Effects of felodipine on haemodynamics and exercise capacity in patients with angina pectoris

Br. J. clin. Pharmac. (1987), 23, 391-396 Effects of felodipine on haemodynamics and exercise capacity in patients with angina pectoris J. V. SHERIDAN, P. THOMAS, P. A. ROUTLEDGE & D. J. SHERIDAN Departments of Cardiology and Clinical Pharmacology, University of Wales College of Medicine, Cardiff 1 We studied the effects of adding felodipine to W3-adrenoceptor blockade on haemodynamics and exercise capacity in 14 patients with stable angina pectoris using a placebo controlled double-blind crossover protocol. 2 Felodipine reduced supine and standing systolic pressure by 13% (P < 0.01) and 14% (P < 0.01) respectively and increased supine heart rate 7.4% (P < 0.05). 3 Felodipine at a plasma concentration of 15.5 ± 3.0 nmol 1-1 increased exercise duration by 16% (P < 0.01) but failed to attenuate the degree of ST segment depression during exercise. 4 The mean daily number of episodes of angina (0.53 ± 0.16 on placebo vs 0.37 ± 0.11 on felodipine) and mean daily GTN consumption (0.51 ± 0.07 on placebo vs 0.36 ± 0.12 on felodipine) were not significantly reduced (0.1 < P > 0.05). 5 These findings suggest that felodipine may provide useful additional benefits in patients with hypertension or angina pectoris, who are already receiving,3-adrenoceptor blockers. Keywords felodipine angina haemodynamics Introduction Felodipine is a dihydropyridine compound which dilates peripheral arterioles (Ljung, 1980) possibly by an interaction with calmodulin (Bostrom et al., 1981). In therapeutic doses, it reduces systemic vascular resistance and increases stroke volume without altering left ventricular contractility (Culling et al., 1984). These effects suggest that it may be useful in the management of chronic stable angina by reducing afterbad and cardiac work. To investigate this, we studied its effects on exercise capacity in patients with chronic stable angina. Since arteriolar vasodilatation is frequently associated with reflex sympathetic activation (Joshi et al., 1981; Rowland et al., 1983) which could be deleterious in this condition patients were studied during concomitant,-adrenoceptor blockade. Methods A preliminary open study was carried out in six male patients aged 37-69 years (mean 52.8 ± 4.8 years) with chronic stable angina to assess the safety of felodipine and to find a suitable dosage. All patients were receiving a 1-adrenoceptor blocker and sublingual GTN. Each subject was given felodipine 5 mg twice daily for 1 week and 10 mg twice daily for a further week depending upon the haemodynamic response. Heart rate and blood pressure were measured at 30 min intervals for 3 h after the initial dose and after treatment for 7 days. Heart rate and blood pressure were also monitored for 3 h at 30 min intervals following initial dose of 10 mg, and then at the end of 1 week's treatment. Fourteen male and one female patient aged 45-70 years (mean 58 years) were recruited to the Correspondence: Professor D. J. Sheridan, Department of Cardiology, St Mary's Hospital, Praed Street, London W2 391

392 J. V. Sheridan et al. main study. Their clinical details are shown in Table 1. All had a typical history of angina pectoris of at least 3 months duration and a positive exercise test (ST depression > 1 mm). Four had sustained a previous myocardial infarction and none gave a history of cardiac failure. All had been receiving,3-adrenoceptor blockade and sublingual GTN, for at least 3 months and these were continued unchanged throughout the study. None was receiving long-acting nitrates or other vasodilators. All gave written informed consent for the study which had been approved by the Hospital Ethics Committee. A random placebo controlled double-blind crossover design was used. Each subject received active and placebo treatment for 3 weeks each following an initial run-in period of 2 weeks during which placebo was given. During active treatment, patients- received felodipine 2.5 mg twice daily for 3 days followed by 5 mg twice daily thereafter, depending upon the blood pressure response. Supine and erect heart rate and blood pressure were measured at the beginning and end of the initial run-in period and at the end of the placebo and active treatment periods. Symptom limited exercise tests (Bruce Protocol) were performed at the beginning and end of the initial run-in period and at the end of the placebo and active treatment periods. All exercise tests were carried out between 09.30 and 11.30 h and at 1.5-2 h after the last dose of treatment. Blood samples were obtained immediately prior to exercise tests, at the end of the placebo and active treatment periods, for assay of plasma felodipine using the method of Ahnoff (1984). Each patient was provided with a special diary and instructed to record all episodes of angina and GTN consumption. Results are presented as the mean ± s.e. mean and comparisons were made within groups using analysis of variance and two tailed testing. Results Preliminary study Four patients reported a subjective improvement in angina while taking felodipine 5 mg twice daily during the preliminary study. One patient reported deterioration in his angina and one patient experienced no change. Felodipine 5 mg twice daily reduced supine systolic blood pressure from 132 ± 6.5 mm Hg to 109 ± 8.2 mm Hg after 1 week and diastolic pressure from 80 ± 4.9 mm Hg to 70 ± 4.9 mm Hg. Standing systolic pressure was reduced from 122 ± 4.1 mm Hg to 97 ± 7.8 mm Hg and diastolic pressure from 76 ± 2 to 69 ± 4.1 mm Hg. Furthermore, standing systolic pressures < 90 mm Hg were recorded in three patients after 1 week of receiving felodipine 5 mg twice daily and in accordance with the protocol, they were withdrawn from the study at this point. No significant adverse effects were noted by the three patients given 10 mg twice daily for 1 week, however, standing systolic blood pressure < 90 mm Hg was noted at the end of 1 week's treatment in one patient. As a result of these observations, the dosing schedule for the main study was reduced to 2.5 mg twice daily for 3 days, increasing to 5 mg twice daily, depending upon initial blood pressure response. Table 1 Clinical features of patients who participated in the double-blind crossover study of felodipine versus placebo Angina HR Age duration NYHA BP (beats (years) Sex (years) class MI (mm Hg) min-') Treatment 1 69 M < 5 II Y 130/80 66 Oxprenolol + GTN 2 63 M 2 II Y 140/90 72 Oxprenolol + GTN 3 57 M > 5 II Y 115/80 72 Acebutolol + GTN 4 53 M < 1 II N 190/100 60 Atenolol + GTN 5 62 M > S III Y 130/80 68 Atenolol + GTN 6 57 M > 5 II N 150/90 64 Acebutolol + GTN 7 64 M > S III N 150/70 58 Atenolol + GTN 8 60 M 2 II N 125/80 62 Propranolol + GTN 9 48 M 2 III N 120/80 70 Atenolol + GTN 10 67 M < 1 III N 155/80 66 Atenolol + GTN 11 64 M < 1 III N 130/85 64 Atenolol + GTN 12 45 M < 1 II N 120/70 48 Atenolol + GTN 13 70 M 2 III N 145/80 72 Atenolol + GTN 14 48 F < 1 II N 120/70 73 Atenolol + GTN 15 60 M 3 II N 130/80 52 Acebutolol + GTN

Main study One patient withdrew from the study because of syncope which occurred 5 h following the initial dose (2.5 mg) of felodipine and immediately following 0.5 mg of sublingual GTN. Plasma felodipine levels measured in the 14 patients who completed the study, were 15.5 ± 3.0 nmol 1-1. Exercise tolerance Figure 1 shows changes in exercise duration for each subject. Felodipine increased duration by 16% from 305 ± 29.1 s during placebo treatment to 353 ± 29.4 s (P < 0.01). No significant change was observed between exercise tests carried out at the beginning and end of the run-in period and at the end of the placebo period. Exercise tests were terminated by the onset of chest pain in 13 patients at the end of the placebo period; one patient stopped because of fatigue and dyspnoea. This latter patient exercised for a longer period (41% increase) on felodipine and stopped because of chest pain and dyspnoea. Four other patients whose exercise was stopped because of chest pain during placebo treatment, experienced dyspnoea (3) or fatigue (1) as the end point during treatment with felodipine despite exercising for longer periods (9% to 34%). Changes in ST segment depression during exercise are illustrated in Figure 2. Felodipine had no effect on the degree of ST segment depression observed at 3 min during exercise, but appeared to increase slightly but non-significantly the degree of ST depression at 6 min (1.5 ± 0.25 mm vs 1.33 + 0.22 mm) and at maximal exercise (1.66 ± 0.22 mm vs 1.55 ± 0.17 mm), (P > 0.05 in both cases).. Felodipine in angina pectoris 393 600[ dh ==:I 5001-41 -a 0).LA 400 _ -,---A- 01) x I0() 3001-0 c 0p m._ 40 2001_ * 1001- Placebo Felodipine Figure 1 Exercise duration for each subject at the end of placebo and active treatment periods. * = P < 0.01 Anginal attacks and GTN consumption Completed diary cards were returned by 13 patients. Felodipine reduced the number of anginal attacks recorded by 30.5% from 0.53 ± 0.16 to 0.37 ± 0.11 attacks per day and GTN consumption by 27% from 0.51 ± 0.07 per day to 0.36 ± 0.12 although in neither case was statistical significance demonstrated (Figure 3). Haemodynamics Changes in heart rate and blood pressure are illustrated in Figure 4. Felodipine induced a small but statistically significant increase in supine heart rate (64 ± 1.9 beats min-') compared with placebo (60 ± 1.4 beats 2.0r- E 0 CI 1.0 Cu 'a ~0 Ce 1L j Fl 3 min 6 min Maximal - - --.1-1 exercise Figure 2 S-T segment depression at 3 min, 6 min and at maximal exercise during exercise tests performed at the end of placebo (0) and active (M) treatment periods. Note that felodipine appeared to accentuate the degree of S-T depression at 6 min and at maximal exercise although these changes did not reach statistical significance.

394.m n -_:2O m.2 r O E 0 on z (li U 01 J. V. Sheridan et al. l'or 0.5h / I v 10 ri Angina/ day / GTN/day min-'), but not when compared with the end of the run-in period (63 ± 2.0 beats min-1). No significant change was observed in standing heart rate. Supine and erect blood pressure were unchanged at the beginning and end of the initial run-in period and the placebo period. Felodipine significantly reduced supine and standing systolic blood pressure (by 13% and 14% respectively, P < 0.01). Felodipine also reduced supine and erect diastolic pressure by 12% and 10% respectively (P < 0.05). In no patient did standing systolic pressure fall below 100 mg Hg during treatment with felodipine 5 mg twice daily. Heart rate and blood pressure measured at peak exercise were unchanged by felodipine, as was the maximal double product (14800 ± 924 vs 15600 + 844) (P > 0.05). Adverse effects With the exception of a patient who withdrew because of syncope associated with GTN consumption 5 h following the initial dose of felodipine, no serious adverse effects were noted. Minor adverse experiences were reported by nine patients during the run-in period and by 12 and 11 patients during placebo and active treatment periods respectively. Headache was the most frequently reported symptom during the run-in period (three patients). Heartburn (three patients) and flushing (three patients) were the symptoms most recorded during the placebo treatment period, while heartburn (three patients), back pain (two patients) and somnolence (two patients) were the symptoms most recorded during the active treatment phase. There was no significant difference in the incidence of any of these symptoms between active and placebo phases, however. Figure 3 Episodes of angina per day and GTN consumption per day during the placebo (J) and active (3) treatment periods. Note that felodipine reduced both number of angina attacks and GTN consumption, although the changes did not reach statistical significance. 1501- Supine Standing I EE 0) L- 1 00 n (A) UA 0) 0 m 50 3. 1501-1o00-501- - _. _ Figure 4 Effects offelodipine on supine and standing blood pressure and heart rate (*). Felodipine produced a small but statistically significant increase in supine heart rate, and reduced supine and systolic and diastolic blood pressure. * = P < 0.01. I = initial values; R = run-in period; P = placebo; F = felodipine.

Discussion This study demonstrates that felodipine possesses beneficial antianginal properties. Exercise duration was increased in all except two patients and was significantly increased in the group as a whole. This was associated with a reduction in the number of episodes of angina and GTN consumption. Felodipine had no significant effect on the degree of ST segment depression at 3 min and at maximal exercise. It did appear to increase the degree of ST depression at 6 min of exercise, however, it should be noted that whereas four patients completed 6 min of exercise during the placebo phase, seven did so while receiving felodipine. The mechanism of action for the hypotensive and antianginal effects observed here are best explained by the reduction in systemic vascular resistance which is known to occur with this compound (Tweddel et al., 1983; Culling et al., 1984). At plasma concentrations comparable to those observed in the present study, felodipine induced a 30% reduction in systemic vascular resistance and a 30% increase in cardiac index without significantly altering left ventricular contractility in a similar group of patients (Culling et al., 1984). Felodipine has also been shown to increase myocardial blood 1983), although this was flow (Tweddel et al., not associated with increased myocardial oxygen consumption. There is no information available concerning the effects of felodipine on the coronary circulation during exercise, so that the possibility that an action of the drug on the coronary circulation might contribute to its antianginal properties, cannot be excluded. Since little information was available about the effects of felodipine in patients with coronary artery disease, it was felt safer to undertake the present study during concomitant 1-adrenoceptor blockade. For this reason, the present results should be interpreted only as indicating benefit in patients already receiving such treatment. We have previously demonstrated a decrease in afterload and increase in stroke volume in patients receiving P-adrenoceptor blockers in response to felodipine (Culling et al., 1984). In Felodipine in angina pectoris 395 clinical practice, vasodilators such as felodipine or nifedipine are most likely to be used in combination with 0-adrenoceptor blockade. Previous studies (Tweddel etal., 1983; Andersson et al., 1985; Johnsson et al., 1983; Leonetti et al., 1984) suggest that felodipine in common with other peripheral vasodilators (Joshi et al., 1981; Rowland et al., 1983) may induce reflex sympathetic action. Such effects should have been largely excluded in the present study due to the presence of concomitant,-adrenoceptor blockade and this is supported by the minimal increase in heart rate observed during active treatment. Since reflex sympathetic activation would be expected to increase myocardial oxygen requirerents, it cannot be assumed that similar beneficial effects would be seen with felodipine alone. Drugs which dilate peripheral systemic arterioles are commonly used in the treatment of angina pectoris, but care is always needed to avoid excessive dosage, since hypotension and reduced coronary perfusion pressure may result. The preliminary study undertaken here clearly demonstrated that felodipine in an initial dose of 5 mg twice daily which has frequently been used in antihypertensive studies, was excessive in the context of angina pectoris and emphasises the need for caution in choosing suitable doses of such compounds. It is of interest that felodipine 5 mg twice daily following an initial treatment period of 2.5 mg twice daily induced no adverse hypotensive effects, and suggests that tolerance may occur during initial exposure to the drug. Monitoring blood pressure during commencement of treatment in patients with coronary artery disease would be advisable. The incidence of adverse effects during active treatment was common, but reported effects were minor and were similar in frequency and severity to those reported during placebo treatment and to previous studies with calcium entry blockers (Dawson et al., 1981), P-adrenoceptor blockers (Winniford et al., 1983; McNeil et al., 1979) and a-adrenoceptor blockers (Collins & Sheridan, 1985). References Ahnoff, M. (1984). Determination of felodipine in plasma by gas chromatography with electron capture detection. J. Pharm. Biomed. Analysis, 2, 519-526. Anderson, 0. K., Granerus, G., Hedner, T. & Wysocki, M. (1985). Systemic and renal haemodynamic effects of single oral doses of felodipine in patients with refractory hypertension receiving chronic therapy with beta-blockers and diuretics. J. cardiovasc. Pharmac., 7, 544-549. Bostrom, S. L., Ljung, B., March, S., Forsen, S. & Thulin, E. (1981). Interaction of the antihypertensive drug felodipine with calmodulin. Nature, 292, 777-778. Collins, P. & Sheridan, D. J. (1985). Improvement in

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