier D, Corvol P, Menard J. Crossover design for the dose determinations of an angiotensin converting enzyme inhibitor in hypertension. J Hypertens 1989; 7: 1005-12. [2] Klebb RL, Miller D, Traina V, Gomez HJ. Benazepril. Cardiovascular Drug Reviews 1990; 8: 89-104. [3] Insel J, Mirvis DM, Boland MJ el al. A multicenter study of the safety and efficacy of benazepril hydrochloride, a long-acting angiotensin-converting enzyme inhibitor, in patients with chronic congestive heart failure. Clin Pharmacol Ther 1989; 45: 312-20. [4] Daly P, Rouleau JL, Cousineau D, Burgess JH. Acute effects of captopril on the coronary circulation of patients with hypertension and angina. Am J Med 1984; 76(5B): 111-5. [5] Daly P, Mettauer B, Rouleau JL, Cousineau D, Burgess JH. Lack of reflex increase in myocardial sympathetic tone after captopnl: potential antianginal effect. Circulation 1985; 71: 317-25. [6] Gibbs JSR, Crean PA, Mockus L, Wright C, Sutton GC, Fox KM. The variable effects of angiotensin converting enzyme inhibition on myocardial ischaemia in chronic stable angina. Br Heart J 1989; 62: 112-7. [7] Tarazi RC, Zanchetti A. Prospectives for angiotensin converting enzyme inhibition in heart disease. J Hypertens 1985; 3 (Suppl. 2): S99-103. [8] Hock CE, Ribeiro LGT, Lefer AM. Preservation of ischemic myocardium by a new converting enzyme inhibitor enalaprilic acid in acute myocardial infarction. Am Heart J 1985; 109: 222-8. [9] Ertl G, Kloner RA, Alexander W, Braunwald E. Limitation of experimental infarct size by an angiotensin converting enzyme inhibitor. Circulation 1982; 65:40-8. [10] Faxon DP, Creager MA, Halperin JL, Sussman HA, Gavras H, Ryan TJ. The effects of angiotensin converting enzyme inhibition on coronary blood flow and hemodynamics in patients without coronary artery disease. Int J Cardiol 1982; 2: 251-62. [11] Magrini F, Shimizu M, Roberts N, Fouad FM, Tarazi RC, Zanchetti A. Converting enzyme inhibition and coronary blood flow. Circulation 1987; 75 (Suppl. 1): 168-74. [12] Tzivoni D, Benhorin J, Gavish A, Stern S. Holter recording during treadmill testing in assessing myocardial ischemic changes. Am J Cardiol 1985; 55: 1200-3. [13] Khurmi NS, Raftery EB. Reproducibihty and validity of ambulatory ST-segment monitoring in patients with chronic stable angina pectoris. Am Heart J 1987; 113: 1091-6. [14] Tzivoni D, Gavish A, Benhorin J, Keren A, Stern S. Myocardial ischaemia during daily activities and stress. Am J Cardiol 1986; 58: 47B-50B. [15] Tzivoni D, Gavish A, Benhorin J, Banai S, Keren A, Stern S. Day-to-day variability of myocardial ischaemic episodes in coronary artery disease. Am J Cardiol 1987; 60: 1003-5.

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[19] Lai C, Onnis E, Orani E, Pirisi R, Soro A, Cherchi A. Antiischaemic activity of ACE inhibitor enalapnl in normotensive patients with stable effort angina. J Am Coll Cardiol 1987; 9: 192A (Abstr.). [20] Klein WW, Khurmi NS, Ebee B, Dusleag J. Effects of benazepril and metoprolol OROS alone and in combination on myocardial ischaemia in patients with chronic stable angina. J Am Coll Cardiol 1990; 16: 948-56.