Br. J. clin. Pharmac. (1990), 30, 203-211
Enalapril and nifedipine in the treatment of mild to moderate essential hypertension: a 6 month comparison D. MACLEAN', L. E. RAMSAY2 & P. J. RICHARDSON3 'University Department of Clinical Pharmacology, Ninewells Hospital, Dundee DD1 9SY, 2Department of Therapeutics, Royal Hallamshire Hospital, Sheffield S10 2JF and 3Cardiac Department, King's College Hospital, London SE5 9RS
1 In a double-blind, randomised, parallel group study, 128 patients with sitting diastolic blood pressure between 95 and 125 mm Hg (Phase V) after 2-4 weeks run-in on placebo, received enalapril 10-40 mg once daily (65 patients) or nifedipine retard 10-40 mg twice daily (63 patients), utilising a double dummy technique. Dual target blood pressures were < 150 mm Hg systolic and < 90 mm Hg sitting diastolic. Inadequate responders had hydrochlorothiazide 12.5-50 mg once daily added. 2 The 3 h post-dose sitting blood pressures were lowered by 18/14 mm Hg (enalapril) and 20/14 mm Hg (nifedipine), but nifedipine gave greater standing reductions (16/13 mm Hg enalapril, 22/17 mm Hg nifedipine). The dual target blood pressures were achieved by 45% of those taking enalapril monotherapy and 43% of those taking nifedipine monotherapy. At the end of the hydrochlorothiazide phase the dual target pressures were achieved by 63% of the enalapril group and 56% of the nifedipine group. 3 Overall, 17 patients reported adverse events during the placebo run-in. During the active treatment-periods, 42 patients in the enalapril group experienced adverse events, as did 49 of those on nifedipine. Orthostatic effects were confined to those taking enalapril, whereas flushing/erythema, oedema and palpitations were more common in the nifedipine group. 4 Five patients in the enalapril and 14 in the nifedipine groups were withdrawn because of adverse events. One of those withdrawn on enalapril had angioneurotic oedema. Three patients developed rises in serum creatinine to over 150 mmol 1-1 and serum urea to over 10 mmol l-1, two in the enalapril group, but only after the addition of the diuretic. 5 Compliance was at least 95% in 85% of the enalapril patients and in 65% of those taking nifedipine. 6 Thus, enalapril 10-40 mg once daily and nifedipine retard 10-40 mg twice daily produce comparable blood pressure control in mild-moderate essential hypertension. Mainly vasodilator-type adverse events proved troublesome for some patients on nifedipine and were associated with diminished compliance and a higher withdrawal rate. Overall, the two agents showed good and comparable safety profiles in these selected patients.
Keywords enalapril nifedipine hypertension efficacy tolerability safety
203
204
D. Maclean, L. E. Ramsay & P. J. Richardson
Introduction
Methods
The widespread availability and increasi acceptance of the angiotensin converti enzyme (ACE) inhibitors and the calcium cha nel blockers has greatly increased the choice antihypertensive therapies. The two class have differing modes of action and are genera characterised by different adverse effec However, they share some common featur their main effect is to dilate arterioles, they a relatively free of adverse metabolic effects a despite their promise, no long term studies end point data are available to document th long term safety and ability to prevent strok or other cardiovascular events. Surprisinj there have been very few direct comparisons these two classes reported. Enalapril, a or daily non-sulphydryl ACE inhibitor and t calcium channel blocker nifedipine in a reta formulation, given twice daily, are now bc widely used antihypertensive therapies and sc is both of interest and relevance to comp; directly these two agents. Three critical e ments of the comparison should be that it objective, i.e., double-blind, of sufficient du tion to allow adequate time for any adve effects to become apparent and thirdly that I study should be of sufficient size and statisti power to detect differences between the tre ments. We have therefore conducted a 6 mo double-blind comparison of these two agents 128 patients with mild to moderate essen hypertension.
Three centres took part in a randomised, double-blind, double-dummy, parallel group study. Men and women aged between 18-70 years, whose sitting diastolic blood pressure was within the range 95-125 mm Hg at the end of the placebo run-in were eligible for the study. They were recruited to the study if their previous therapy had proved ineffective or was inappropriate because of unwanted effects. Intolerance to, or lack of efficacy of either drug class in the past, were reasons for exclusion. Patients with malignant hypertension, those who had had a myocardial infarction or cerebrovascular event within the past 6 months, or any contraindication to either of the trial treatments, those with heart failure requiring maintenance diuretics or known or suspected renovascular disease were excluded from the study, as were women of reproductive potential. Informed patient consent was obtained and the study had ethics committee approval in each of the participating centres.
Study protocol (see Figure 1) Eligible patients were given a 2-4 week course of placebo drugs (single-blind), during which any previous antihypertensive therapies (Table 1) were withdrawn according to manufacturer's recommendations. At week 0, patients were randomized and assigned an allocation number. Dosage of drug was initiated at 10 mg once daily + Hydrochlorothiazide
E40 mg once
12.5, 25, 50 mg
E20 mg once daily Enalapril 10 mg once daily Placebo
Monotherapy
(
i
± Diuretic -
Nifedipine 10 mg twice daily N20 mg twice daily N40 mg twice daily ± Hydrochlorothiazide 12.5, 25, 50 mg to
I
Week -4 Visit 1 Figure 1 Study design
Week 0 Visit 2
Week 2 Visit 3
Week 4 Visit 4
Week 8 Visit 5
Week 24 Visit 9
Enalapril and nifedipine in hypertension
205
Table 1 Previous antihypertensive therapy Previous therapy
n
None Diuretic
46 11 18 ,B-adrenoceptor blocker ACE-inhibitor 18 Calcium antagonist 8 Diuretic + ,-adrenoceptor blocker 10 4 Diuretic + ACE-inhibitor 1 Diuretic + calcium antagonist 3 Calcium antagonist + ACE-inhibitor Calcium antagonist + ,3-adrenoceptor blocker 5 1 Hydralazine + j3-adrenoceptor blocker 1 Diuretic + ACE-inhibitor + calcium antagonist Diuretic + ACE-inhibitor + 3-adrenoceptor blocker 1 1 Methyldopa
with enalapril and 10 mg twice daily with nifedipine retard. However, to comply with data sheet recommendations, a lower dose of enalapril, 5 mg, was used on the first day only of active treatment. At the end of weeks 2 and 4, dosage of the trial medication was doubled if the dual blood pressure targets of < 150 mm Hg systolic and < 90 mm Hg diastolic in the sitting position, had not been achieved. At the end of 8 weeks monotherapy, patients whose sitting blood pressure had still not achieved these same target levels had hydrochlorothazide added to their trial medication starting with a dosage of 12.5 mg, titrating at 4 weekly intervals, if necessary, to a maximum of 50 mg at week 16. If the patients' blood pressure had still not achieved the target levels at week 20, a third antihypertensive of the physician's choice could be added. The interval between dose titrations could be shortened if a patient's sitting diastolic blood pressure was > 120 mm Hg. Furthermore, if it was felt that the appearance of an adverse event was dose-related, the dose titration was staggered or reversed. The study was conducted on a double-blind basis using a double-dummy technique and treatment was continued for 24 weeks. For each individual all assessments were made at approximately the same time of day. Blood pressure, heart rate and weight were recorded at every visit. Blood pressure was measured using a Hawksley random zero sphygmomanometer and recording phase V diastolic pressure. Two readings were taken with the patient sitting following a 5 min rest period and the mean value recorded. Standing blood pressure was measured after standing for 2 min. Heart rate was measured at
the wrist at the same time intervals. In addition, concurrent illnesses and details of concomitant drug therapy were recorded at every visit.
Patients were withdrawn from the study if at any time there were intolerable side-effects, patient non-compliance or lack of therapeutic effect (i.e., sitting blood pressure > 200/125 mm Hg despite titration to maximum dose levels and addition of diuretic). The reasons for all withdrawals were recorded. Compliance was assessed by counting the tablets at each visit and the tolerability of the two treatments was assessed by the response to a standard nonleading question at every visit. Laboratory assessments were performed at each visit for haematology and biochemistry.
Statistical analysis Sample size for the study was calculated to detect a 5 mm Hg difference in final sitting diastolic blood pressure between the two groups. Assuming a standard deviation of diastolic blood pressure of 10 mm Hg, 65 patients per group were calculated to be required to detect such a change in BP with a probability of 80% at the 5% significance level. Efficacy data were analysed at week 0 (baseline), week 8, (end of 8 weeks monotherapy), and week 24 (end of study). Blood pressure changes during the first 8 weeks monotherapy were investigated further, using analysis of variance to examine possible factors which might cause variation in the results. A chi-squared test was used to compare the treatment groups with respect to the number of patients withdrawn from the study.
206
D. Maclean, L. E. Ramsay & P. J. Richardson
Results A total of 128 patients were enrolled into the study. Characteristics of patients at randomisation to enalapril (n = 65) or nifedipine (n = 63) are shown in Table 2. The groups were comparable in their baseline parameters, including origin, sex, duration of known hypertension and baseline blood pressure values. The mean age of the enalapril group was higher than that of the nifedipine group, but the overall ranges were similar. Body weight did not alter significantly in either group during the course of the study. The time interval following the last dose of medication at which blood pressure measurements were recorded, was comparable in the two treatment groups, 2.98 h in the enalapril group and 3.22 h in the nifedipine group. Compliance as judged by tablet counts showed that 85% of patients treated with enalapril versus 65% of patients treated with nifedipine achieved a compliance of at least 95%. With the exception of only one patient per group, all patients had achieved a compliance level of at least 80%.
Blood pressure End dose titration (monotherapy) Following 8 weeks monotherapy, at which time patients reached the maximum titrated or tolerated dosage, substantial decreases in blood pressure were recorded in both treatment groups (Table 3). All mean changes from baseline (both sitting and standing), within the treatment groups were highly significant (P < 0.001). The sitting blood pressure reduction was 18/14 mm Hg in the
enalapril group and 20/14 mm Hg in the nifedipine treated group, with no statistically differences between the two. The standing blood pressure reduction was 16/13 mm Hg in the enalapril treated group and 22/17 mm Hg in the nifedipine treated group. These greater decreases in standing systolic and diastolic blood pressures in the nifedipine group were significant (P = 0.02 and P = 0.01 respectively). An analysis of variance was used to elucidate the effect of age, treatment group, investigator and baseline blood pressure on the changes seen during monotherapy. Only the effect of baseline blood pressure was shown to influence the results. The estimates of treatment group differences and their confidence intervals are shown in Table 4. The differences in sitting blood pressure between groups were comparable to those shown using the ttest analysis, i.e., not significant, but the between group differences in standing blood pressure were again significant, but at a reduced level of significance (i.e., 10% level only). Monotherapy + hydrochlorothiazide Between weeks 8 and 24 (end of 8 weeks monotherapy and end of study), all mean changes within treatment groups were highly significant (P < 0.001) and no statistical differences between the two groups for any blood pressure parameter could be shown. However, these results include patients who remained on monotherapy throughout the study, together with those who received additional hydrochlorothiazide following week 8. Further analysis was therefore performed on these sub-
Table 2 Demographic details
Total number of patients Male Female Age (years) Mean Range s.d. Origin Caucasian Negro Other Duration of hypertension Mean Range (months) s.d.
Enalapril
Nifedipine
65 38 27
63 36 27
53.0
Total 128 74 (58%) 54 (42%)
49.0
25.0-70.0
23.0-70.0
10.6
10.8
59 5 1
53 8 2
59.6
49.6
2.0-336.0
1.0-216.0
70.1
46.6
112 (88%) 13 (10%) 3 (2%)
Enalapril and nifedipine in hypertension
207
Table 3 Mean (s.d.) measurements of blood pressure (mm Hg) at baseline, in patients receiving enalapril or nifedipine monotherapy (week 8) and ± hydrochlorothiazide (HCTZ) at week 24
Nifedipine
Enalapril
Standing
Sitting
Standing
Sitting
Week number
Diastolic BP
Systolic
Diastolic
Systolic
BP
BP
BP
BP
Diastolic BP
Systolic BP
Diastolic BP
Randomisation (week 0)
160 (18)
104 (18)
159 (17)
108 (8)
161 (20)
105 (8)
162 (20)
110 (9)
End-dose titration
142 (22)
91 (11)
142 (21)
95 (11)
141 (16)
91 (10)
140 (16)
93 (10)
129 (14)
85 (8)
129 (16)
89 (8)
133 (14)
86 (7)
131 (14)
90 (9)
Systolic
(Monotherapy) (week 8) End of study monotherapy ± HCTZ
(week 24)
Table 4 Mean (s.d.) reductions in blood pressure (mmHg) from baseline at week 8 (end of monotherapy) and a comparison of the effects of enalapril and nifedipine Measurement
Diastolic pressure Sitting
Mean changes Enalapril Nifedipine
Mean of difference 95% confidence intervals
P value
14.0 (11.0) 12.7 (10.5)
13.9 (11.6)
Standing
17.2(11.5)
0.1 4.5
-4.1 to 3.9 0.6to 8.4
NS 150 mm Hg systolic and/or > 90 mm Hg diastolic. When these incomplete responders were assessed for tablet compliance (using tablet counts), two patients only, one from each group, failed to take at least 80% of the doses of study medica-
D. Maclean, L. E. Ramsay & P. J. Richardson
208
200
200
180
180
E 160 E
160
a)
140
140
-a 120
120
-0 c 100
100
:
Un Un a)
0 0
_-
U)
80
T
80
Baseline
End of study End of 8 weeks
Baseline End of 8 weeks
Monotherapy
End of study
+ Hydrochlorothiazide
200
200
180
180
EE 160
160
I
a)
140
140
0120
120
100
100
80
80
u) cn
a)
-0
0 .0 0)
-c
T
U)
_
Baseline
_
_
End of study End of 8 weeks
Monotherapy
Baseline
End of study End of 8 weeks
+ Hydrochlorothiazide
Figure 2 Changes in blood pressure (mm Hg) from baseline in the subgroup of patients continuing on monotherapy compared with those in the subgroup that required additional hydrochlorothiazide enalapril, * nifedipine, * P < 0.05
Enalapril and nifedipine in hypertension tion as directed. Of the remaining 12 incomplete non-responders (six per group), four of six in the enalapril group and two of six in the nifedipine group showed signs of excessive alcohol consumption (as indicated by elevated MCV levels (> 98 f 1-1).
209
fatigue/drowsiness/tiredness were reported with similar frequencies in both treatment groups. The total number of events experienced on treatment was 120 in the enalapril group vs 166 in the nifedipine treated group.
Safety Heart rate No heart rate changes of clinical relevance occurred in either treatment group.
Withdrawals A total of six of 65 patients (9%) in the enalapril group were withdrawn during the course of the study, five (8%) during the first 8 weeks of the trial. In the nifedipine group a total of 14 of 63 patients (22%) were withdrawn, five (8%) during the initial 8 weeks (Table 5). Of the six patients withdrawn in the enalapril group, five were withdrawn due to adverse events and one because of poor compliance leading to lack of therapeutic effect (i.e. sitting blood pressure > 200/125 mm Hg despite titration to maximum dose levels). In the nifedipine group all fourteen patients were withdrawn due to adverse events. Seven of these patients stopped taking the tablets themselves because they found vasodilator-type adverse events intolerable. In only one case in each of the treatment groups did an adverse event leading to withdrawal first occur on the addition of hydrochlorothiazide. In all other cases the adverse events leading to withdrawal were first reported whilst the patient was receiving monotherapy only. The greater frequency of withdrawal in the nifedipine group was significant (X2 = 5.22, P
150 mmol 1-1 and serum urea > 10 mmol l-1, but these did not occur until after the addition of hydrochlorothiazide. No other clinically significant changes were noted in any of the additional routine biochemical and haematological parameters monitored. Discussion
Angiotensin converting enzyme inhibitors and calcium antagonists are now widely used in the treatment of essential hypertension as alternatives to thiazide diuretics and 3-adrenoceptor antagonists. Subject to demonstration of their comparable efficacy, the success of these agents in long-term treatment is likely to depend largely on their tolerability and safety profiles. Their ability over the long-term to prevent strokes or other cardiovascular events will take time to ascertain, but consistently good BP control is likely to be the most important determining factor in achieving this goal. In some patients, twice daily nifedipine may be more effective than low dose captopril given twice daily, but tolerability problems were prominent with the calcium antagonist (Klein et al., 1986; Salvetti et al., 1987); there were no important safety concerns with either drug over the short-term in these fixed dose studies. On the other hand, two variable dose studies comparing the once daily long-acting ACE-inhibitor lisinopril with twice daily nifedipine retard over 3 months (Morlin et al., 1987) and 6 months (Richardson et al., 1987) respectively showed both drugs to be equally effective in controlling hypertension, but again significantly more tolerability problems occurred with the calcium antagonist monotherapy: as with the captopril studies, no important safety concerns arose in either study. Enalapril, which is the most widely used long-acting ACE-inhibitor, has been shown in two very small studies (Gilchrist et al., 1988; Morgan et al., 1988), one confined to the elderly
210
D. Maclean, L. E. Ramsay & P. J. Richardson
Table 5 Withdrawals and adverse events
Number of patients randomized
Enalapril
Nifedipine
65
63
1
0
4 + (1)#
13 + (1)#
Withdrawals due to lack of efficacy Number of patients Due to major adverse events Number of patients Details of major adverse events* necessitating withdrawal Flushing/Erythema Oedema Headache Fatigue/Drowsiness/Tiredness Malaise Hypotension Faintness/Dizziness Tachycardia/Palpitations Angioneurotic oedema Panic attack Nausea Shakiness Leg pains Thirst Minor adverse events* No treatment change required Number of patients
0 0 1 1 + (1)# 0 1 1 0 1 0 1 + (1)# 0 1 0
10 9 5 5 3 0 1 2 + (1)# 0 1 1
33 + (4)#
31 + (4)#
(1)# 0 1
Details of minor adverse events
Flushing/Erythema Oedema Headache Fatigue/Drowsiness/Tiredness Malaise Hypotension Faintness/Dizziness Tachycardia/Palpitations Nausea Gastrointestinal upset
Angina Dry cough
10 + (4)# 5 + (1)# 12 + (3)# 6
7
(1)# 10 6 + (3)# 1 1 1 0 2 + (2)# 0 1
(1)# 0 3 2 1 1 + (1)# 2 + (1)# 0
(3)#
Number of adverse events on placebo Number of patients
8
9
No adverse events Number of patients
23
14
*
Most patients experienced more than one adverse event.
( )# These figures indicate that the adverse events occurred only
chlorothiazide
on
the addition of hydro-
Enalapril and nifedipine in hypertension (Gilchrist et al., 1988), to have comparable antihypertensive efficacy with that of nifedipine, where again there was a hint that tolerability may be better to the ACE-inhibitor than on the calcium antagonist (Gilchrist et al., 1988). Neither study had the power to give reliable information on the comparative efficacy, tolerability and safety of the two drugs, and neither was long-term. Enalapril may have some advantages in efficacy over another calcium antagonist, diltiazem (Brunner et al., 1987) but the differences are of doubtful
clinical significance. Our study had sufficient power to determine the relative long-term efficacies of the two drugs and was of sufficient duration to determine reliably their tolerability profiles and to assess the effects of any differences in tolerability on compliance and withdrawal rates. The 6 months duration of the active treatments is sufficient to indicate, but not to prove, the likely long-term safety of the two agents. Our results confirm that within the limitations of our trial design the two drugs had similar efficacy in our patients, but nifedipine proved superior in terms of standing BP control. The addition of hydrochlorothiazide in inadequate responders to either monotherapy produced a significantly better reduction in systolic BP in those on enalapril than in those on nifedipine. Tolerability was much better in the enalapril group than in the nifedipine group, with conse-
211
quently better compliance and many fewer withdrawals. One patient in the enalapril group withdrew because of angioneurotic oedema; other withdrawals because of major adverse events were because of the intensity of symptoms or signs but none was a hazard to the patient. Three patients showed deterioration in renal function after the addition of hydrochlorothiazide, two of them in the enalapril group. We conclude that each monotherapy provides good BP control, the calcium antagonist having the added advantage of better standing control. Enalapril was particularly welltolerated with significantly few withdrawals or concerns over its short and long-term safety in the selected group of patients. For some patients on nifedipine monotherapy, vasodilator-type adverse events were sufficiently troublesome to affect compliance and even to necessitate withdrawal, but there were no concerns over safety. Many of these adverse events experienced on nifedipine could be ameliorated through the complementary co-prescription of a ,-adrenoceptor blocker (Maclean et al., 1988), though this was not re-tested in this study. One cohort of our patients participated in an extension of this protocol, in which they crossed over to the alternative agent, still double-blind, for a further 6 months. The results of this cross-over comparison will be made available in a separate report.
References Brunner, H. R., Bidiville, J., Waeber, P., Porchet, M., Nussberger, J. & Waeber, B. (1987). Angiotensin-converting enzyme inhibitor versus calcium antagonist in the treatment of hypertension. Nephron, 47 (Suppl. 1), 87-89. Gilchrist, N. L., Nicholls, M. G., Ewer, T. C., Livesey, J. H. & Sainsbury, R. (1988). A comparison of long acting nifedipine and enalapril in elderly hypertensives: a randomised, single-blind, cross-over study. J. Human Hypertension, 2, 33-39. Klein, W. W., Stuhlinger, W. & Mahr, G. (1986). Cross-over comparison between captopril and nifedipine. Postgrad. med. J., 62 (Suppl. 1), 108-110. Maclean, D., Mitchell, E. T., Coulson, R. R., Fitzsimmons, T. J. & McDevitt, D. G. (1988). Atenolol-nifedipine combinations compared to atenolol alone in hypertension: efficacy and tolerability. Br. J. clin. Pharmac., 25, 425-431. Morgan, T., Anderson, A. & Hopper, J. (1988). Enalapril and nifedipine in essential hypertension; synergism of the hypotensive effects in com-
bination. Clin. exp. Hyper. - Theory & Prac., A10 (Suppl. 5), 779-789. Morlin, C., Baglivo, H., Boeijinga, J. K., Breckenridge, A. M., Clement, D., Johnston,
G.D.,Klein,W.,Kramer,R.,Luccioni,R.,Meurer, K. A., Richardson, P. J., Rosenthal, J., Six, R. & Witzgall, H. (1987). Comparative trial of lisinopril and nifedipine in mild to severe essential hypertension. J. cardiovasc. Pharmac., 9 (Suppl. 3), S48-S52. Richardson, P. J., Meany, B., Breckenridge, A. M., Grimmer, S. F. M., Johnston, G. D. & Kondowe, G. (1987). Lisinopril in essential hypertension: a six month comparative study with nifedipine. J. Human Hypertension, 1, 175-179. Salvetti, A., Innocenti, P. F., lardella, M., Pambianco, F., Saba, G. C., Rossetti, M. & Botta, G. F. (1987). Captopril and nifedipine interactions in the treatment of essential hypertensives: a crossover study. J. Hypertension, 5 (Suppl. 4), S139-S142.
(Received S January 1990, accepted 9 April 1990)
Enalapril and nifedipine in the treatment of mild to moderate essential hypertension: a 6 month comparison D. MACLEAN', L. E. RAMSAY2 & P. J. RICHARDSON3 'University Department of Clinical Pharmacology, Ninewells Hospital, Dundee DD1 9SY, 2Department of Therapeutics, Royal Hallamshire Hospital, Sheffield S10 2JF and 3Cardiac Department, King's College Hospital, London SE5 9RS
1 In a double-blind, randomised, parallel group study, 128 patients with sitting diastolic blood pressure between 95 and 125 mm Hg (Phase V) after 2-4 weeks run-in on placebo, received enalapril 10-40 mg once daily (65 patients) or nifedipine retard 10-40 mg twice daily (63 patients), utilising a double dummy technique. Dual target blood pressures were < 150 mm Hg systolic and < 90 mm Hg sitting diastolic. Inadequate responders had hydrochlorothiazide 12.5-50 mg once daily added. 2 The 3 h post-dose sitting blood pressures were lowered by 18/14 mm Hg (enalapril) and 20/14 mm Hg (nifedipine), but nifedipine gave greater standing reductions (16/13 mm Hg enalapril, 22/17 mm Hg nifedipine). The dual target blood pressures were achieved by 45% of those taking enalapril monotherapy and 43% of those taking nifedipine monotherapy. At the end of the hydrochlorothiazide phase the dual target pressures were achieved by 63% of the enalapril group and 56% of the nifedipine group. 3 Overall, 17 patients reported adverse events during the placebo run-in. During the active treatment-periods, 42 patients in the enalapril group experienced adverse events, as did 49 of those on nifedipine. Orthostatic effects were confined to those taking enalapril, whereas flushing/erythema, oedema and palpitations were more common in the nifedipine group. 4 Five patients in the enalapril and 14 in the nifedipine groups were withdrawn because of adverse events. One of those withdrawn on enalapril had angioneurotic oedema. Three patients developed rises in serum creatinine to over 150 mmol 1-1 and serum urea to over 10 mmol l-1, two in the enalapril group, but only after the addition of the diuretic. 5 Compliance was at least 95% in 85% of the enalapril patients and in 65% of those taking nifedipine. 6 Thus, enalapril 10-40 mg once daily and nifedipine retard 10-40 mg twice daily produce comparable blood pressure control in mild-moderate essential hypertension. Mainly vasodilator-type adverse events proved troublesome for some patients on nifedipine and were associated with diminished compliance and a higher withdrawal rate. Overall, the two agents showed good and comparable safety profiles in these selected patients.
Keywords enalapril nifedipine hypertension efficacy tolerability safety
203
204
D. Maclean, L. E. Ramsay & P. J. Richardson
Introduction
Methods
The widespread availability and increasi acceptance of the angiotensin converti enzyme (ACE) inhibitors and the calcium cha nel blockers has greatly increased the choice antihypertensive therapies. The two class have differing modes of action and are genera characterised by different adverse effec However, they share some common featur their main effect is to dilate arterioles, they a relatively free of adverse metabolic effects a despite their promise, no long term studies end point data are available to document th long term safety and ability to prevent strok or other cardiovascular events. Surprisinj there have been very few direct comparisons these two classes reported. Enalapril, a or daily non-sulphydryl ACE inhibitor and t calcium channel blocker nifedipine in a reta formulation, given twice daily, are now bc widely used antihypertensive therapies and sc is both of interest and relevance to comp; directly these two agents. Three critical e ments of the comparison should be that it objective, i.e., double-blind, of sufficient du tion to allow adequate time for any adve effects to become apparent and thirdly that I study should be of sufficient size and statisti power to detect differences between the tre ments. We have therefore conducted a 6 mo double-blind comparison of these two agents 128 patients with mild to moderate essen hypertension.
Three centres took part in a randomised, double-blind, double-dummy, parallel group study. Men and women aged between 18-70 years, whose sitting diastolic blood pressure was within the range 95-125 mm Hg at the end of the placebo run-in were eligible for the study. They were recruited to the study if their previous therapy had proved ineffective or was inappropriate because of unwanted effects. Intolerance to, or lack of efficacy of either drug class in the past, were reasons for exclusion. Patients with malignant hypertension, those who had had a myocardial infarction or cerebrovascular event within the past 6 months, or any contraindication to either of the trial treatments, those with heart failure requiring maintenance diuretics or known or suspected renovascular disease were excluded from the study, as were women of reproductive potential. Informed patient consent was obtained and the study had ethics committee approval in each of the participating centres.
Study protocol (see Figure 1) Eligible patients were given a 2-4 week course of placebo drugs (single-blind), during which any previous antihypertensive therapies (Table 1) were withdrawn according to manufacturer's recommendations. At week 0, patients were randomized and assigned an allocation number. Dosage of drug was initiated at 10 mg once daily + Hydrochlorothiazide
E40 mg once
12.5, 25, 50 mg
E20 mg once daily Enalapril 10 mg once daily Placebo
Monotherapy
(
i
± Diuretic -
Nifedipine 10 mg twice daily N20 mg twice daily N40 mg twice daily ± Hydrochlorothiazide 12.5, 25, 50 mg to
I
Week -4 Visit 1 Figure 1 Study design
Week 0 Visit 2
Week 2 Visit 3
Week 4 Visit 4
Week 8 Visit 5
Week 24 Visit 9
Enalapril and nifedipine in hypertension
205
Table 1 Previous antihypertensive therapy Previous therapy
n
None Diuretic
46 11 18 ,B-adrenoceptor blocker ACE-inhibitor 18 Calcium antagonist 8 Diuretic + ,-adrenoceptor blocker 10 4 Diuretic + ACE-inhibitor 1 Diuretic + calcium antagonist 3 Calcium antagonist + ACE-inhibitor Calcium antagonist + ,3-adrenoceptor blocker 5 1 Hydralazine + j3-adrenoceptor blocker 1 Diuretic + ACE-inhibitor + calcium antagonist Diuretic + ACE-inhibitor + 3-adrenoceptor blocker 1 1 Methyldopa
with enalapril and 10 mg twice daily with nifedipine retard. However, to comply with data sheet recommendations, a lower dose of enalapril, 5 mg, was used on the first day only of active treatment. At the end of weeks 2 and 4, dosage of the trial medication was doubled if the dual blood pressure targets of < 150 mm Hg systolic and < 90 mm Hg diastolic in the sitting position, had not been achieved. At the end of 8 weeks monotherapy, patients whose sitting blood pressure had still not achieved these same target levels had hydrochlorothazide added to their trial medication starting with a dosage of 12.5 mg, titrating at 4 weekly intervals, if necessary, to a maximum of 50 mg at week 16. If the patients' blood pressure had still not achieved the target levels at week 20, a third antihypertensive of the physician's choice could be added. The interval between dose titrations could be shortened if a patient's sitting diastolic blood pressure was > 120 mm Hg. Furthermore, if it was felt that the appearance of an adverse event was dose-related, the dose titration was staggered or reversed. The study was conducted on a double-blind basis using a double-dummy technique and treatment was continued for 24 weeks. For each individual all assessments were made at approximately the same time of day. Blood pressure, heart rate and weight were recorded at every visit. Blood pressure was measured using a Hawksley random zero sphygmomanometer and recording phase V diastolic pressure. Two readings were taken with the patient sitting following a 5 min rest period and the mean value recorded. Standing blood pressure was measured after standing for 2 min. Heart rate was measured at
the wrist at the same time intervals. In addition, concurrent illnesses and details of concomitant drug therapy were recorded at every visit.
Patients were withdrawn from the study if at any time there were intolerable side-effects, patient non-compliance or lack of therapeutic effect (i.e., sitting blood pressure > 200/125 mm Hg despite titration to maximum dose levels and addition of diuretic). The reasons for all withdrawals were recorded. Compliance was assessed by counting the tablets at each visit and the tolerability of the two treatments was assessed by the response to a standard nonleading question at every visit. Laboratory assessments were performed at each visit for haematology and biochemistry.
Statistical analysis Sample size for the study was calculated to detect a 5 mm Hg difference in final sitting diastolic blood pressure between the two groups. Assuming a standard deviation of diastolic blood pressure of 10 mm Hg, 65 patients per group were calculated to be required to detect such a change in BP with a probability of 80% at the 5% significance level. Efficacy data were analysed at week 0 (baseline), week 8, (end of 8 weeks monotherapy), and week 24 (end of study). Blood pressure changes during the first 8 weeks monotherapy were investigated further, using analysis of variance to examine possible factors which might cause variation in the results. A chi-squared test was used to compare the treatment groups with respect to the number of patients withdrawn from the study.
206
D. Maclean, L. E. Ramsay & P. J. Richardson
Results A total of 128 patients were enrolled into the study. Characteristics of patients at randomisation to enalapril (n = 65) or nifedipine (n = 63) are shown in Table 2. The groups were comparable in their baseline parameters, including origin, sex, duration of known hypertension and baseline blood pressure values. The mean age of the enalapril group was higher than that of the nifedipine group, but the overall ranges were similar. Body weight did not alter significantly in either group during the course of the study. The time interval following the last dose of medication at which blood pressure measurements were recorded, was comparable in the two treatment groups, 2.98 h in the enalapril group and 3.22 h in the nifedipine group. Compliance as judged by tablet counts showed that 85% of patients treated with enalapril versus 65% of patients treated with nifedipine achieved a compliance of at least 95%. With the exception of only one patient per group, all patients had achieved a compliance level of at least 80%.
Blood pressure End dose titration (monotherapy) Following 8 weeks monotherapy, at which time patients reached the maximum titrated or tolerated dosage, substantial decreases in blood pressure were recorded in both treatment groups (Table 3). All mean changes from baseline (both sitting and standing), within the treatment groups were highly significant (P < 0.001). The sitting blood pressure reduction was 18/14 mm Hg in the
enalapril group and 20/14 mm Hg in the nifedipine treated group, with no statistically differences between the two. The standing blood pressure reduction was 16/13 mm Hg in the enalapril treated group and 22/17 mm Hg in the nifedipine treated group. These greater decreases in standing systolic and diastolic blood pressures in the nifedipine group were significant (P = 0.02 and P = 0.01 respectively). An analysis of variance was used to elucidate the effect of age, treatment group, investigator and baseline blood pressure on the changes seen during monotherapy. Only the effect of baseline blood pressure was shown to influence the results. The estimates of treatment group differences and their confidence intervals are shown in Table 4. The differences in sitting blood pressure between groups were comparable to those shown using the ttest analysis, i.e., not significant, but the between group differences in standing blood pressure were again significant, but at a reduced level of significance (i.e., 10% level only). Monotherapy + hydrochlorothiazide Between weeks 8 and 24 (end of 8 weeks monotherapy and end of study), all mean changes within treatment groups were highly significant (P < 0.001) and no statistical differences between the two groups for any blood pressure parameter could be shown. However, these results include patients who remained on monotherapy throughout the study, together with those who received additional hydrochlorothiazide following week 8. Further analysis was therefore performed on these sub-
Table 2 Demographic details
Total number of patients Male Female Age (years) Mean Range s.d. Origin Caucasian Negro Other Duration of hypertension Mean Range (months) s.d.
Enalapril
Nifedipine
65 38 27
63 36 27
53.0
Total 128 74 (58%) 54 (42%)
49.0
25.0-70.0
23.0-70.0
10.6
10.8
59 5 1
53 8 2
59.6
49.6
2.0-336.0
1.0-216.0
70.1
46.6
112 (88%) 13 (10%) 3 (2%)
Enalapril and nifedipine in hypertension
207
Table 3 Mean (s.d.) measurements of blood pressure (mm Hg) at baseline, in patients receiving enalapril or nifedipine monotherapy (week 8) and ± hydrochlorothiazide (HCTZ) at week 24
Nifedipine
Enalapril
Standing
Sitting
Standing
Sitting
Week number
Diastolic BP
Systolic
Diastolic
Systolic
BP
BP
BP
BP
Diastolic BP
Systolic BP
Diastolic BP
Randomisation (week 0)
160 (18)
104 (18)
159 (17)
108 (8)
161 (20)
105 (8)
162 (20)
110 (9)
End-dose titration
142 (22)
91 (11)
142 (21)
95 (11)
141 (16)
91 (10)
140 (16)
93 (10)
129 (14)
85 (8)
129 (16)
89 (8)
133 (14)
86 (7)
131 (14)
90 (9)
Systolic
(Monotherapy) (week 8) End of study monotherapy ± HCTZ
(week 24)
Table 4 Mean (s.d.) reductions in blood pressure (mmHg) from baseline at week 8 (end of monotherapy) and a comparison of the effects of enalapril and nifedipine Measurement
Diastolic pressure Sitting
Mean changes Enalapril Nifedipine
Mean of difference 95% confidence intervals
P value
14.0 (11.0) 12.7 (10.5)
13.9 (11.6)
Standing
17.2(11.5)
0.1 4.5
-4.1 to 3.9 0.6to 8.4
NS 150 mm Hg systolic and/or > 90 mm Hg diastolic. When these incomplete responders were assessed for tablet compliance (using tablet counts), two patients only, one from each group, failed to take at least 80% of the doses of study medica-
D. Maclean, L. E. Ramsay & P. J. Richardson
208
200
200
180
180
E 160 E
160
a)
140
140
-a 120
120
-0 c 100
100
:
Un Un a)
0 0
_-
U)
80
T
80
Baseline
End of study End of 8 weeks
Baseline End of 8 weeks
Monotherapy
End of study
+ Hydrochlorothiazide
200
200
180
180
EE 160
160
I
a)
140
140
0120
120
100
100
80
80
u) cn
a)
-0
0 .0 0)
-c
T
U)
_
Baseline
_
_
End of study End of 8 weeks
Monotherapy
Baseline
End of study End of 8 weeks
+ Hydrochlorothiazide
Figure 2 Changes in blood pressure (mm Hg) from baseline in the subgroup of patients continuing on monotherapy compared with those in the subgroup that required additional hydrochlorothiazide enalapril, * nifedipine, * P < 0.05
Enalapril and nifedipine in hypertension tion as directed. Of the remaining 12 incomplete non-responders (six per group), four of six in the enalapril group and two of six in the nifedipine group showed signs of excessive alcohol consumption (as indicated by elevated MCV levels (> 98 f 1-1).
209
fatigue/drowsiness/tiredness were reported with similar frequencies in both treatment groups. The total number of events experienced on treatment was 120 in the enalapril group vs 166 in the nifedipine treated group.
Safety Heart rate No heart rate changes of clinical relevance occurred in either treatment group.
Withdrawals A total of six of 65 patients (9%) in the enalapril group were withdrawn during the course of the study, five (8%) during the first 8 weeks of the trial. In the nifedipine group a total of 14 of 63 patients (22%) were withdrawn, five (8%) during the initial 8 weeks (Table 5). Of the six patients withdrawn in the enalapril group, five were withdrawn due to adverse events and one because of poor compliance leading to lack of therapeutic effect (i.e. sitting blood pressure > 200/125 mm Hg despite titration to maximum dose levels). In the nifedipine group all fourteen patients were withdrawn due to adverse events. Seven of these patients stopped taking the tablets themselves because they found vasodilator-type adverse events intolerable. In only one case in each of the treatment groups did an adverse event leading to withdrawal first occur on the addition of hydrochlorothiazide. In all other cases the adverse events leading to withdrawal were first reported whilst the patient was receiving monotherapy only. The greater frequency of withdrawal in the nifedipine group was significant (X2 = 5.22, P
150 mmol 1-1 and serum urea > 10 mmol l-1, but these did not occur until after the addition of hydrochlorothiazide. No other clinically significant changes were noted in any of the additional routine biochemical and haematological parameters monitored. Discussion
Angiotensin converting enzyme inhibitors and calcium antagonists are now widely used in the treatment of essential hypertension as alternatives to thiazide diuretics and 3-adrenoceptor antagonists. Subject to demonstration of their comparable efficacy, the success of these agents in long-term treatment is likely to depend largely on their tolerability and safety profiles. Their ability over the long-term to prevent strokes or other cardiovascular events will take time to ascertain, but consistently good BP control is likely to be the most important determining factor in achieving this goal. In some patients, twice daily nifedipine may be more effective than low dose captopril given twice daily, but tolerability problems were prominent with the calcium antagonist (Klein et al., 1986; Salvetti et al., 1987); there were no important safety concerns with either drug over the short-term in these fixed dose studies. On the other hand, two variable dose studies comparing the once daily long-acting ACE-inhibitor lisinopril with twice daily nifedipine retard over 3 months (Morlin et al., 1987) and 6 months (Richardson et al., 1987) respectively showed both drugs to be equally effective in controlling hypertension, but again significantly more tolerability problems occurred with the calcium antagonist monotherapy: as with the captopril studies, no important safety concerns arose in either study. Enalapril, which is the most widely used long-acting ACE-inhibitor, has been shown in two very small studies (Gilchrist et al., 1988; Morgan et al., 1988), one confined to the elderly
210
D. Maclean, L. E. Ramsay & P. J. Richardson
Table 5 Withdrawals and adverse events
Number of patients randomized
Enalapril
Nifedipine
65
63
1
0
4 + (1)#
13 + (1)#
Withdrawals due to lack of efficacy Number of patients Due to major adverse events Number of patients Details of major adverse events* necessitating withdrawal Flushing/Erythema Oedema Headache Fatigue/Drowsiness/Tiredness Malaise Hypotension Faintness/Dizziness Tachycardia/Palpitations Angioneurotic oedema Panic attack Nausea Shakiness Leg pains Thirst Minor adverse events* No treatment change required Number of patients
0 0 1 1 + (1)# 0 1 1 0 1 0 1 + (1)# 0 1 0
10 9 5 5 3 0 1 2 + (1)# 0 1 1
33 + (4)#
31 + (4)#
(1)# 0 1
Details of minor adverse events
Flushing/Erythema Oedema Headache Fatigue/Drowsiness/Tiredness Malaise Hypotension Faintness/Dizziness Tachycardia/Palpitations Nausea Gastrointestinal upset
Angina Dry cough
10 + (4)# 5 + (1)# 12 + (3)# 6
7
(1)# 10 6 + (3)# 1 1 1 0 2 + (2)# 0 1
(1)# 0 3 2 1 1 + (1)# 2 + (1)# 0
(3)#
Number of adverse events on placebo Number of patients
8
9
No adverse events Number of patients
23
14
*
Most patients experienced more than one adverse event.
( )# These figures indicate that the adverse events occurred only
chlorothiazide
on
the addition of hydro-
Enalapril and nifedipine in hypertension (Gilchrist et al., 1988), to have comparable antihypertensive efficacy with that of nifedipine, where again there was a hint that tolerability may be better to the ACE-inhibitor than on the calcium antagonist (Gilchrist et al., 1988). Neither study had the power to give reliable information on the comparative efficacy, tolerability and safety of the two drugs, and neither was long-term. Enalapril may have some advantages in efficacy over another calcium antagonist, diltiazem (Brunner et al., 1987) but the differences are of doubtful
clinical significance. Our study had sufficient power to determine the relative long-term efficacies of the two drugs and was of sufficient duration to determine reliably their tolerability profiles and to assess the effects of any differences in tolerability on compliance and withdrawal rates. The 6 months duration of the active treatments is sufficient to indicate, but not to prove, the likely long-term safety of the two agents. Our results confirm that within the limitations of our trial design the two drugs had similar efficacy in our patients, but nifedipine proved superior in terms of standing BP control. The addition of hydrochlorothiazide in inadequate responders to either monotherapy produced a significantly better reduction in systolic BP in those on enalapril than in those on nifedipine. Tolerability was much better in the enalapril group than in the nifedipine group, with conse-
211
quently better compliance and many fewer withdrawals. One patient in the enalapril group withdrew because of angioneurotic oedema; other withdrawals because of major adverse events were because of the intensity of symptoms or signs but none was a hazard to the patient. Three patients showed deterioration in renal function after the addition of hydrochlorothiazide, two of them in the enalapril group. We conclude that each monotherapy provides good BP control, the calcium antagonist having the added advantage of better standing control. Enalapril was particularly welltolerated with significantly few withdrawals or concerns over its short and long-term safety in the selected group of patients. For some patients on nifedipine monotherapy, vasodilator-type adverse events were sufficiently troublesome to affect compliance and even to necessitate withdrawal, but there were no concerns over safety. Many of these adverse events experienced on nifedipine could be ameliorated through the complementary co-prescription of a ,-adrenoceptor blocker (Maclean et al., 1988), though this was not re-tested in this study. One cohort of our patients participated in an extension of this protocol, in which they crossed over to the alternative agent, still double-blind, for a further 6 months. The results of this cross-over comparison will be made available in a separate report.
References Brunner, H. R., Bidiville, J., Waeber, P., Porchet, M., Nussberger, J. & Waeber, B. (1987). Angiotensin-converting enzyme inhibitor versus calcium antagonist in the treatment of hypertension. Nephron, 47 (Suppl. 1), 87-89. Gilchrist, N. L., Nicholls, M. G., Ewer, T. C., Livesey, J. H. & Sainsbury, R. (1988). A comparison of long acting nifedipine and enalapril in elderly hypertensives: a randomised, single-blind, cross-over study. J. Human Hypertension, 2, 33-39. Klein, W. W., Stuhlinger, W. & Mahr, G. (1986). Cross-over comparison between captopril and nifedipine. Postgrad. med. J., 62 (Suppl. 1), 108-110. Maclean, D., Mitchell, E. T., Coulson, R. R., Fitzsimmons, T. J. & McDevitt, D. G. (1988). Atenolol-nifedipine combinations compared to atenolol alone in hypertension: efficacy and tolerability. Br. J. clin. Pharmac., 25, 425-431. Morgan, T., Anderson, A. & Hopper, J. (1988). Enalapril and nifedipine in essential hypertension; synergism of the hypotensive effects in com-
bination. Clin. exp. Hyper. - Theory & Prac., A10 (Suppl. 5), 779-789. Morlin, C., Baglivo, H., Boeijinga, J. K., Breckenridge, A. M., Clement, D., Johnston,
G.D.,Klein,W.,Kramer,R.,Luccioni,R.,Meurer, K. A., Richardson, P. J., Rosenthal, J., Six, R. & Witzgall, H. (1987). Comparative trial of lisinopril and nifedipine in mild to severe essential hypertension. J. cardiovasc. Pharmac., 9 (Suppl. 3), S48-S52. Richardson, P. J., Meany, B., Breckenridge, A. M., Grimmer, S. F. M., Johnston, G. D. & Kondowe, G. (1987). Lisinopril in essential hypertension: a six month comparative study with nifedipine. J. Human Hypertension, 1, 175-179. Salvetti, A., Innocenti, P. F., lardella, M., Pambianco, F., Saba, G. C., Rossetti, M. & Botta, G. F. (1987). Captopril and nifedipine interactions in the treatment of essential hypertensives: a crossover study. J. Hypertension, 5 (Suppl. 4), S139-S142.
(Received S January 1990, accepted 9 April 1990)
