felodipine extended release or nifedipine retard

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1 Br. J. clin. Pharmac. (1990), 30, Control of blood pressure in hypertensive patients with felodipine extended release or nifedipine retard W. A. LITTLER Felodipine United Kingdom Hospital Study Group* 1 This multicentre hospital study compared the antihypertensive efficacy and the tolerability of once daily felodipine extended release (ER) with twice daily nifedipine retard (R) in hypertensive patients inadequately controlled on metoprolol monotherapy. 2 One hundred patients, aged years, whose seated diastolic blood pressure was mmhg after 4 to 6 weeks of metoprolol (200 mg day-) monotherapy, were randomised, double-blind, to receive felodipine ER 10 mg once daily or nifedipine R 20 mg twice daily for 8 weeks. The dosage of felodipine or nifedipine was doubled if seated diastolic blood pressure exceeded 95 mmhg, 2 or 4 weeks after randomisation. Metoprolol 200 mg once daily was taken throughout the trial. 3 Fifty-one patients received felodipine ER and 49 nifedipine R; 46 and 45 respectively completed the 8 week trial. About half of patients on each treatment needed the higher dose. The baseline characteristics of the felodipine and nifedipine groups were generally well balanced. 4 Seated diastolic blood pressure was reduced by 17 mmhg for felodipine (24 h postdose) and by 9 mmhg for nifedipine (12 h post-dose), a difference between treatments of 8 mmhg (95% confidence interval 5 to 12 mmhg, P < ). The attained blood pressures at the end of the study (felodipine 90 ± 10, mmhg, mean ± s.d.; nifedipine ) were also significantly different (95% confidence interval for the S mmhg difference, -9 to -1 mmhg, P < 0.02). 5 In contrast, 3 h post-dose, the reduction in diastolic blood pressure was similar for both drugs; felodipine 17 mmhg, nifedipine 14 mmhg (difference 3 mmhg, 95% confidence interval - 3 to +7 mmhg, P > 0.2). The attained blood pressures were also similar (felodipine 81 ± 9; nifedipine 83 ± 8 mmhg). 6 The pattern and prevalence of adverse events were similar for the two drugs, with the most common adverse events being ankle oedema, flushing and headache. In response to a questionnaire, 'vasodilator' adverse events were reported by 31% of patients on metoprolol alone and increased to over 50% during treatment with the calcium antagonists. 7 In this trial felodipine ER produced a greater reduction in blood pressure than nifedipine R when blood pressure was measured at the end of the dose interval. Felodipine had a more even effect at 3 and 24 h post-dose than did nifedipine 3 and 12 h post-dose. Correspondence: Professor W. A. Littler, Department of Cardiovascular Medicine, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH *Felodipine United Kingdom Hospital Study Group - a list of collaborating centres and investigators is given at the end of the paper 871

2 872 W. A. Littler This trial supports the view that felodipine is suitable for once daily use as an addition to,-adrenoceptor blocker therapy. The short duration of the trial gives no guidance on long-term tolerability. Keywords calcium antagonists felodipine nifedipine hypertension Introduction Commonly used dihydropyridine calcium antagonists have to be given at least twice daily which is a disadvantage especially when combined with a once-daily P-adrenoceptor antagonist. Felodipine, a dihydropyridine calcium antagonist with a selective action on peripheral resistance vessels (Ljung, 1985) is an effective antihypertensive agent when given alone (Campbell et al., 1990; Cooperative Study Group, 1987; Kronig & Flygt, 1987) or in combination with a f-adrenoceptor blocker (Freeling etal., 1987; Groom etal., 1988) and the extendedrelease (ER) formulation is suitable for oncedaily use (Campbell et al., 1989, 1990). We have compared felodipine-er once daily with nifedipine retard (R) twice daily in hypertensive patients who required treatment in addition to a,-adrenoceptor blocker. Methods Study design Patients whose seated phase V diastolic pressure (dbp) was mmhg after 4-6 weeks monotherapy with metoprolol 200 mg once daily sustained release (BetalocSA, Astra) were randomised double-blind to receive felodipine- ER 10 mg once daily or nifedipine-r 20 mg twice daily in a parallel-group design. Randomisation was carried out by assigning to patients, numbers in sequence from a computer-generated randomisation list. Blindness was maintained using the double dummy technique. During the 8-week double-blind period, patients were seen every 2 weeks; if the target dbp (c 95 mmhg) was not attained after 2 or 4 weeks, the dose of felodipine-er or nifedipine-r was doubled to 20 mg once daily or 40 mg twice daily respectively. Metoprolol was continued unchanged throughout the study. The doses and dose intervals of nifedipine and felodipine were those recommended by the manufacturers. Patients Eligible patients, recruited from five teaching hospitals, were males, or females who were post-menopausal or who had been sterilized, aged years. Exclusion criteria were: BP > 200/115 mmhg on treatment; secondary hypertension; severe concurrent disease; potential problems with compliance; angina pectoris requiring treatment other than metoprolol 200 mg plus sublingual glyceryl trinitrate; cerebrovascular accident or myocardial infarction in the past 3 months; left ventricular failure, papilloedema or encephalopathy associated with 'malignant' hypertension; symptomatic right ventricular failure; unwillingness. Ethics The Ethics Committee at each trial centre approved the study. Patients were given verbal and written explanations of the trial, informed of their right to withdraw and gave written informed consent to participate. Assessment of blood pressure and heart rate Systolic (sbp) (Korotkoff phase I) and diastolic (Korotkoff phase V) arterial pressures were recorded, seated (having been seated for at lest 5 min) and standing (having stood for 1 min) using a Hawksley random-zero sphygmomanometer and appropriate size of cuff. Heart rate was measured by pulse palpation. Measurements were made in duplicate and the average values used for analyses. Blood pressure and heart rate were recorded in the morning, 12 h after the last dose of nifedipine R and 24 h after the last dose of felodipine ER: in addition, at the start of the double-blind period and after 2 and 8 weeks, blood pressure and heart rate were recorded 3 h post-dose. Assessment of tolerability Adverse events were recorded at each visit in response to an open question. In addition, active questioning by questionnaire (for a list of questions see Table 3) was used at the start and end of the double-blind period. At the start and end of treatment, a 12-lead ECG and the results of routine blood and urine tests were recorded.

3 Statistical analysis The main analysis was performed at the end of the study after dose titration. Absolute values and changes in blood pressure after 2 and 8 weeks treatment were analysed by two-way analysis of variance with treatment and centre as factors and changes as dependent variables. The completion of 45 patients in each treatment group gave a power of approximately 80% to detect a difference between reductions in diastolic blood pressure of 5 mmhg with - P < 0.05 and standard deviation for the change between groups in diastolic blood pressure of 6 mmhg. Results One hundred patients (14-23 patients/centre) entered the double-blind trial, 51 receiving felodipine and 49 nifedipine. Forty-six patients in the felodipine group and 45 in the nifedipine group completed the study. Fifty-nine percent of felodipine patients, and 56% of nifedipine patients required the higher dose (20 mg once daily for felodipine, 40 mg twice daily for nifedipine). Felodipine and nifedipine in hypertension 873 Baseline characteristics The felodipine and nifedipine groups were generally well-balanced at randomisation (Table 1). Diastolic blood pressure values were 6-10 mmhg lower 3 h post-dose than 24 h postdose, for metoprolol alone. Diastolic blood pressure was not adequately controlled 24 h post-dose by metoprolol in either group. Effects on blood pressure and heart rate Two weeks after randomisation, on the lower doses of either felodipine or nifedipine, there was no difference in absolute blood pressure between treatments (Figure 1). At the end of the study, seated diastolic blood pressure was lower in the felodipine group 24 h post-dose (90 ± 10 mmhg; mean ± s.d.) than in the nifedipine group 12 h post-dose (95 ± 10 mmhg; 95% confidence interval for the difference between treatments -9 to -1 mmhg, P < 0.02). The difference in systolic blood pressure between treatments at the end of the dose interval (felodipine 148 ± 19 mmhg; nifedipine 155 ± 19 mmhg) did not reach statistical significance (95% confidence interval -16 to 0 mmhg, P = 0.06). There were no differences in blood pressures Table 1 Patient characteristics at randomisation. Mean ± s.d. or number (*) of patients is given. Patients were taking metoprolol SA 200 mg once daily. Age (years) Sex (M:F) * Height (cm) Weight (kg) Duration of diagnosed hypertension (c 1 year: > 1 year) WHO stage (I:II:III) * Angina * Previous MI * Abnormal ECG * Seated blood pressure (mmhg) 3 h post metoprolol sbp dbp 24 post metoprolol sbp dbp Seated heart rate (beats min-') 3 h post metoprolol 24 h post metoprolol Felodipine ER group (n = 51) 53 ± 11 32: ± ± 14 11:40 35:14: ± ± ± ± 6 64 ± 8 72 ± 11 Nifedipine R group (n = 49) 55 ± 7 25: ± 8 78 ± 13 15:34 34:12: ± ± ± ± 5 63 ± 8 71 ± 12

4 874 W. A. Littler 0) I EE c) L- CA a) Co m0. ~ r 180 F 160F h post-dose 24/12 h post-dose '- Week Dose nil low low/high nil low low/high n Seated blood pressure recorded 3 h (left hand side) or 24/12 h (right hand side) after metoprolol Figure 1 alone (week 0), metoprolol plus felodipine-er-10 mg once daily or nifedipine-r 20 mg twice daily (week 2) and metoprolol plus felodipine-er 10 or 20 mg once daily, or nifedipine 20 or 40 mg twice daily (week 8). Mean ± s.d.; 2 felodipine-er; O nifedipine-r. c 0 C., Systolic Time post-dose (h) Diastolic a) a) a) ci) 0). Co mco 0 'a -lo E L ns J L *** i A = -2 (-12 to +7) = -16 (-24 to -8) mmhg A = -3 (-7 to +3) A = -8 (-12 to -5) mmhg n n Figure 2 Reduction in seated blood pressure after 8 weeks' treatment. E2 felodipine-er; 0 nifedipine- R. ***, P < between groups; NS, P > 0.2. A, mean difference (95% confidence interval). between the groups when measured 3 h postdose. The blood pressure response was similar in all centres. The reductions in blood pressure after 8 weeks' treatment were significantly greater for the felodipine group than for the nifedipine group when measurements were made at the end of the dose interval but not for measurements 3 h post-dose (Figure 2). The reductions in blood pressure produced by felodipine 3 h and 24 h post-dose were the same. In contrast, nifedipine produced a greater reduction of blood pressure 3 h post-dose than 12 h post-dose. Doubling the dose of nifedipine in 59% of patients produced no further fall in blood pressure (Table 2). The reductions in blood pressures were similar whether the measurements were taken with the patient seated or standing and there was no evidence of symptomatic postural hypotension. At randomisation, the distributions of diastolic blood pressures for the felodipine and nifedipine groups were similar (Figure 3). By the end of

5 Felodipine and nifedipine in hypertension 875 Table 2 Seated diastolic blood pressure (at the end of the dose interval) at baseline, after 2 weeks and at the end of the study. Data are given separately for patients treated with low dose throughout (LD-group: felodipine ER 10 mg once daily; nifedipine R 20 mg twice daily) and for patients who had a dose increment (HD-group: felodipine ER 20 mg once daily; nifedipine R 40 mg twice daily). All patients in the HD-group had received the low dose at 2 weeks. Data are given as mmhg, mean ± s.d. Felodipine ER Nifedipine R LDgroup HD group LDgroup HD group (n = 19) (n = 27) (n = 20) (n = 25) Baseline (mmhg) 104 ± ± ± ± 4 2 weeks (mmhg) 89 ± ± 7 87 ± ± 8 8 weeks (mmhg) 86 ± ± 7 87b ± ± 7 8or 70 F- wf- Felodipine Nifedpino ' ; 0:,: ; 1. E 2I;!i~. 2. ;>,! - g ;-..,az kmoduw Figure 3 Distribution of seated diastolic blood pressure (mmhg) at randomisation (0) and at the end of the study; 24 h post-dose for felodipine ER (M), 12 h post-dose for nifedipine R (I). the study, more nifedipine patients remained with diastolic blood pressure above 100 mmhg than felodipine patients. Heart rate was unaltered in each treatment group throughout the double-blind period. Tolerability Nine patients withdrew, one in each group being lost to follow-up, four associated with adverse events in the felodipine-er group and three in the nifedipine-r group. Two of the four in the felodipine-er group died from causes judged by the physician to be unrelated to the medication. One patient developed unstable angina (blood pressure was controlled and heart rate had not increased), was discovered to have a stenosis in the main stem of the left coronary artery and died after coronary artery bypass surgery. The second patient, a diabetic man of 63 years, suffered a fatal brain stem cerebrovascular accident. The pattern and number of adverse events were similar for both groups (Table 3). In response to open questioning, 61% (n = 51) of felodipine patients and 73% (n = 49) of nifedipine patients reported adverse events during the double-blind period. The total number of adverse events recorded were felodipine 88, nifedipine 101. No ECG, haematological or biochemical abnormalities arose.

6 876 W. A. Littler Table 3 Adverse events elicited by specific enquiry. Figures show number of patients responding to each question. * Total number of patients with any positive response to that group of questions. Felodipine ER (n = 46) Nifedipine R (n = 45) Before After Before After felodipine 8 weeks nifedipine 8 weeks Vasodilator effects Flushing Ankle swelling Headache Palpitations Total * Others Fatigue Cold extremities Nocturia Impaired libido Impotence Diarrhoea Rash Wheezing Total * Discussion Hypertension is generally an asymptomatic condition and its treatment requires a balance between the efficacy and tolerability of the therapeutic agent. In this study, patients achieved a lower blood pressure and a greater reduction in blood pressure on felodipine treatment than on nifedipine in patients receiving metoprolol once daily when blood pressure response was measured at the end of the dose interval. In the absence of a placebo control it is not possible to determine whether all the response was due to the drugs alone but the difference between the treatments would be unaffected. The advantage in antihypertensive efficacy for felodipine was achieved without any increase in the incidence of side-effects, so that the balance of efficacy and tolerability appeared more favourable for felodipine than for nifedipine in our study. The short duration of the study gives no guidance on long-term tolerability. The efficacy of felodipine achieved in this dose-titration study was consistent with that observed in a parallel-group placebo-controlled study using the same doses (Campbell et al., 1989). Thus, Campbell et al. (1989) observed reductions in diastolic blood pressure of 14 and 18 mmhg for the 10 mg and 20 mg doses respectively compared with the reduction of 17 mmhg in this study. Increasing the nifedipine dose from 20 mg twice daily to 40 mg twice daily in the 56% of patients not achieving target blood pressure on the low dose, failed to reduce mean blood pressure further at the end of the dose interval. The interpretation of this is probably not that 20 mg twice daily is near the top of the doseresponse curve, since an additional effect of the increased dose was seen at 3 h post-dose. The most likely explanation of the lack of increased effect after 12 h is that the duration of the effect of nifedipine retard is less than 12 h. A similar observation has been reported by Heagerty & Swales (1989) for nifedipine used as monotherapy. They found that 10 out of 16 patients failed to respond (diastolic blood pressure < 95 mmhg) to nifedipine retard 20 mg twice daily and that blood pressure failed to fall significantly when the dose of nifedipine was increased to 40 mg twice daily. An ideal once-daily antihypertensive is expected to have an even effect throughout the day. Although 24 h monitoring was not performed in this study, the equal blood pressure reductions seen for felodipine 3 h and 24 h post-dose indicate that felodipine is likely to have an even effect throughout the day and is suitable for oncedaily use as an addition to P-adrenoceptor blockers. Using ambulatory blood pressure measurement in a small group of patients, McGrath et al. (1989) demonstrated that felodi-

7 Felodipine and nifedipine in hypertension 877 pine ER produced similar reductions in diastolic blood pressure 5 h and 24 h post-dose. They also found that blood pressure reduction was greatest 2 h post-dose although peak plasma concentrations are usually obtained 3 to 5 h post-dose (Hasselgren et al., 1987). Continuous ambulatory intra-arterial recording of blood pressure during nifedipine treatment indicate that nifedipine mg twice-daily can provide 24 h control of blood pressure (Hornung et al., 1983). These data are not inconsistent with the present study since it is quite possible for blood pressure to remain below some chosen criterion of blood pressure control while at the same time showing variation in the degree of blood pressure reduction during the day. Our study design did not permit an assessment of how far short of 12 h, blood pressure control in the nifedipine group fell. The incidence and pattern of adverse events were similar for both felodipine-er and nifedipine-r. The most common adverse experiences were flushing, ankle oedema and fatigue in both groups: the first two are well-established consequences of arteriolar vasodilation while fatigue is a common complaint on antihypertensive drugs. 'Vasodilator' side effects were experienced by over half the patients in each group during treatment with the calcium antagonist. However, over 30% of the patients complained of 'vasodilator' adverse events during the runin phase on metoprolol alone. In the absence of a placebo-control group, the absolute level of adverse events cannot be assessed, only the difference between the treatment groups. Using an open style of questioning can result in 39% of patients on placebo reporting adverse events (Campbell et al., 1989) and the questionnaire style of eliciting adverse events used in this study, increases the reporting of adverse events. This study emphasises the importance of investigating the blood pressure response at the end of the dose interval in any trial with an antihypertensive drug, for example, metoprolol was clearly not as effective throughout the 24 h in our patients. In the present study, there was no difference in efficacy between the,-adrenoceptor blocker plus nifedipine R or felodipine ER 3 h after tablet intake, yet at the end of the dosing intervals, once-daily P-adrenoceptor blocker plus felodipine-er was significantly more effective an antihypertensive regimen than,b-adrenoceptor blocker plus twice-daily nifedipine R. Collaborating centres and investigators - Department of Cardiovascular Medicine, East Birmingham Hospital: W. A. Littler, J. N. W. West; Department of Medicine and Nephrology, Freeman Hospital, Newcastle-upon-Tyne: R. Wilkinson, H. Mansy, S. Mansy; Department of Cardiology, The General Infirmary, Leeds: E. J. Perrins, M. W. Baig; Coronary Care Unit, Aberdeen Royal Infirmary: A. C. F. Kenmure, M. Galea; Cardiac Unit, King's College Hospital, London: G. Jackson, D. Chee; Medical Department, Astra Pharmaceuticals Ltd, Kings Langley: P. D. I. Richardson, S. J. B. Timerick. We thank the technical support staff of all the hospitals and Bayer UK Ltd for the nifedipine tablets (Adalat Retard%)). References Campbell, L. M., Ross, J. R. M., Goves, J. R., Lees, C. T. W., McCullagh, A., Barnes, P., Timerick, S. J. B. & Richardson, P. D. I. (1989). A dose finding, placebo-controlled study of felodipine- ER once daily in the treatment of hypertension. J. cardiovasc. Pharmac., 14, Campbell, L. M., Cowen, K. J., Cranfield, F. R., Goves, J. R., Jones, D. F., Lees, C. T. W., Richardson, P. D. I., Teal, J. A. & Timerick, S. J. B. (1990). Felodipine-ER once daily as monotherapy in hypertension. J. cardiovasc. Pharmac., (in press). Cooperative Study Group (1987). Felodipine, a new calcium antagonist as monotherapy in mild or moderate hypertension. Drugs, 34, (Suppl. 3), Freeling, P., Harvard Davis, R., Goes, J. R., Burton, R. H. & Orme-Smith, E. A. (1987). Control of hypertension in elderly patients with felodipine and metoprolol: a double-blind, placebo-controlled clinical trial. Br. J. clin. Pharmac., 24, Groom, P., Simpson, R. J., Singh, B., Ward, D. E., Peers, E. & Richardson, P. D. I. (1988). A doubleblind comparison of felodipine and hydrochlorothiazide added to metoprolol to control hypertension. Eur. J. clin. Phamac., 34, Hasselgren, B., Edgar, B., Johansson, P. & Ronn, 0. (1987). Different doses of extended relese felodipine, diuretic, pharmacokinetic and haemodynamic effects. Cardiovasc. Drugs Ther., 1, 245. Heagerty, A. M. & Swales, J. D. (1989). A doubleblind randomized cross-over study of the efficacy and tolerability of nifedipine and nitrendipine in the treatment of mild to moderate hypertension. Br. J. clin. Pharmac., 27, Hornung, R. S., Gould, B. A., Jones, R. I., Sonecha, T. & Raftery, E. B. (1983). Nifedipine tablets for hypertension: a study using continuous ambulatory

8 878 W. A. Littler intra-arterial recording. Postgrad. Med. J., 59, Krbnig, B. & Flygt, G. (1987). Felodipine versus a double-blind parallel group multicentre study. Drugs, 34, (Suppl 3), Ljung, B. (1985). Vascular selectivity of felodipine. Drugs, 29 (Suppl 2), McGrath, B. P., Langton, D., Matthews, P. G., Syme, S., Treloar, K. & McNeil, J. J. (1989). Comparison of felodipine extended release and conventional tablets in essential hypertension using ambulatory bood pressure monitoring. J. Hypertension, 7, (Received 22 March 1990, accepted 2 July 1990)