A randomised, double-blind comparison of the angiotensin II receptor ...

Journal of Human Hypertension (1998) 12, 203–208  1998 Stockton Press. All rights reserved 0950-9240/98 $12.00

ORIGINAL ARTICLE

A randomised, double-blind comparison of the angiotensin II receptor antagonist, irbesartan, with the full dose range of enalapril for the treatment of mild-tomoderate hypertension A Mimran1, L Ruilope2, L Kerwin3, M Nys4, D Owens3, K Kassler-Taub3 and M Osbakken3 1

Lapeyronie Hospital, Montpellier, Cedex 5, France; 2Unidad de Hipertension Arterial Servicio de Nefrologia Hospital Universitario 12 de Octubre, Madrid, Spain; 3Bristol-Myers Squibb, Princeton NJ, USA and 4Waterloo, Belgium

Objective: To compare the anti-hypertensive efficacy, safety, and tolerability of irbesartan with those of the full dose range of enalapril in patients with mild-to-moderate hypertension. Design and methods: A total of 200 patients were randomised to irbesartan 75 mg or enalapril 10 mg (once daily). Doses were doubled at Weeks 4 and/or 8 if seated diastolic blood pressure (DBP) was ⭓90 mm Hg. Trough blood pressure was measured after completion of a 4to 5-week placebo lead-in period and again after 2, 4, 8, and 12 weeks of treatment. Main outcome measures: Efficacy was evaluated by determining the change from baseline in trough seated blood pressure and the proportion of patients normalised (seated DBP ⬍90 mm Hg) at Week 12. Safety and tolerability were assessed by adverse events reported by physicians, by patients in response to a specific-

symptoms questionnaire, by open-ended questioning of patients by physicians, and by clinical laboratory evaluations. Results: Both treatments significantly lowered blood pressure with no significant difference in efficacy between treatment groups. At Week 12, the percentage of patients titrated to either enalapril 40 mg or irbesartan 300 mg was 24% and 28%, respectively. The frequency of overall adverse events was similar in both groups. The incidence of cough in the enalapril and irbesartan groups was 17% and 10%, respectively. In contrast to other AII receptor antagonists, there was no change in uric acid concentrations with irbesartan. Conclusions: Irbesartan was as effective as the full dose range of enalapril. Irbesartan also demonstrated an excellent tolerability profile.

Keywords: angiotensin II receptor antagonist; irbesartan; angiotensin-converting enzyme inhibitor; enalapril; hypertension

Introduction The renin-angiotensin system (RAS) plays a crucial role in regulating blood pressure. High concentrations of angiotensin II (AII) are associated with elevated systemic blood pressure. The pressor effect of AII appears to be mediated by the AT1 receptor subtype of AII.1–3 One approach to lowering systemic blood pressure is to reduce the level of AII, for example by inhibiting angiotensin-converting enzyme (ACE)—the enzyme responsible for AII production.4–6 However, AII is also produced through non-ACE-dependent pathways;7 thus, treatment with ACE inhibitors may not completely prevent AII Correspondence: Dr Mary Osbakken, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, J4017, Princeton, NJ 08543-4000, USA Received 15 September 1997; revised and accepted 28 November 1997

production. Moreover, because ACE is also involved in the breakdown of bradykinin, inhibition of ACE tends to increase circulating levels of this peptide,8–10 which may account for the increased incidence of cough reported in up to 20% of patients treated with ACE inhibitors.11–13 All receptor antagonists, however, inhibit the potent pressor effect of AII by blocking its binding to the receptor. Therefore, it is expected that they will effectively lower systemic blood pressure without inducing adverse effects, such as cough, that are associated with ACE inhibitors. Irbesartan (BMS-186295; SR 47436; Bristol-Myers Squibb/Sanofi) is a potent, long-acting AII receptor antagonist, with high selectivity for the AT1 receptor subtype.14,15 Results of recent clinical studies show that irbesartan safely and effectively lowers blood pressure within 1 week in patients with mild-tomoderate hypertension.15,16 The objective of this study was to compare the

Irbesartan vs enalapril in hypertension A Mimran et al

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anti-hypertensive efficacy, safety, and tolerability of irbesartan with those of the full dose range of the ACE inhibitor enalapril, in patients with mild-tomoderate hypertension.

despite doubling of dose at Week 4, doses were doubled again (irbesartan was increased from 150 mg to 300 mg; enalapril was increased from 20 mg to 40 mg).

Materials and methods

Clinical evaluation

Patients

At enrolment a full medical history and chest X-ray were performed, and patients were given a complete physical examination. Blood and urine samples were collected for routine laboratory analysis, and a pregnancy test, if necessary, was obtained. On Days 22 or 29, blood and urine samples were again collected, a 12-lead electrocardiogram (ECG) was performed, and, if pregnancy was suspected, a pregnancy test was obtained. During each lead-in visit, blood pressure and heart rate were measured, and patient compliance was assessed. Blood pressure was measured with a standard, calibrated mercury sphygmomanometer. The mean of three readings, taken 1 min apart, was used for analysis of efficacy. During the double-blind treatment period, routine visits were scheduled for Weeks 0, 2, 4, 8, and 12 (±3 days). At each visit, the patient’s weight, seated systolic blood pressure (SBP), seated DBP, standing SBP, standing DBP, seated heart rate (HR), and standing HR were measured.

Patients ⭓18 years of age with mild-to-moderate hypertension (seated diastolic blood pressure (DBP) 95–110 mm Hg) were included in this study. Exclusion criteria were limited to concomitant diseases or medication that would present safety hazards or interfere with the assessment of the safety or efficacy of the study medications. Women who were pregnant, lactating, or of childbearing potential were also excluded. This study was approved by the local ethics committees, and all patients gave their informed consent at the time of enrolment. Study protocol This study was a multicentre, randomised, doubleblind trial conducted in 51 centres in France and Spain. The first study phase consisted of a 4- to 5week, single-blind, placebo lead-in period. The second phase consisted of a 12-week, double-blind treatment period that began immediately after eligibility was established. All blood pressure measurements were obtained with patients in the seated position except where otherwise noted. During the leadin period, visits were scheduled for Days 1, 15, 22, and 29 (an additional visit was scheduled for Day 36 if necessary, see below). To be eligible for randomisation into the double-blind phase of the study, patients were to have completed all pretreatment evaluations (described below) and met all inclusion and exclusion criteria. At each visit during the leadin and treatment periods, enough medication was dispensed to last until the next scheduled visit. Investigators checked return bottles to assess patient compliance. This method of estimating patient compliance has been used in similarly designed studies of anti-hypertensive agents (eg, see reference 17). Patients had to demonstrate good compliance (expected lead-in medication consumption ⬎80% and ⬍120%) to be eligible for randomisation. In addition, DBP on Days 22 and 29 had to be between 95 mm Hg and 110 mm Hg inclusive, and the values for each day must not have differed by more than 8 mm Hg. If a patient failed to meet blood pressure criteria on Day 22, an optional visit on Day 36 was allowed, and eligibility was determined based on DBP values for Days 29 and 36. Patients who qualified for the treatment phase of the study were randomised to receive either irbesartan 75 mg (n = 98) or enalapril 10 mg (n = 102). Patients were instructed to take one capsule once per day between 6 am and 10 am. If DBP at trough (ie, 24 ± 3 h after the previous dose) was ⭓90 mm Hg at Weeks 4 or 8, the dosage of study medication was doubled (irbesartan was increased from 75 mg to 150 mg; enalapril was increased from 10 mg to 20 mg). If DBP remained ⭓90 mm Hg at Week 8

Evaluation of safety Safety was assessed by evaluating the incidence of clinical and laboratory adverse events. Blood and urine samples were collected and a brief physical examination was performed at Weeks 4, 8, and 12. At Week 12, a 12-lead ECG was obtained. Patients were monitored for adverse events by examination and by general open-ended questioning during each lead-in and treatment-period visit. At Week 12, patients were asked specifically whether they had experienced any of the following events during the treatment period: cold extremities, drowsiness/ sleepiness, fatigue/tiredness/lethargy, headache, impotence, weakness, dizziness, cough, or rash. Adverse events were further categorised as follows: adverse drug experiences were those adverse events considered by the investigator to be related, possibly related, probably related, or of unassessable relationship to the study medication. Serious adverse events were those adverse events that were either fatal, life threatening, permanently disabling, resulted in inpatient or prolonged hospitalisation, a congenital anomaly, cancer, or overdose. Statistical analysis For patient demographic and baseline efficacy measures, quantitative data were analysed using a oneway analysis of variance (ANOVA). Qualitative data were assessed using a Fisher’s Exact Test. Changes from baseline in blood pressure and heart rate within treatment regimens were analysed using a paired t-test. Changes from baseline in blood pressure and heart rate between treatment regimens were analysed using an analysis of covariance (ANCOVA). The proportion of patients whose blood


pressure was normalised (DBP ⬍90 mm Hg) at each timepoint was analysed using a Cochran-MantelHaenszel chi-squared test stratified by site. All statistical tests were two-tailed, and P values ⬍0.05 were considered significant. In addition, a retrospective examination of the effects of incremental dose increases on changes in blood pressure at each timepoint was performed. Patients were summarised according to those who remained on the lowest dosage of study medication throughout the study, those whose dosage was doubled once at either Weeks 4 or 8, and those whose dosage was doubled at Week 4 and again at Week 8. No statistical tests were performed.

Results Patient characteristics A total of 200 patients were randomised to treatment. There were no statistically significant or clinically important differences between treatment regimens for any of the demographic or baseline efficacy values (Table 1). Of the patients randomised to treatment, 124 (62%) had previously received anti-hypertensive medication within 1 months prior to the beginning of this study (ACE inhibitors, 35%; diuretics, 17%; ␤-blockers, 13%; calcium channel blockers, 12%). Nine patients (three in the irbesartan group; six in the enalapril group) withdrew from the study following randomisation; four because of adverse events (one in the irbesartan group; three in the enalapril group; see Safety and Tolerability section); three at the patient’s request (two in the irbesartan group; one in the enalapril group); and two patients, both from the enalapril group, were lost to followup. Anti-hypertensive efficacy Blood pressure: Table 2 shows the percentage of patients receiving different doses of study medication at Weeks 4, 8, and 12. At Week 12, 42% of Table 1 Patient demographic and baseline characteristics* Enalapril (n = 102)

Irbesartan (n = 98)

Gender (%) Male Female

49 51

54 46

Age (years)

58.4 ± 10.8

58.2 ± 11.8

70 30 6

72 28 9

Baseline seated DBP (mm Hg)

101.8 ± 4.2

101.0 ± 4.1

Baseline seated SBP (mm Hg)

164.9 ± 12.8

163.9 ± 12.5

72 28

76 24

73.7 ± 9.2

74.1 ± 9.6

⬍65 years (%) ⭓65 years (%) ⭓75 years (%)

DBP subgroup (%) ⬍104 mm Hg ⭓104 mm Hg Sitting HR (beats per min) *Data expressed as mean ± s.d.

patients in the irbesartan group were still receiving the lowest dose (irbesartan 75 mg) compared with 36% of patients in the enalapril group (enalapril 10 mg). A total of 40 and 35 patients received irbesartan 75 mg and enalapril 10 mg, respectively, for the entire duration of the study; 28 and 38 patients received irbesartan titrated to 150 mg or enalapril titrated to 20 mg, respectively; 27 and 23 patients received irbesartan titrated to 300 mg or enalapril titrated to 40 mg, respectively. The mean changes from baseline in SBP and DBP at each timepoint are shown in Figure 1. Both treatment with irbesartan and enalapril resulted in statistically significant decreases from baseline in trough SBP and trough DBP at all measured timepoints (Weeks 2 to 12), as well as in trough standing SBP and trough standing DBP (data not shown). There were no statistically significant differences between the two treatment regimens with respect to decrease from baseline in DBP or SBP. This similarity between treatment groups extended across all timepoints examined (Figure 1). No clinically important changes from baseline were observed in seated HR or standing HR at any timepoint for either treatment regimen (data not shown). Changes from baseline in all efficacy variables were consistent for both genders and age groups. Table 3 shows the baseline and on-therapy DBP at Weeks 4, 8, and 12 for patients who were maintained on the lowest dosage of study medication, and for those who required dosage titration because DBP remained above 90 mm Hg at the lower dosage. For patients who received either irbesartan 75 mg (40/95; 42%) or enalapril 10 mg (35/96; 36%) throughout the study, DBP decreased by approximately 15 mm Hg within 4 weeks with no further decrease at Weeks 8 or 12. In patients whose dosage of study medication was doubled only once to irbesartan 150 mg (28/95; 29%) or enalapril 20 mg (38/96; 40%) mean DBP decreased by approximately 8 mm Hg while patients were receiving the lowest dosages, but mean DBP was still above 90 mm Hg. Doubling the dosage to irbesartan 150 mg or enalapril 20 mg was associated with an additional reduction of 5 mm Hg between Weeks 4 and 8 for both treatment groups, resulting in a total decrease from baseline of 13 mm Hg with little change thereafter. Mean DBP at Week 8 for both treatment groups was ⬍90 mm Hg. In patients whose dosage of study medication was doubled twice to a final dosage of irbesartan 300 mg (27/95; 28%) or enalapril 40 mg (23/96; 24%), DBP decreased by 5 mm Hg and 1 mm Hg in the enalapril and irbesartan groups, respectively, while patients were receiving the lowest dosages. Doubling the dosage once at Week 4 and again at Week 8 was associated with further reductions in DBP of about 6 mm Hg in both treatment groups, resulting in a total decrease from baseline of approximately 11 mm Hg and 8 mm Hg in the enalapril and irbesartan groups, respectively, at Week 12. In general, mean baseline DBP was higher in patients who required dosage titration either once or twice compared with those of patients who were maintained on the lowest dosages of study medication (Table 3). Changes in SBP

205


206

Table 2 Percentage of patients receiving different doses of enalapril irbesartan at Weeks 4, 8, and 12 Enalapril

Week 4 Week 8 Week 12

Irbesartan

n

10 mg (%)

20 mg (%)

40 mg (%)

n

75 mg (%)

150 mg (%)

300 mg (%)

101 100 96

100 46 36

– 54 40

– – 24

98 96 95

100 46 42

– 54 30

– – 28

Safety and tolerability There was no difference in the incidence of overall adverse events reported in each treatment group (43%, enalapril; 45%, irbesartan) (Table 4). The most common adverse events in both treatment groups were cough and headache. One patient in the enalapril group was withdrawn from the study because of cough and weakness. Cough was reported as an adverse event in 10% of patients in the irbesartan group compared with 17% of patients in the enalapril group (not statistically significant). One patient (1%) in the irbesartan group and three patients (2.9%) in the enalapril group discontinued therapy because of adverse events (Table 4). Of the three patients who discontinued treatment in the enalapril group, one patient discontinued as a result of cough and weakness, one patient as a result of musculoskeletal pain and oedema which was sub¨ sequently diagnosed as Sjogren’s disease, and one patient as a result of tinnitus, dizziness, and an episode of instability. The patient who discontinued therapy in the irbesartan group experienced a severe, but non-serious hypertensive crisis after 69 days of treatment, despite having been titrated to the highest dosage (300 mg). This patient’s compliance was inconsistent throughout the study, ranging form slight undercompliance at Week 8, to moderate overcompliance at Week 12. Analysis of serum concentrations of potassium and uric acid revealed no statistically significant changes from baseline (Table 5).

Discussion Figure 1 Change from baseline in seated SBP (a) and seated DBP (b). There were no significant differences between treatment groups at any timepoint.

were consistent with those for DBP (data not shown). Therapeutic response: At Week 12, 66% of patients treated with irbesartan were normalised (trough DBP ⬍90 mm Hg) compared with 63% in the enalapril group. The percentage of patients normalised was similar at all timepoints in both treatment groups (Figure 2).

This study is the first to compare an AII receptor antagonist to the full dose range of the ACE inhibitor enalapril in patients with mild-to-moderate hypertension. Monotherapy with irbesartan at dosages up to 300 mg was as effective in lowering blood pressure as monotherapy with enalapril over the entire approved dose range of enalapril (ie, up to 40 mg). Reductions in seated and standing blood pressures were evident within 2 weeks and treatment with irbesartan for 12 weeks normalised blood pressure in 66% of hypertensive patients compared with 63% of patients in the enalapril treatment group. Maximum response was achieved by 4 weeks for patients who remained on the lowest dosage of irbesartan and remained constant thereafter. For patients with moderate response at the lowest dosage, or higher baseline BP, there was a greater blood


207

Table 3 Mean DBP at baseline and at Weeks 4, 8, and 12 for patients receiving different dose regimens Patients who remained on lowest dosage Seated DBP (mm Hg)

Patients whose dosage was doubled once

Patients whose dosage was doubled twice

enalapril (n = 35)

irbesartan (n = 40)

enalapril (n = 38)

irbesartan (n = 28)

enalapril (n = 23)

irbesartan (n = 27)

Baseline

99.6

99.3

101.4

101.1

105.7

103.3

Week 4 Week 8 Week 12

85.8 84.1 84.4

83.9 84.1 83.7

93.5 88.4 85.9

93.4 87.8 88.0

100.6 99.2 94.9

102.1 98.6 95.7

Figure 2 Therapeutic response at Weeks 2, 4, 8, and 12.

Table 4 Safety results of enalapril and irbesartan Patients (%)

Adverse drug experiences Cough as an adverse drug experience Adverse events Serious adverse events Discontinuations

Enalapril (n = 102)

Irbesartan (n = 98)

26 15

19 7

43 1.0 2.9

45 4.1 1.0

Table 5 Mean change (95% confidence intervals) from baseline in laboratory parameters at Week 12 Serum concentration Creatinine (mg/dL) Potassium (mEq/L) Uric acid (mg/dL) Hemoglobin (g/dL)

Enalapril (n = 96) 0.03 (0 to 0.06) −0.01 (−0.11 to 0.09)

Irbesartan (n = 94) 0.01 (−0.02 to 0.04) 0 (−0.0 to 0.10)

−0.03 (−0.20 to 0.15)

−0.11 (−0.33 to 0.11)

−0.16 (−0.27 to −0.05)

−0.10 (−0.25 to 0.04)

pressure response after doubling the dosage; dosage had to be tripled in more resistant patients. Overall, blood pressure continued to decrease in both treatment groups throughout the course of the doubleblind period. Patients who required incremental increases in the dosage of irbesartan in order to achieve normalised blood pressure appeared to gain additional benefits from increased exposure, including higher dosages (see Table 3). This is consistent with results of previous studies that showed a doserelated anti-hypertensive effect of irbesartan,16 but with no dose-related increase in adverse events. In the present study, the incidence of overall adverse events, adverse drug experiences, and serious adverse events reported in each treatment group was similar, and the discontinuation rate as a result of adverse events was low in both treatment groups. The incidence of cough, as reported by patients in response to questioning by physicians using a specific symptoms questionnaire, as well as open-ended questions, was 17% in the enalapril group compared with 10% in the group treated with irbesartan. Although these percentages may appear to be excessive, using a specific symptoms questionnaire to elicit adverse events (as opposed to spontaneously reported symptoms) tends to sensitise patients to any adverse event listed on the questionnaire. This study was not designed to specifically compare the incidence of cough. Results of other studies have shown that treatment with ACE inhibitors is associated with increased incidence of cough11–13 whereas treatment with AII receptor antagonists is not.18,19 The overall database incidence of cough is 2.7% for placebo and 2.8% for irbesartan (Data on file, Bristol-Myers Squibb). In addition, another study compared irbesartan with enalapril in patients with severe hypertension. The incidence of cough was significantly lower in the group of patients treated with irbesartan compared with the group treated with enalapril.20 These findings indicate that, similar to other AII receptor antagonists, irbesartan does not induce cough. In addition, there was no significant change in uric acid concentration with irbesartan. Previous studies have shown a significant increase in uric acid concentrations with losartan.21 Angiotensin II receptor antagonists are a relatively recent development in the treatment of hypertension. A previous study comparing losartan with enalapril demonstrated comparable efficacy


208

between losartan 50 mg/day and enalapril 5 mg/day titrated to 10 mg/day.17 In a study conducted by Gradman et al,22 the effects of losartan 10 mg to 150 mg were compared with those of enalapril 20 mg in patients with mild-to-moderate hypertension. There was no significant difference in change from baseline in trough supine DBP between patients treated with losartan 10–150 mg and patients treated with enalapril 20 mg. The mean decrease in trough supine SBP was significantly greater in patients receiving enalapril 20 mg compared with that of patients receiving losartan 10 mg, 25 mg, 100 mg, and 150 mg. However, no significant difference was observed between the mean decrease in trough supine SBP of patients receiving losartan 50 mg and enalapril 20 mg. The high percentage of patients achieving blood pressure control with irbesartan, combined with its exceptional tolerability profile, suggests that irbesartan represents a valuable therapy for the long-term treatment of hypertension.

10 11 12

13 14

15 16 17

References 1 Timmermans PBMWM et al. Angiotensin II receptors and functional correlates. Am J Hypertens 1992; 5: 221S–225S. 2 Bernstein KE, Berk BC. The biology of angiotensin II receptors. Am J Kidney Dis 1993; 22: 745–754. 3 Unger T. Angiotensin II receptors: signalling pathways, cell growth and differentiation [abstract]. Am J Hypertens 1996; 9: 195A. 4 Kaplan NM. Guidelines for the treatment of hypertension: an American view. J Hypertens 1995; 13 (Suppl 2): S113–S117. 5 Laragh JH. Renin system blockade as a therapeutic strategy. Past, present, and future. Am J Hypertens 1991; 4 (pt 2): 273S–274S. 6 Kaplan NM. Treatment of hypertension: drug therapy. In: Kaplan NM (ed). Clinical Hypertension. Williams & Wilkins: Baltimore, MD, 1994, 6th edn, pp 191–280. 7 Husain A. The chymase-angiotensin system in humans. J Hypertens 1993; 11: 1155–1159. 8 Pellacani A, Brunner HR, Nussberger J. Plasma kinins increase after angiotensin-converting enzyme inhibition in human subjects. Clin Sci 1994; 87: 567–574. 9 Dzau VJ, Mukoyama M, Pratt RE. Molecular biology of

18 19

20 21

22

angiotensin receptors: target for drug research? J Hypertens 1994; 12 (Suppl 2): S1–S5. Gavras I. Bradykinin-mediated effects of ACE inhibition. Kidney Int 1992; 42: 1020–1029. Simon SR, Black HR, Moser M, Berland WE. Cough and ACE inhibitors. Arch Intern Med 1992; 152: 1698–1700. Israili ZH, Hall WD. Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophysiology. Ann Intern Med 1992; 117: 234 –242. Fletcher AE, Palmer AJ, Bulpitt CJ. Cough with angiotensin converting enzyme inhibitors: how much of a problem? J Hypertens 1994; 12 (Suppl 2): S43–S47. Cazaubon C et al. Pharmacological characterization of SR 47436, a new nonpeptide AT1 subtype angiotensin II receptor antagonist. J Pharmacol Exp Ther 1993; 265: 826–834. van den Meiracker AH et al. Hemodynamic and biochemical effects of the AT1 receptor antagonist irbesartan in hypertension. Hypertension 1995; 25: 22–29. Pool JL et al. The antihypertensive effects of irbesartan in patients with mild-to-moderate hypertension [abstract]. Am J Hypertens 1996; 9: 152A. Townsend R, Haggert B, Liss C, Edelman JM. Efficacy and tolerability of losartan versus enalapril alone or in combination with hydrochlorothiazide in patients with essential hypertension. Clin Ther 1995; 17: 911–923. ` Lacourciere Y et al. Effects of modulators of the reninangiotensin-aldosterone system on cough. J Hypertens 1994; 12: 1387–1393. Faison EP, Snavely DB, Thiyagarajan B, Nelson EB. The incidence of cough with the angiotensin II receptor antagonist (ANG II RA), losartan, is significantly less than with angiotensin converting enzyme (ACE) inhibitors (ACEI) and is similar to that of placebo [abstract]. Am J Hypertens 1994; 7 (pt 2): 34A. Larochelle P et al. Irbesartan versus enalapril in severe hypertension [abstract]. Am J Hypertens 1997; 10 (pt 2): 131A. Burnier M et al. Studies of the renal effects of angiotensin II receptor blockade: the confounding factor of acute water loading on the action of vasoactive systems. Am J Kidney Dis 1995; 26: 108–115. Gradman AH et al. A randomized, placebo-controlled, double-blind, parallel study of various doses of losartan potassium compared with enalapril maleate in patients with essential hypertension. Hypertension 1995; 25: 1345–1350.