Felodipine vs hydralazine: a controlled trial as third line therapy

Transcription

1 Br. J. clin. Pharmac. (1986), 21, Felodipine vs hydralazine: a controlled trial as third line therapy in hypertension CO-OPERATIVE STUDY GROUP* *Members of the co-operative study group were: Responsible investigators: D. Maclean (Ninewells Hospital, Dundee); B. D. Vallance (Hairmyres Hospital, East Kilbride); R. G. Wilcox (University Hospital, Nottingham); A. L. Muir (Royal Infirmary, Edinburgh). Statistician: R. A. Elton (Medical Computing and Statistics Unit, University of Edinburgh). Monitor: A. S. Readman (Astra Clinical Research Unit, Edinburgh). Co-investigators: E. T. Mitchell (Dundee); M. M. Vallance (East Kilbride); D. Macleod, L. Tucker, C. G. Wathen (Edinburgh) 1 In a placebo-controlled, double-blind, randomized, parallel group study one hundred and one patients with supine diastolic blood pressure - 1 mm Hg phase V, despite treatment with atenolol 1 mg plus chlorthalidone 25 mg once daily also received either felodipine 5-2 mg twice daily or hydralazine 25-1 mg twice daily for 6 weeks. 2 Felodipine achieved a lower supine blood pressure (mean + s.d. 177/ /8-138/82 ± 19/8 mm Hg) than hydralazine (174/ /8-149/ /11 mm Hg), (P <.5/P <.1). Felodipine also lowered supine diastolic blood pressure to < 9 mm Hg more often than hydralazine (42 vs 22 patients, P <.1). 3 The incidence of unwanted effects was similar in both groups. The felodipine treated patients experienced more ankle swelling and flushing than those in the hydralazine group who experienced more headache and minor gastro-intestinal upset. Keywords felodipine hydralazine hypertension Introduction Hydralazine is one preferred 'third line' drug in hypertension (McAreavey et al., 1984). The risk of drug-induced lupus limits its use (Cameron & Ramsay, 1984; Bing & Russell, 198) and calcium antagonists such as nifedipine are now being increasingly used (Murphy et al., 1983). Felodipine is a new dihydropyridine calcium antagonist which, in animals, selectively dilates arterial resistance vessels (Ljung, 1985). It has pronounced antihypertensive effects (Elmfeldt & Hedner, 1983) and is more potent than nifedipine (Ljung, 1985) with a longer elimination half-life (felodipine, 23.5 h (Elmfeldt & Hedner, 1985); nifedipine, 1 h (Raemsch & Sommer, 1983)) in steady state. It has no negative inotropic activity at therapeutic plasma concentrations (Culling et al., 1984). This study compared the therapeutic usefulness of felodipine with that of hydralazine in hypertensive patients uncontrolled despite a fixed,3-adrenoceptor blocker/diuretic combination. Methods Males and females aged 2-75 years, attending the hypertension clinics of the participating hospitals, were studied if their hypertension (WHO grades I-III) required treatment with three drugs, either because of poor efficacy or intolerance to existing therapy. Exclusion criteria were: child-bearing potential; myocardial infarction less than 3 months or cerebrovascular accident less than 6 months prior to entry; significant angina pectoris; 2nd or 3rd degree heart block; significantly impaired liver Correspondence: Dr D. Maclean, Department of Pharmacology and Clinical Pharmacology, Ninewells Medical School, Dundee, UK 621

2 622 Co-operative Study Group function; known previous poor compliance; severe concurrent disease; known contraindications to hydralazine. Existing,B-adrenoceptor blocker and diuretic treatment was standardised to atenolol 1 mg plus chlorthalidone 25 mg (as Tenoretic, Stuart Pharmaceuticals) once daily. Other antihypertensive drugs (hydralazine 19, methyldopa 12, nifedipine 11, captopril 7, prazosin 7 and others 9 patients) were discontinued and placebo felodipine and placebo hydralazine added 2 or 4 weeks before the study vasodilator was started. Study design All patients were studied 2-4 h after taking the morning tablets. Blood pressure (systolic and diastolic phase V) was measured (using the same arm at each visit) in the supine (after 5 min) and standing (after 1 min) positions using a Hawksley random zero sphygmomanometer. Pulse rate was measured over 3 s in each position immediately after blood pressure measurement. Body weight was also measured at each visit. Placebo, felodipine and hydralazine tablets were dispensed in dosette boxes. Returned tablets were counted at each visit. In addition to a fixed combination of atenolol 1 mg and chlorthalidone 25 mg orally once daily throughout, the patients were given placebo felodipine (identical to the 5 mg active tablet) twice daily, and placebo-hydralazine (identical to the 25 mg active tablet) twice daily, for 2 or 4 weeks. If the supine diastolic pressure after 2 weeks exceeded 11 mm Hg or was associated with unacceptable symptoms, patients were randomized within each centre, doubleblind, to the additional vasodilator. Otherwise the run-in treatment was continued for a further 2 weeks and those then with a supine diastolic blood pressure 2 1 mm Hg (phase V, mean of three consecutive readings) were randomised within each centre to receive either felodipine (one 5 mg tablet twice daily) or hydralazine (one 25 mg tablet twice daily). A double-dummy technique was used and individual treatment codes were not broken, except in emergency, until the study was complete. If after 2 weeks of three drug therapy supine diastolic blood pressure 2 9 mm Hg without significant unwanted effects, the dose of vasodilator was doubled to 1 mg felodipine or 5 mg hydralazine each twice daily (otherwise the doses remained unchanged) for the next 2 weeks. Doses could then be doubled again, according to the same criteria, to a maximum of 2 mg twice daily felodipine or 1 mg twice daily hydralazine for the final 2 weeks (otherwise doses again remained unchanged or could be reduced again if unwanted effects had proved troublesome at the previous dose). The total length of the double-blind period was therefore 6 weeks. There were two opportunities to alter the dose of vasodilator for each patient. Routine biochemical and haematological screening was performed at the beginning and end of the study, together with urinalysis. Acetylator phenotype was determined by the dapsone high pressure liquid chromatography method and classified as fast, intermediate or slow in order to look for any correlation between acetylator status and the required dose of hydralazine (Carr et al., 1978). The biotransformation of felodipine was not assessed. Antinuclear factor titre was measured at the beginning and the end of the study for 6 patients. Adverse experiences were recorded at every visit. Statistical methods All available data from all patients were used in the analysis. The two treatment groups were compared by Wilcoxon rank sum tests or chi-square tests as appropriate. Changes from baseline within treatment groups were tested with Wilcoxon signed-ranks tests. Kendall's rank correlation was used to test the relationship between acetylator status and hydralazine dose. The antihypertensive effects of the two treatments were compared between centres by analysis of variance. Results One hundred and one patients (57 males and 44 females) were randomized to active three drug treatments, 51 to felodipine and 5 to hydralazine. Their mean age was 53.4 (s.d. 9.9) years (range years) and all had a supine diastolic blood pressure 2 1 mm Hg despite 2-4 weeks treatment with atenolol plus chlorthalidone in addition to placebo. Sixty-six patients had a 4 week atenolol/chlorthalidone plus placebo run-in; the remaining 35 had a 2 week run-in period because their supine diastolic blood pressure then exceeded 11 mm Hg or was associated with unacceptable symptoms. At randomization, there were no significant differences between the two groups with respect to age, sex distribution, WHO stage or duration of hypertension, mean systolic or diastolic pressure (supine and erect), pulse rate (supine and erect), weight, acetylator phenotype distribution or any laboratory variable.

3 Table 1 Dose distribution at the end of the study Felodopine (mg twice daily) Withdrawn Hydralazine (mg twice daily) Withdrawn * *includes one death due to hypertensive heart disease and one death due to a gliding accident. Compliance was judged by the investigators to be 'good' for 98.8% of the double-blind assessment period; 81% of the dosette boxes were returned empty, and in the other boxes an average of only 2.8 tablets/patient/visit remained (i.e. less than one full dose). There was an even distribution of patients previously treated with hydralazine (nine in the felodipine and 1 in the hydralazine group) but not for those previously treated with the related dihydropyridine nifedipine (two in the felodipine and nine in the hydralazine group). Clinical assessments Dose distribution Fewer patients required dose increments on felodipine than on hydralazine (P <.1). The dose distribution for active vasodilator at the end of dose titration was that shown in Table 1. Two patients on felodipine required dose reduction, one as a result of ankle swelling, the other because of flushing, headache and fatigue. One patient on hydralazine required dose reduction because of fatigue and another temporarily stopped hydralazine due to headache and nausea. Blood pressure (Figure 1) After 6 weeks diastolic blood pressure (P <.1, supine and erect) was lower on felodipine than on hydralazine. Similarly, systolic blood pressure (P <.5, supine and erect) was then lower on felodipine than on hydralazine. There were no significant differences in these effects between centres. Of the six patients requiring 2 mg twice daily felodipine, only two did not reach the target supine diastolic blood pressure of < 9 mm Hg. Twenty of the patients receiving hydralazine required the maximum dose of 1 mg twice daily and fifteen of these had supine diastolic blood pressure > 9 mm Hg at the end of the study. More patients reached the target supine diastolic blood pressure after 6 weeks using felodipine (42) than hydralazine (22) (P <.1) (Figure 2). Felodipine or hydralazine in hypertension ; *- NS 2 E 18 -E e 16 5 :1 E14 cl g 12 c 1 CA 8 E E o1 2C 1ec l1 14C :35 12C I la Q- wii l1' 8C NSI..I NS *, Randofnization NS P <.6 TI L-j Fin'al "I P < ~I'.6 3;NS l P < Random.Ution Final Figure 1 Supine and erect blood pressures (mean + s.d.). Felodipine () compared with hydralazine (x) at randomization and at the end of the study. No significant differences in pulse rate occurred between the two groups at any stage. Unwanted effects, withdrawals and deaths The most frequently reported unwanted effects associated with vasodilator therapy during this study are shown in Table 2. Ankle swelling and flushing were more frequent in the felodipine group, headache and nausea in the hydralazine group. One felodipine-treated patient was withdrawn after 2 weeks (flushing) and one hydralazinetreated patient after 5 days (rash). Two patients died after approximately 4 weeks on hydralazine: a coroner's post-mortem in one recorded death as caused by 'hypertensive heart disease' which was associated with pulmonary

4 624 Co-operative Study Group 13 r I EE 12 I CA C C.a Un : i : : V - * * :: *... * * : *@ 6 L Figure 2 study. I bmg. - 1mg 2 mg Felodipine (twice daily) 25 mg 5 mg 1 mg Hydralazine (twice daily) Supine diastolic blood pressure of all patients according to treatment and dose at the end of the Table 2 Most frequently reported unwanted effects Number ofpatients Unwanted effect Felodipine Hydralazine (n = 51) (n = 5) Headache 5 14 Ankle swelling 11 3 Flushing 8 2 Fatigue 4 5 Dizziness 4 5 Minor gastro-intestinal upset 1 5 oedema. No unwanted effects had been reported by this patient but his blood pressure had not been well controlled (supine blood pressure of 184/98 mm Hg) by the addition of 5 mg hydralazine twice daily. The other patient died as a result of multiple injuries following a gliding accident believed to be unrelated to his medical condition or its treatment. There were no deaths in the felodipine-treated group. The reporting of ankle swelling on felodipine was not associated with weight gain. Laboratory variables There was a fall in mean serum potassium concentration ( (s.d.) to mmol 1[1 (meq l-1)) from baseline to the 6 week measurement on felodipine (P <.1) but a similar fall in the hydralazine group ( to mmol 17' (meq [1)) was not significant; the difference between these two mean falls in serum potassium concentration was not significant. There were no other significant changes in laboratory variables, including liver enzymes and random blood glucose levels or in antinuclear factor titre. The urinalysis showed no abnormality except in one patient from the hydralazine group who developed glycosuria and diabetes mellitus during the study.

5 Fast acetylators (21 patients) tended to require a higher dose of hydralazine than slow (23 patients) or intermediate (four patients) acetylators but these differences were not significant; two patients in the hydralazine group did not have their acetylator status determined. Discussion This is the first completed, double-blind, comparative study of felodipine with hydralazine as the third drug in a large group of hypertensive patients. The combination of atenolol and chlorthalidone was chosen as baseline therapy because of its widespread use in the United Kingdom. Hydralazine was prescribed from the recommended starting dose of 25 mg twice daily to a maximum dose of only 1 mg twice daily because of the risk of developing the lupus syndrome at higher doses (Cameron & Ramsay, 1984; Bing & Russell, 198). Felodipine was prescribed from a starting dose of 5 mg twice daily because at the time the study was designed this initial dose was considered to be the lowest dose with a useful antihypertensive effect and was known to be well tolerated by most patients (Collste et al., 1985). No formal study to determine the dose of felodipine equivalent in hypotensive potency to the starting dose of hydralazine has been published. Having used three dose levels for hydralazine, this dose of felodipine was increased in the same way to a maximum of 2 mg twice daily. This study design allowed at least 2 weeks for the maximum necessary or tolerated dose of either felodipine or hydralazine to express its antihypertensive potential. This interval is well in excess of five times the known elimination half-life for felodipine, 23.5 h, and the very much shorter half-life for hydralazine. Felodipine reduced the blood pressure more effectively than hydralazine in terms of final blood pressure, the change in blood pressure over the 6 week period and the number of patients achieving target (supine diastolic blood Felodipine or hydralazine in hypertension 625 pressure < 9 mm Hg). Hydralazine at the maximum prescribed dose of 1 mg twice daily did not bring the supine diastolic blood pressure below the target for 53% (25) of the patients whereas at the maximum prescribed dose of 2 mg twice daily felodipine was not fully effective in only 16% (eight) of the patients. The two treatment regimens were associated with a similar overall incidence but a different spectrum of mainly vasodilator-related unwanted effects. More of the hydralazine-treated patients reported headache or nausea and more of the felodipine-treated patients reported ankle swelling or flushing. No concomitant increase in weight was observed in those patients reporting ankle swelling, supporting the theory (Elmfeldt & Hedner, 1983) that this oedema may result from pronounced precapillary vasodilatation rather than fluid retention. The apparent hypokalaemic effects of felodipine or hydralazine in combination with atenolol plus chlorthalidone were more marked but not significantly different in the case of felodipine. Although a similar effect of nifedipine in combination with atenolol and bendrofluazide has been reported (Murphy et al., 1983), differences in pre-study diuretic usage prior to the introduction of the long-acting diuretic chlorthalidone may be responsible for these changes whilst on chlorthalidone too; no useful conclusions can therefore be drawn from these observations. No changes in antinuclear factor titre were observed and no symptoms suggestive of the lupus syndrome developed. We conclude that felodipine, at least in the short-term, is a better third line antihypertensive drug than hydralazine. Longer-term studies of its efficacy and acceptability are warranted. We thank our hospital laboratory staffs for their help, and in particular Dr P. E. G. Mitchell, Dundee. We also thank Dr P. A. Meredith, Department of Materia Medica, University of Glasgow for acetylator phenotype determinations. The Astra Clinical Research Unit, Edinburgh, sponsored this study and gave financial support. References Bing, R. F., Russell, G. I., Thurston, H. & Swales, J. D. (198). Hydralazine in hypertension: Is there a safe dose? Br. med. J., 281, Cameron, H. A. & Ramsay, L. E. (1984). The lupus syndrome induced by hydralazine: a common complication with low dose treatment. Br. med. J., 289, Carr, K., Oates, J. A., Nies, A. S. & Woosley, R. L. (1978). Simultaneous analysis of dapsone and monoacetyldapsone employing high performance liquid chromatography: a rapid method for determination of acetylator phenotype. Br. J. clin. Pharmac., 6, Collste, P., Danielsson, M., Elmfeldt, D., Feleke, E., Gelin, A., Hedner, T. & Ryden, L. (1985). Long term experience of felodipine on combination with beta-blockade and diuretics in refractory hypertension. Drugs, 29, (Suppl. 2),

6 626 Co-operative Study Group Culling, W., Ruttley, M. S. M. & Sheridan, D. J. (1984). Acute haemodynamic effects of felodipine during beta blockade in patients with coronary artery disease. Br. Heart J., 52, Elmfeldt, D. & Hedner, T. (1983). Felodipine - a new vasodilator, in addition to beta-receptor blockade in hypertension. Eur. J. clin. Pharmac., 25, Elmfeldt, D. & Hedner, T. (1985). Antihypertensive effects of felodipine compared with placebo. Drugs, 29 (Suppl. 2), Ljung, B. (1985). Vascular selectivity of felodipine. Drugs, 29, (Suppl. 2), McAreavey, D., Ramsay, L. E. & Latham, L., McLaren, A. D., Lorimer, A. R., Reid, J. L., Robertson, J. I. S., Robertson, M. P. & Weir, R. J. (1984). 'Third drug' trial: comparative study of antihypertensive agents added to treatment when blood pressure remains uncontrolled by a beta blocker plus thiazide diuretic. Br. med. J., 288, Murphy, M. B., Scriven, A. J. I. & Dollery, C. T. (1983). Role of nifedipine in treatment of hypertension. Br. med. J., 287, Raemsch, K. D. & Sommer, J. (1983). Pharmacokinetics and metabolism of nifedipine. Hypertension, 5 (Suppl. II, No 4), II-18-II-24. (Received 3 October 1985, accepted 3 January 1986)