OPEN EVALUATION OF LABETALOL IN THE TREATMENT OF ANGINA PECTORIS OCCURRING IN HYPERTENSIVE PATIENTS

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1 Br. J. clin. Pharmac. (1979), 8, 25S-29S OPN VALUATION OF LABTALOL IN TH TRATMNT OF ANGINA PTORIS ORRING IN HYPRTIV PATINTS.M.M. BSTRMAN & M. SPNR ardiological Department, St Mary's Hospital, Norfolk Place, London W2 1 PG, UK 1 In nine hypertensive subjects with angina pectoris, labetalol diminished the incidence of chest pain occurring spontaneously or induced by exercise. 2 Labetalol lowered BP in all subjects. 3 xercise tolerance at maximum levels was increased by labetalol. 4 Improved cardiac function by labetalol may be related to decreased afterload on the left ventricle, and diminished oxygen utiliation by the myocardium. Introduction WHRAS fl-adrenoceptor antagonists have an established position in the treatment of angina pectoris and hypertension, a-adrenoceptor antagonists have found little favour as sole treatment in either condition. Indeed, they may induce angina pectoris in patients with coronary heart disease by a reflex tachycardia. The possibility that a-adrenoceptor blockade might play a part in preventing myocardial ischaemia was suggested when patients with coronary disease were shown to have an increase in coronary vascular resistance following the cold pressor test, and was reversed by phentolamine (Mudge et al., 1976). a-adrenoceptor blockade has also been found to be useful adjunct to therapy in selected patients with variant angina (Orlick et al., 1977). Labetalol is unique in that it is a combined a- and fl-antagonist, the ratio of a :# antagonist effect being approximately 1:3 (Richards, 1976). It is a hypertensive drug of considerable potency (Dollery, 1976). It has been shown to produce a significant increase in exercise tolerance in patients with angina pectoris, but without any clear dose-response relationship (Boakes & Prichard, 1973). Normotensive patients with coronary heart disease treated with labetalol 2 mg daily have shown-increased exercise tolerance and electrocardiographic evidence of improvement when compared with placebo (Brevetti et al., 1978). The object of the present study was to determine the effect of long-tenn treatment with labetalol on angina pectoris in patients with hypertension. Methods /79/ $1. Nine patients were studied (five female, four male; age range yr) (Table 1). An additional patient was eliminated from the trial as he developed sideeffects. Supine BP of 14/1 mmhg or greater in patients under 45 years, or of 16/11 mmhg in patients over 45 years and below 7 years were the criteria for selection for inclusion in the trial. Stable angina was required to be present for at least 6 months. Diuretics were continued throughout the trial, but other antihypertensive drugs were gradually withdrawn and then stopped before labetalol was introduced. The initial dose of labetalol was 1 mg three times daily, and the ultimate dose range in the series of patients was 3-1,6 mg daily. Treatment with labetalol was maintained for at least 1 year. ardiac status was assessed by exercise stress testing using an lema Schonander bicycle ergometer and the load changed sequentially every 3 min starting at 5 W, and increasing if necessary to W. For comparative purposes the exercise test was carried out at 2-week intervals for 1 month before labetalol treatment was started. During labetalol administration it was repeated at 2-week intervals over a period of at least 1 year. In each instance a standard 12-lead G and BP were taken when sitting before and after each exercise test at intervals of 2, 4 and utes. Lead V5 was recorded and the BP ascertained during the last 15 s of each phase of the exercise test or before stopping to pedal. The stress test was stopped if angina occurred, or sudden shortness of breath, or overwhelming exhaustion, or if the heart rate exceeded the maximum expected for a particular patient. All BP measurements were made with a standard mercury sphygmomanometer, the diastolic BP being taken at Phase V (Korotkoff). Before administration of labetalol, and thereafter at 3-month intervals, blood samples were taken for full blood count, lipid levels, liver and renal function tests, and antinuclear factor (ANF) titre. Macmillan Journals Ltd 1979

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3 ANGINA PTORIS AND HYPRTION 27S Ophthalmological examination was carried out in each patient before commencement of the trial, and thereafter at intervals of 6 months until completion of the trial. In addition to heart rate and BP, the QT ratio and triple product were measured at rest, at maximum exercise and at 2, 4 and after the exercise test. The QT calculations were based on Baett's formula to correct for ventricular cycle length { QTm l.4 R-RJ The triple product formula, 3. IAheart rate x BP x QT ratio, was used as an index of myocardial oxygen consumption. The statistical evaluation is based on three readings taken during the assessment period, and whenever possible three readings taken at monthly intervals at the end of the study. The sign test was used for: (a) comparing BP values before and after treatment with labetalol; (b) comparing BP values du-ring exercise at each stage (excluding diastolic BP readings at 1 W; and (c) comparing BP values and heart rate before and after treatment. Wilcoxon's signed rank test was used for: (a) pre-trial and trial average work load; (b) QT ratio at rest, and at 2, 4 and after exercise; and (c) triglycerides and cholesterol levels. Results Blood pressure BP was lowered in all patients, whether or not other hypertensive treatment was given before administration of labetalol (Table 2). Mean values of systolic and diastolic BPs for the group of patients as a whole, supine and standing, during exercise, and in the postexercise phase are given in Table 2. (P <.5 to P Supine Standing xercise Rest 5W W 1 W Table 2 <.1 compared with pre-labetalol for both systolic and diastolic BPs). Heart rate Mean heart rates for all patients at rest, during different stress loads, and at the different postexercise time phases are shown in Table 2. There was a tendency to reduced heart rates at rest and during exercise, but pooled values of pre-treatment and posttreatment values were not statistically significant (P <.1). QT ratio Before treatment with labetalol the QT ratio on maximum exercise was 1.8 or more in all but two readings. Table 3 shows the mean values for QT ratios for the group as a whole. On maximum exercise the mean QT ratio pre-treatment was 1.12, compared with 1.3 after treatment (P<.5, Table 3). The changes in QT ratios were not significant at 2, 4 and 6 min, or finally after exercise, or at rest (Table 3). In one patient with a ventricular aneurysm the QT ratio on maximum exercise before treatment was.87, and increased to.9 after treatment despite clinical improvement. Triple product The mean values of the triple product for the group was reduced from 431 to 325 at rest (P<.1, Table 3). In only one patient was the triple product not reduced (Table 1, number 8). On maximum exercise the triple product was reduced from a mean value of 86 to 66 (P =.1, Table 3). The only patient who did not show a reduction in the exercise triple product was one (Table 1, number 5) who had a high incidence of angina diminished by labetalol with persistent improvement during the follow-up period of 3 months. ffects of labetalol on BP and heart rate Pre-treatment Blood pressure (mmhg) Heart rate Systolic Diastolic *P<.5; tp<.1 compared with pre-labetalol; tp<.1. Post-treatment Blood pressure (mmhg) Heart Rate Systolic Diastolic 144t 98t 131* 96t 132* 157' 1* 19* 157t 139* 13* 94t 99t 15t 16t 96t 92t 9* 67t

4 28S.M.M. BSTRMAN & M. SPNR Maximum exercise Maximum exercise capacity (min x W) was increased following labetalol treatment in five patients, unchanged in three patients and reduced in one patient (Table 3). There was no significant difference in the product (min x W) for the group (P <.1). Laboratory investigations No abnormalities were found in haematology, or in liver and renal function tests. There was no significant difference between triglyceride and cholesterol levels after labetalol treatment compared with pretreatment levels. Before treatment with labetalol one patient with a history of recurrent jaundice in childhood had ANF titre of 1:1 throughout the trial. ye changes Six patients out of a total of 18 examined ophthalmologically, have shown marked reduction in tear flow and they are being followed up. The significance of this is not yet fully understood. Side-effects The patient withdrawn from the trial complained of general fatigue and diiness while taking labetalol 3 mg daily. Direct questioning of patients in the trial elicited sexual problems in three patients. Two of them complained of diminished libido, and the third stated that he failed to obtain an erection or to ejaculate. Discussion The fall in BP observed was expected from the previous reports of the hypotensive effects of labetalol. The open uncontrolled nature of the study precludes attributing any of the observed changes to labetalol alone. Myocardial oxygen consumption during upright exercise relates well with heart rate (correlation <.88), and with the product of heart rate and systolic BP (correlation <.96). However, neither the double products or the triple product takes account of changes in contractibility and ventricular volume, which may negate the other factors. The significant reduction in the triple product at rest and at maximum exercise in the patients studied Table 3 ffects of labetalol on QT ratio triple product and exercise tolerance in hypertensive patients with angina pectoris QT ratio At rest On maximum exercise Final Triple product at rest On maximum exercise Final Maximum exercise (min x W) Pre-treatment x x Post-treatment x 2.5 x 1 1 P values

5 ANGINA PTORIS AND HYPRTION 29S during labetalol administration suggests that myocardial oxygen consumption is reduced by the drug. The symptomatic improvement in anginal symptoms may be due to diminished left ventricular work and diminished myocardial oxygen demand. In the nine patients studied it seems that labetalol controlled BP and had a beneficial effect on their angina. Further clinical trials to confirm these results are being carried out. We thank Mr J.L. Kennerley Banks for undertaking ophthalmological examinations and Mr W.D. Robinson for statistical help. References BOAKS, A.J. & PRIHARD, B.N.J. (1973). The effect of AH 5158, pindolol, propranolol and D-propranolol on acute exercise tolerance in angina pectoris. Br. J. Pharmac., 47, BRVTTI, G., HIARILLO, M., RNGO, F., HIARILLO, L., PAUDI, G., LARATIA, G. & ONDORLLI, M. (1978). Labetalol in coronary artery disease. Abstracts VIII World ongress of ardiology, 1, 194. DOLLRY,.T. (1976). losing remarks: current status of labetalol. Br. J. clin. Pharmac., 3, suppl. 3, MUDG, G.H., Jr, GROSSMAN, W., MILLS, R.M.J., LSH, M. & BRAUNWALD,. (1976). Reflext increase in coronary vascular resistance in patients with ischaemic heart disease. New ngl. J. Med., 295, ORLIK, A.., RII, D.R., IPRIANO, P., GUTHANR, D. & HARRISON, D.. (1977). The role of alpha adrenergic receptors in the pathogenesis of coronary artery spasm. lin. Res., 25, 456. RIHARDS, D.A. (1976). Pharmacological effects of labetalol in man. Br. J. clin. Pharmac., 3, suppl. 3,