function in patients with ischaemic heart disease

Transcription

1 Br. J. clin. Pharmac. (1986), 22, 319S-324S Calcium antagonist treatment and its effects on left ventricular function in patients with ischaemic heart disease E. A. RODRIGUES, I. M. AL-KHAWAJA, A. LAHIRI & E. B. RAFTERY The Department of Cardiology and the Division of Clinical Sciences, Northwick Park Hospital and Clinical Research Centre, Harrow, Middlesex 1 A double-blind, cross-over protocol was used to study the effects of chronic therapy with nicardipine and verapamil on left ventricular function in 21 patients with chronic stable angina. Rest and exercise radionuclide angiography was performed before and after each 4 week treatment period. 2 Resting and exercise heart rates were significantly lower on verapamil than on nicardipine. Rest and exercise systolic blood pressures were not significantly altered by either drug, but peak exercise time increased on both nicardipine and verapamil compared with placebo. 3 Left ventricular ejection fraction and ejection time were comparable on both drugs. Resting ejection rate was unaltered but resting ejection rate index was greater on verapamil than on nicardipine. 4 On exercise, however, ejection rate was significantly higher on nicardipine than on verapamil suggesting improved exercise systolic left ventricular function on nicardipine. Keywords nicardipine verapamil stable angina LV function radionuclide angiography Introduction The arrival of the slow calcium channel blocking agents has opened up a new era in the management of all forms of angina (Bala Subramanian, 1982; Corbalan et al., 1981; Dawson et al., 1981). These agents, however, vary widely in their clinical effects (Snyder & Reynolds, 1985). Nicardipine hydrochloride is a dihydropyridine derivative which has been shown to reduce anginal frequency and severity (Bowles et al., 1985; Scheidt et al., 1985; Khurmi et al., 1984). It is a powerful vasodilator and does not possess negative inotropic effects (Lipkin & Poole-Wilson, 1984). Verapamil, in contrast, is a papaverine derivative. It, too, is a potent anti-anginal agent (Bala Subramanian et Correspondence: Dr E. B. Raftery, Department of Cardiology, Northwick Park Hospital and Clinical Research Centre, Watford Road, Middlesex. 319S al., 198) but is negatively inotropic (Seabra- Gomes et al., 1976). The purpose of this study was to compare the effects of nicardipine and verapamil on left ventricular function at rest and on exercise in patients with ischaemic heart disease using radionuclide angiography. Methods Patients recruited for this study had stable exertional angina of at least 3 months' duration and positive treadmill exercise tests. Patients with unstable angina were excluded as were those with clinical or radiological evidence of heart failure. Women of reproductive age were excluded as were those with arterial hypertension or conduction abnormalities on the electrocardiogram.

2 32S E. A. Rodrigues et al. Study design After a 2 week placebo phase patients entered a double-blind, cross-over protocol using the double-dummy technique. They were randomised to nicardipine 3 mg three times daily or verapamil 12 mg three times daily for 4 weeks after which they crossed over to the alternative treatment. Rest and exercise radionuclide angiography was performed at the end of the placebo phase and after each treatment period. > o Z +1 V Radionuclide angiography Radionuclide angiography was performed at C rest and on exercise after in vivo labelling of red o Z blood cells with 74 MBq of technetium-99 m. i v Imaging was carried out in the 3 LAO projection with caudal tilt to produce the best septal z > separation. Five million counts were collected r; Z Z for the rest study. Patients then underwent ; supine cycle ergometric exercise starting at a workload of 25 watts and increasing by 25 watts _ every 3 min. Imaging was performed during the co last 2 min of exercise. At subsequent scans H+1 imaging during exercise was carried out at the o same workload for each patient. Heart rate, _ blood pressure and ST segment level in lead ' CM5 was recorded at rest and at peak exercise. Data analysis was performed using methods A. previously described (Bourguignon et al., 1981). ' b o From this ejection fraction, ejection rate and :2l' ejection time were obtained. Informed consent was obtained from each 'U patient and the study was approved by the Hos-.. o - pital Ethics Committee o C 9 z zzzzzzz zo e-4 ^~~~ z zdzzzzzzz vo^o oo.t z _ OO +1 +I +l -H +I+I +l +l +l +l +1 N so _ Nt- as o F en n * t X Oo o _;OR t +l +l +l +l -H +l +l+i +l +l +1 o1 O Wt t O or oo er4 m 8 1 le ^'fn N-1R no e4 en %o +1 +I+I+I-H + +I +I +I + +1 ~~o ~~o Ōs "e 4 S~ e~ - Results Twenty-one patients were studied. There were ' i 18 men and three women with a mean age of 6 ' years (age range 43 to 69 years). One patient E. &' s was withdrawn whilst on nicardipine because of 'o 8., unstable angina and one whilst on verapamil. Et Two other patients required early cross-over because of severe angina whilst on nicardipine,. whilst in one case treatment with verapamil was terminated early because of severe constipation.. Resting and exercise heart rates were lower on X verapamil than on nicardipine (P <.1, P = NS respectively) (Table 1) (Figure 1). Resting and exercise systolic blood pressures were similar on both drugs (Table 1). Mean (± s.d.) exercise time on placebo was min and this rose to min on nicardipine (P <.2) and to min on verapamil (P <.1) (Figure 2). ST segment change at the

3 same workload on exercise was lower on verapamil and higher on nicardipine but the differences were not statistically significant (Table 1) (Figure 3). Ejection fraction at rest and on exercise (Figure 4) were similar on both drugs as was ejection time. Resting ejection rate was comparable in the two drugs but when indexed to a heart rate Calcium antagonists in ischaemic heart disease 321S of 7 beats min 1, verapamil showed a significantly greater ejection rate than nicardipine (P <.5) (Figure 5). On exercise however, ejection rate was EDVs-' on nicardipine and EDVs-1 on verapamil, the difference being statistically significant (P <.5) (Figure 6). 14 E cn P< _ P<.1 I ei 4-8 (D I 6. Figure 1 Rest N Exercise Resting and exercise heart rates on placebo (CO), nicardipine (1) and verapamil (U) (mean + s.d.). v 14 P<.1 P<.2 12 E ;1 C) E ( CD U)8 x P N V P N V Figure 3 Mean (± s.d.) ST segment change at the IFigure 2 Mean ( s.d.) exercise time on placebo (O), same workload on exercise during treatment with uicardipine (M) and verapamil (U). placebo (EO), nicardipine (1) and verapamil (O).

4 322S E. A. Rodrigues et al. 8,r C 4- L.._ C 7 6..F S-._._ 51- C e -J 4 P N Rest v Exercise Figure 4 Left ventricular ejection fraction at rest and on exercise during treatment with placebo (El), nicardipine (U) and verapamil (U) (mean + s.d.). x 4a a) (D -J 2.5r P<O.5 I I P N V Figure 5 Resting ejection rate index on placebo (O), nicardipine (U) and verapamil (H) (mean + s.d.). Discussion This study confirms the efficacy of nicardipine and verapamil in improving exercise tolerance in patients with ischaemic heart disease. Although mean exercise time was greater on verapamil than on nicardipine, the difference was not statistically significant. At rest verapamil caused a reduction in heart rate whilst nicardipine caused an increase. Blood pressure was not significantly altered by either drug but the rate-pressure product, which is a reflection of myocardial oxygen consumption, was significantly lower on verapamil than on nicardipine. Peak exercise heart rate remained significantly lower on verapamil indicating that even on exercise myocardial oxygen consumption is lower on this drug. Left ventricular ejection fraction was comparable on both treatments. Both agents were associated with a smaller drop in ejection fraction on exercise when compared with placebo implying less global left ventricular dysfunction on exercise, but differences did not reach statistical significance. Ejection rate is dependent on the contractile state of the left ventricle but is also affected by heart rate. Slower heart rates tend to reduce ejection rate and faster heart rates increase the rate of ejection. Since a significant difference in heart rate was detected between the two medications, it was thought important to correct ejection rate values to a heart rate of 7 beats min -. When this was done verapamil showed a greater increase in ejection rate than nicardipine. Thus in the patients studied, any negative inotropic action of verapamil was more than offset by its beneficial effect on myocardial ischaemia and hence on left ventricular performance. On exercise nicardipine produced higher ejection rates compared with placebo

5 Calcium antagonists in ischaemic heart disease 3. P< S _1.. jl.5 Figure 6 P N V P N V Rest Exercise Mean (± s.d.) rest and exercise ejection rate on placebo (O3), nicardipine (U1) and verapamil (E). and significantly higher ejection rates compared with verapamil. The difference in ejection rates on exercise is due not only to a reduction in the ejection rate on verapamil but also to an increase in the ejection rate on nicardipine. This reinforces previous studies which have shown an improvement in myocardial contractility in patients with stressed vascular systems whilst taking nicardipine (Visser et al., 1984; Rousseau et al., 1985). Conclusion Nicardipine and verapamil were both effective in improving exercise capacity of patients with chronic stable angina. Verapamil showed a significant improvement in ejection rate index in patients at rest. Ejection rate on exercise was significantly greater on nicardipine than on verapamil suggesting improved exercise systolic function on nicardipine. References Bala Subramanian, V. (1982). Calcium channel blockers in chronic stable angina. Herz, 7, Bala Subramanian, V., Lahiri, A., Paramasivan, R. & Raftery, E. B. (198). Verapamil in chronic stable angina. A controlled study with computerised multistage treadmill exercise. Lancet, i, Bourguignon, M. H., Douglass, K. H., Links, J. M. & Wagner, H. N. (1981). Fully automated data acquisition, processing and display in equilibrium radioventriculography. Eur. J. nucl. Med., 6, Bowles, M. J., Khurmi, N. S., O'Hara, M. J. & Raftery, E. B. (1985). Nicardipine in chronic stable angina: objective assessment with computerassisted exercise testing and ambulatory ST segment monitoring. Br. J. clin. Pharmac., 2 (Suppl. 1), 177S. Corbalan, R., Gonzalez, R., Chamorro, G., Munoz, M., Rodriguez, J. A. & Casanegra, P. (1981). Effect of a calcium inhibitor, nifedipine, on exercise tolerance in patients with angina pectoris. Chest, 79, Dawson, J. R., Whitaker, N. H. G. & Sutton, G. C. (1981). Calcium antagonist drugs in chronic stable angina. Comparison of verapamil and nifedipine. Br. Heart J., 46, Khurmi, N. S., Bowles, M. J., Bala Subramanian, V. & Raftery, E. B. (1984). Short- and long-term eflicacy of nicardipine, assessed by placebo-controlled

6 324S E. A. Rodrigues et al. single- and double-blind crossover trials in patients with chronic stable angina. J. Am. Coll. Cardiol., 4, Lipkin, D. & Poole-Wilson, P. A. (1984). Effect of nicardipine on myocardial contractility and on angina induced by atrial pacing in patients with coronary artery disease. Postgrad. med. J., 6 (Suppl. 4), Rousseau, M. F., Vincent, M. F., Cheron, P., Van den Berghe, G., Charlier, A. A. & Pouleur, H. (1985). Effects of nicardipine on coronary blood flow, left ventricular inotropic state and myocardial metabolism in patients with angina pectoris. Br. J. clin. Pharmac., 2, 147S-157S. Scheidt, S., Lewinter, M. M., Hermanovich, J., Venkataraman, K. & Freedman, D. (1985). Nicardipine for stable angina pectoris. Br. J. clin. Pharmac., 2 (Suppl. 1), 178S-186S. Seabra-Gomes, R., Rickards, A. & Sutton, R. (1976). Hemodynamic effects of verapamil and practolol in man. Eur. J. Cardiol., 4, Snyder, S. H. & Reynolds, I. J. (1985). Calciumantagonist drugs. Receptor interactions that clarify therapeutic effects. New Engl. J. Med., 313, Visser, C. A., Jaarsma, W., Kan, G. & Lie, K. I. (1984). Immediate and longer-term effects of nicardipine, at rest and during exercise, in patients with coronary artery disease. Postgrad. med. J., 6 (Suppl. 4), 17-2.