The Long-Term Antihypertensive Activity and Tolerability of Irbesartan with Hydrochlorothiazide

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Journal of Human Hypertension (1999) 13, 683–687  1999 Stockton Press. All rights reserved 0950-9240/99 $15.00 http://www.stockton-press.co.uk/jhh ORIGINAL ARTICLE The long-term antihypertensive activity and tolerability of irbesartan with hydrochlorothiazide

P Raskin1, R Guthrie2, JM Flack3, RA Reeves4 and R Saini4 1University of Texas Southwestern Medical Center, Dallas, TX; 2The Ohio State University Medical Center, Columbus, OH; 3Harper Hospital School of Medicine, Detroit, MI; and 4Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ, USA

and ؊20.6/؊15.6 mm Hg ,(948 ؍ The long-term safety, tolerability, and antihypertensive ؊15.7 mm Hg (n -respectively. From months 2 to 12, normalis ,(898 ؍ effects of irbesartan/hydrochlorothiazide (HCTZ) were (n assessed in hypertensive patients (seated diastolic ation rates (trough SeDBP Ͻ90 mm Hg) ranged from 75– blood pressure [SeDBP] 95–110 mm Hg). Patients 85% and total responder rates (normalised or у10 (n = 1098) completing two randomised, double-blind mm Hg trough SeDBP reduction) ranged from 81–91%, trials of irbesartan alone, HCTZ alone, irbesartan/HCTZ while target BP was achieved in 65–75% of patients. At combinations, or placebo, took 1 year of open-label all time-points, most patients (у87%) were receiving therapy starting with irbesartan 75 mg/HCTZ 12.5 mg irbesartan/HCTZ alone. Eighty-two patients (7.5%) dis- once daily. If target blood pressure (BP) (Ͻ140/Ͻ90 continued the study due to adverse events, with half of mm Hg) was not achieved, the dose was titrated sequen- these events considered unrelated to study medication. tially at 2- to 4-week intervals to irbesartan 150 mg/HCTZ There were no reports of serious adverse events related 12.5 mg, then to irbesartan 300 mg/HCTZ 25 mg. If to study medication. Long-term therapy with necessary, adjunctive therapies were added. Mean irbesartan/HCTZ is safe, well tolerated, and maintains changes in trough seated systolic BP/SeDBP at months normalised BP in Ͼ80% of patients. /؊20.7 ,(941 ؍ and 12 were ؊19.1/؊14.2 mm Hg (n ,6 ,2

Keywords: irbesartan; hydrochlorothiazide; angiotensin II receptor antagonist; diuretic; combination therapy

Introduction In clinical trials, irbesartan monotherapy has dem- onstrated dose-related lowering of BP in hyperten- Although most patients with hypertension are sive patients6,7 with placebo-like tolerability.8 Short- 1 treated initially with monotherapy, only one out of term studies of irbesartan/HCTZ have shown no two successfully control their blood pressure (BP) 9 2 pharmacokinetic interaction and greater reductions with monotherapy. Thus, many patients will in BP than either antihypertensive agent adminis- require combination therapy, most rationally, with tered alone.10 Controlled studies have shown that the addition of a second drug from a different phar- irbesartan/HCTZ, is well tolerated.6,9–12 macological class. The primary objective of this study was to evalu- The diuretic hydrochlorothiazide (HCTZ), ate the long-term safety, tolerability, and antihyper- although commonly used as initial monotherapy for tensive effects of irbesartan/HCTZ (alone or with hypertension, is associated with several dose-related adjunctive antihypertensive medications) in adverse metabolic effects including increases in glu- patients with mild-to-moderate hypertension. cose, cholesterol, uric acid, and calcium and decreases in magnesium and potassium.3 Irbesartan is a potent angiotensin II receptor antagonist with Materials and methods 4 high affinity for the AT1 receptor subtype. Because Study design irbesartan has a complementary mechanism of action to HCTZ,4,5 its use in combination may allow Two similar open-label extension studies were con- the use of a lower dose of HCTZ. Irbesartan may also ducted at 93 centres in Argentina, Brazil, Mexico, blunt some of the adverse metabolic effects of HCTZ, and the United States. Each of these two studies was particularly hypokalaemia. preceded by a 4- to 5-week, single-blind, placebo lead-in period, followed by a double-blind period in which patients were randomised to receive parallel Correspondence: Ravi Saini, Bristol-Myers Squibb Pharmaceut- treatment with several doses of irbesartan alone, ical Research Institute, Route 206 & Provinceline Road, Princeton, NJ 08543–4000, USA HCTZ alone, irbesartan/HCTZ, or placebo. During Received 31 March 1999; revised 27 April 1999; accepted 24 the double-blind period of Study 1, irbesartan doses May 1999 ranged from 37.5–300 mg and HCTZ doses ranged Long-term study of irbesartan/HCTZ P Raskin et al 684 from 6.25–25 mg. During the double-blind period of therapy, within 4 weeks following initiation or Study 2, the irbesartan doses were 75 mg and upward titration of doses, and every 4 months there- 150 mg and the HCTZ dose was 12.5 mg. Each 1- after. A physical examination and 12-lead electro- year, open-label extension study began immediately cardiogram were performed at entry and at the end after the double-blind period. In each study, the of the open-label period. starting dose was irbesartan 75 mg/HCTZ 12.5 mg once daily. If target BP (Ͻ140/Ͻ90 mm Hg) was not Statistical methods achieved, the dose was titrated sequentially at 2- to 4-week intervals to irbesartan 150 mg/HCTZ All patient data from both protocols were pooled for 12.5 mg, then to irbesartan 300 mg/HCTZ 25 mg. If this analysis. Quantitative demographic and base- necessary, atenolol (25–50–100 mg) and/or nifedip- line (ie, as determined at entry to the double-blind ine sustained release (30–60 mg) could be added and period) characteristics were summarised and quali- titrated as necessary to achieve target BP. Once tar- tative data were tabulated. No hypothesis testing get BP was achieved, the treatment regimen was was performed. Efficacy variables were summarised continued for the remainder of the open-label exten- using the available data from all patients at each sions. Patients who did not achieve target BP were time-point. Normalisation rates (trough SeDBP Ͻ90 discontinued. mm Hg), total responder rates (normalised or у10 mm Hg trough SeDBP reduction from baseline) and the percentage of patients who achieved target BP Patients (Ͻ140/Ͻ90 mm Hg) were summarised. Adverse For enrolment into both double-blind studies, men events were summarised according to treatment pre- and postmenopausal or surgically sterile women scribed at the time of the event. Mean changes from у18 years of age with mild-to-moderate essential baseline (ie, prior to receiving double-blind drug) hypertension (seated diastolic BP [SeDBP] 95–110 laboratory values were also summarised. mm Hg) were eligible. Exclusion criteria for the open-label extension phase included: (1) SeDBP Results Ͼ110 mm Hg or seated systolic BP (SeSBP) Ͼ200 mm Hg; (2) significant cardiovascular, neurologic, Demographic and baseline characteristics psychiatric, endocrinologic, pulmonary, renal, auto- To be eligible for the open-label extensions, patients immune, haematologic, or gastrointestinal disease, a had to complete double-blind therapy, continue to malignancy, or any other diseases considered by the satisfy all exclusion criteria, and be willing to par- investigator to make participation in the study not ticipate. Of the 1098 individuals enrolled into the in the best interests of the patient; (3) need for con- open-label extensions of the two studies comitant medications that might interfere with the (representing 73% of all patients completing double- assessment of efficacy or safety (eg, drugs known to blind therapy), 1095 received at least one dose of affect BP, prolonged courses of non-steroidal anti- open-label study medication and had at least one inflammatory drugs); and (4) allergy to HCTZ or any follow-up visit. One hundred and ninety-eight sulpha-containing medication. Patients completing patients discontinued open-label therapy: the most double-blind therapy and who continued to satisfy common reasons for discontinuation were adverse all of the exclusion criteria listed above were given events (7.5%), site, sponsor, or patient request the option of continuing into the 1-year, open-label (5.8%), lost to follow-up (2.3%), and poor com- extensions. All patients provided written informed pliance (1%). Poor BP control accounted for Ͻ1% consent, and the open-label extensions were of discontinuations. approved by the relevant local institutional review The majority of patients were men (58%), White boards and conducted according to Good Clinical (76%), and Ͻ65 years of age (84%), and most (79%) Practice guidelines. had a SeDBP Ͻ104 mm Hg. Mean age was 54 years, and mean seated Bp was 152/100 mm Hg (Table 1). Blood pressure measurements Demographic characteristics were similar between the two protocols, except that in Study 1, the racial Trough (24 ± 3 h after ingestion of study medication) composition was 86% White, 8% Black, and 6% seated BP was measured using a mercury sphygmo- manometer at all clinic visits (months 2, 4, 6, 8, and 12). Three measurements were taken at least 1-min apart after the patient rested for 10 min in the seated Table 1 Demographics and baseline blood pressure position. If the SeDBP readings were not within 8 n = 1098 mm Hg of each other, an additional two readings were obtained and incorporated into the calculated Male/female (%) 58/42 mean. Heart rate was determined by pulse count White/Black/other (%) 76/10/14 after the last BP reading. Mean age ± s.d. (years) 54 ± 10.3 Ͼ65 years of age (%) 16 Mean SeSBP ± s.d. (mm Hg) 151.6 ± 14.7 Safety Mean SeDBP ± s.d. (mm Hg) 100.4 ± 4.1 SeDBP Ͻ104 mm Hg (%) 79 Reported adverse events were recorded at all clinic visits. Blood and urine samples were obtained for s.d., standard deviation; SeSBP, seated systolic blood pressure; standard laboratory tests at initiation of open-label SeDBP, seated diastolic blood pressure. Long-term study of irbesartan/HCTZ P Raskin et al 685 from baseline) were 81%, 91%, and 90%. Target BP (Ͻ140/Ͻ90 mm Hg) was achieved in 65%, 75%, and 70% of patients at months 2, 6, and 12, respectively.

Distribution of dose regimens Throughout both open-label extensions, most patients required only irbesartan/HCTZ, without the need for additional antihypertensive agents (Table 2). From months 2 through 12, at least 87% of patients were receiving irbesartan/HCTZ alone.

Figure 1 Mean reductions from baseline trough seated diastolic Subgroup analyses blood pressure (SeDBP) and trough seated systolic blood pressure (SeSBP) over the 1-year study period. (ᮀ) normalised, (᭿) total Analyses of the therapeutic responses according to responder, (a) target blood pressure. gender, race, and age were performed. At month 12, similar reductions in trough SeDBP were achieved in men and women. A slightly higher percentage of other races, and in Study 2 was 69% White, 11% women were normalised compared with men (87% Black, and 20% other races. vs 80%), even though more women were receiving irbesartan/HCTZ alone (90% vs 84% for men). Simi- Changes in trough seated blood pressure lar mean reductions in trough SeDBP and SeSBP and response rates were achieved among the various Clinically signiﬁcant reductions from baseline races (White, Black, and other) at month 12. Only trough SeDBP and trough SeSBP were achieved dur- 10% to 15% of the patients in each racial subgroup ing the ﬁrst clinic visit (2 months) and maintained required adjunctive antihypertensive therapy in until the end of the study period (12 months). Mean addition to irbesartan/HCTZ. changes in trough SeSBP/SeDBP at months 2, 6, and Compared with patients who were Ͻ65 years of 12 were −19.1/−14.2 mm Hg (n = 941), −20.7/−15.7 у = − − = age, patients who were 65 years of age had a higher mm Hg (n 948), and 20.6/ 15.6 mm Hg (n 898), mean baseline SeSBP (161 mm Hg vs 150 mm Hg) respectively (Figure 1). Heart rate remained stable and a slightly larger mean decrease in trough SeSBP throughout. at month 12 (24 mm Hg vs 20 mm Hg). In contrast, both groups had the same mean baseline SeDBP (100 Therapeutic response mm Hg) and similar decreases in trough SeDBP at month 12 (Ͻ65 years, 15 mm Hg vs у65 years, 16 For most patients BP control was achieved by 2 mm Hg). Although SeDBP normalisation rates at months and was sustained throughout (Figure 2). Ͻ Ͻ month 12 were similar in these two groups ( 65 Normalisation rates (trough SeDBP 90 mm Hg) years, 83% vs у65 years, 84%), a smaller percentage were 75%, 85%, and 83% at months 2, 6, and 12, of patients у65 years achieved both systolic and respectively. Corresponding total responder rates у diastolic target BP at month 12 (55% vs 73%). The (normalised or 10 mm Hg trough SeDBP reduction percentage of patients у65 years and Ͻ65 years

Table 2 Distribution of dose regimens during open-label therapy

Dose regimen Month 2 Month 6 Month 12 n = 941 n = 948 n = 898

Irbesartan/HCTZ without adjuncta Irbesartan 75 mg/HCTZ 504 (54%) 474 (50%) 430 (48%) 12.5 mg Irbesartan 316 (34%) 228 (24%) 209 (23%) 150 mg/HCTZ 12.5 mg Irbesartan 74 (8%) 110 (12%) 102 (11%) 300 mg/HCTZ 12.5 mg Irbesartan/HCTZ with 21 (2%) 93 (10%) 106 (12%) adjuncta Otherb 28 (3%) 43 (4%) 51 (6%)

n, number of patients included at timepoint; HCTZ, hydrochlorothiazide. aAtenolol, nifedipine, or both. Figure 2 Normalisation rates (trough SeDBP Ͻ90 mm Hg), total bIncludes patients who had interruptions in therapy or who responder rates (normalised or у10 mm Hg trough SeDBP received regimens not specified in the protocol (ie, irbesartan reduction from baseline), and the percentage of patients achieving monotherapy, irbesartan/non-HCTZ, irbesartan/HCTZ doses target blood pressure (Ͻ140/Ͻ90 mm Hg) over the 1-year study other than irbesartan 75 mg/HCTZ 12.5 mg, irbesartan 150 period. mg/HCTZ 12.5 mg, or irbesartan 300 mg/HCTZ 25 mg). Long-term study of irbesartan/HCTZ P Raskin et al 686 receiving irbesartan/HCTZ without adjunctive anti- Discussion hypertensive therapy were similar (85% vs 87%). For many hypertensive patients, BP is not adequately controlled by monotherapy. A combi- Safety and tolerability nation of two antihypertensive drugs with a comp- The mean duration of exposure to irbesartan lementary mechanism of action (eg, a diuretic plus (±HCTZ or other adjunctive therapy) was 325 days, angiotensin II receptor antagonist) has the potential giving a total exposure of 975 patient-years. A total to improve efficacy.1,2 Furthermore, the use of lower of 82 patients (7.5%) discontinued the study due to doses of diuretics, as is usually the case with combi- adverse events. The most frequent causes were nation therapy, can result in improved toler- fatigue (0.8%), rash (0.5%), atrial rhythm disturb- ability.1,2 This may be particularly important for ances (0.4%), dizziness (0.4%), and increased liver diuretics, which are often associated with dose- enzymes (0.4%). The adverse events resulting in dis- related side effects.3,13 Improvements in efficacy and continuation were considered unrelated to study tolerability may lead to increased patient com- medication in 41 of these 82 patients (50%). pliance and thus improve long-term management A total of 75 serious adverse events were reported of hypertension.3 by 58 patients (5.3%), none of which was con- The present clinical trials demonstrate that long- sidered by the investigator to be related to study term therapy of irbesartan (75–300 mg)/HCTZ medication. Two patients died: one during open- (р25 mg), alone or with adjunctive antihypertensive label therapy (motor vehicle accident) and one post medications, is safe, well-tolerated, and effective in study (cardiac arrest); neither death was considered patients with mild-to-moderate hypertension. Fur- by the investigators to be attributed to study medi- thermore, adverse events were not dose-related. cation. The most frequently occurring serious Although previous double-blind, placebo-controlled adverse events were myocardial infarction, angina clinical trials of irbesartan/HCTZ were of short dur- pectoris, and invasive cardiac procedures (three ation,6,9–11 they were not intended to assess long- patients each) which is not unexpected for this term efficacy or safety. The present 1-year, open- population. label extensions of two double-blind, randomised, During open-label therapy, 794 patients (72%) placebo-controlled trials allowed for titration and reported one or more adverse events. The most com- addition of adjunctive antihypertensive agents when mon events were musculoskeletal pain, upper res- necessary. This study design is also useful in that it piratory infection, headache, and fatigue (Table 3). mimics the conditions found in actual clinical prac- No relationship to dose was observed. Orthostatic tice. dizziness was reported in 3.2% of patients. One The long-term efficacy results in the present patient (irbesartan 75 mg/HCTZ 12.5 mg) experi- report are in agreement with those of short-term enced tongue and throat swelling that was reported trials with irbesartan/HCTZ.6,9–12 In long-term use, as angioedema and judged unrelated to study medi- BP was well controlled with titration of once-daily cation. irbesartan/HCTZ followed, if necessary, by the Clinically important abnormalities in laboratory addition and titration of adjunctive antihypertensive values were rarely seen. A total of 11 patients (1%) agents. BP was normalised (trough SeDBP Ͻ90 discontinued due to laboratory adverse events, the mm Hg) in 75% of patients at month 2 and in 83% most common cause being increased liver enzymes of patients at month 12. The total responder rate or bilirubin (0.4%). Elevated creatine kinase, glu- (normalised or у10 mm Hg trough SeDBP reduction cose, potassium, and triglycerides led to discontinu- from baseline) increased from 81% at month 2 to ation of one patient each. Mean changes in total 90% at month 12. The target BP of Ͻ140/Ͻ90 cholesterol, low-density and high-density lipopro- mm Hg was achieved in 70% of the patients at tein cholesterol, glucose, potassium, sodium, cal- month 12. About 90% of patients whose BP was nor- cium, magnesium, and uric acid concentrations malised or who achieved target BP (Ͻ140/Ͻ90 were not clinically significant. There were also no mm Hg) were receiving irbesartan/HCTZ alone, ie, clinically significant changes in physical examin- without the need for further antihypertensive ation or electrocardiogram findings. agents. Poor BP control accounted for only 1% of all patients entering the study. Less than one-third of patients receiving angiotensin-converting enzyme (ACE) inhibitors, calcium Table 3 Most common adverse events channel blockers, beta-blockers, or diuretics continue the same therapy for more than 1 year.14 No Adverse event Any irbesartan n = 1095 significant long-term tolerability concerns were Musculoskeletal pain 143 (13.1) associated with irbesartan/HCTZ (even with adjunc- Upper respiratory infection 137 (12.5) tive antihypertensive agents), which confirms the Headache 113 (10.3) excellent short-term safety profile of the combi- Fatigue 82 (7.5) nation.6,9–12 Although the incidence of withdrawal Dizziness 81 (7.4) due to adverse events was higher during the open- Sinus abnormality 71 (6.5) Pharyngitis 59 (5.4) label extensions (7.5%) than during the double- Influenza 56 (5.1) blind phases of the studies (3.6%), this is likely due Cough 56 (5.1) to the longer duration of observation or possibly due to the presence of additional antihypertensive Long-term study of irbesartan/HCTZ P Raskin et al 687 agents. No relationship between dose and incidence and angiotensin II receptor antagonists. Pharmacol Rev of adverse events was observed, consistent with the 1993; 45: 205–251. short-term experience with irbesartan monother- 6 Pool JL et al. Dose-related antihypertensive effects of apy.8 irbesartan in patients with mild-to-moderate hyperten- The results of this study demonstrate that long- sion. Am J Hypertens 1998; 11: 462–470. 7 Reeves RA, Lin C-S, Kassler-Taub K, Pouleur H. Dose- term therapy with irbesartan/HCTZ (alone or with related efficacy of irbesartan for hypertension: an inte- adjunctive antihypertensive medications) in grated analysis. Hypertension 1998; 31: 1311–1316. patients with mild-to-moderate hypertension is safe, 8 Simon TA et al. Safety of irbesartan in the treatment of well tolerated, and maintains normalised BP in at mild to moderate systemic hypertension. Am J Cardiol least 80% of patients. 1998; 82: 179–182. 9 Marino MR et al. Effect of hydrochlorothiazide on the pharmacokinetics and pharmacodynamics of the angi- References otensin II blocker irbesartan. Clin Drug Invest 1997; 14: 1 Kaplan NM. Implications for cost-effectiveness. Com- 383–391. bination therapy for systemic hypertension. Am J Car- 10 Kochar M et al. Matrix study of irbesartan with hy- diol 1995; 76: 595–597. drochlorothiazide in mild-to-moderate hypertension. 2 Waeber B, Brunner HR. Main objectives and new Am J Hypertens 1999; 12: (in press). aspects of combination treatment of hypertension. 11 Phillips P et al. Antihypertensive efficacy of the com- J Hypertens 1995; 13 (Suppl 2): S15–S19. bination of irbesartan and hydrochlorothiazide 3 Joint National Committee on Prevention, Detection, assessed by 24-hour ambulatory blood pressure moni- Evaluation, and Treatment of High Blood Pressure. toring [abstract]. J Hypertens 1997; 15 (Suppl 4): S181. The sixth report of the Joint National Committee on 12 Rosenstock J et al. The effects of irbesartan added to Prevention, Detection, Evaluation, and Treatment of hydrochlorothiazide for the treatment of hypertension High Blood Pressure. Arch Intern Med 1997; 157: in patients non-responsive to hydrochlorothiazide 2413–2446. alone. J Clin Pharm Ther 1998; 23: 433–440. 4 Cazaubon C et al. Pharmacological characterization of 13 McVeigh GE, Flack J, Grimm R. Goals of antihyperten-

SR 47436, a new nonpeptide AT1 subtype angiotensin sive therapy. Drugs 1995; 49: 161–175. II receptor antagonist. J Pharmacol Exp Ther 1993; 265: 14 McCombs JS, Nichol MB, Newman CM, Sclar DA. The 826–834. costs of interrupting antihypertensive drug therapy in 5 Timmermans PBMWM et al. Angiotensin II receptors a Medicaid population. Med Care 1994; 32: 214–226.