Original Paper

Efficacy and Safety of Fixed Combinations of Irbesartan/Hydrochlorothiazide in Older vs Younger Patients With Hypertension Uncontrolled With Monotherapy
William c. cushman, Md;1 Joel M. neutel, Md;2 Elijah saunders, Md;3 George l. bakris, Md;4 Keith c. ferdinand, Md;5 Elizabeth o. ofili, Md;6 James r. sowers, Md;7 robert Madder, do;8 Michael a. Weber, Md9
From the University of Tennessee College of Medicine and Veterans Affairs Medical Center, Memphis, TN;1 Orange County Research Center, Tustin, CA;2 the University of Maryland School of Medicine, Baltimore, MD;3 the Department of Medicine, University of Chicago, Chicago, IL;4 the Association of Black Cardiologists, Atlanta, GA;5 Morehouse School of Medicine, Atlanta, GA;6 the University of Arizona, Tucson, AZ;7 Tri-State Medical Group, Inc, Beaver, PA;8 and State University of New York Health Science Center at Brooklyn, Brooklyn, NY9 Address for correspondence: William C. Cushman, MD, 279 North Avalon Street, Memphis, TN 38112 E-mail: wcushman@pol.net Manuscript received July 17, 2007; accepted July 25, 2007

Subgroup analysis of the Irbesartan/Hydrochlorothiazide Blood Pressure Reductions in Diverse Patient Populations (INCLUSIVE) trial evaluated the efficacy and safety of irbesartan/hydrochlorothiazide (HCTZ) fixed combinations in patients aged 65 years or older with uncontrolled systolic blood pressure (SBP) after 4 weeks of antihypertensive monotherapy. The INCLUSIVE trial was a prospective, open-label, single-arm trial carried out in 119 sites. Of 844 patients completing placebo treatment, 212 were aged 65 years or older. Participants received treatment with placebo (45 weeks), HCTZ 12.5 mg (2 weeks), irbesartan/HCTZ 150/12.5 mg (8 weeks), and then irbesartan/HCTZ 300/25 mg (8 weeks). From baseline to week 18 (n=184, intent-totreat population), mean change in SBP was 23.013.3 mm Hg (P<.001) and diastolic BP (DBP) was 10.97.7 mm Hg (P<.001). Mean SBP/DBP at study end was 134.014.7/75.18.4 mm Hg, and SBP DBP and SBP/DBP goal was achieved in 73%, 96%, and 72% of patients, , , respectively. Irbesartan/HCTZ combination therapy allowed SBP goal attainment in 73% of patients aged 65 years or older whose hypertension was previously uncontrolled with antihypertensive monotherapy. (Am J Geriatr Cardiol. 2008;17:2736) 2008 Le Jacq

ypertension is the most prevalent modifiable risk factor for cardiovascular disease. Data from the 19992000 National Health and Nutrition Examination Survey (NHANES)1 indicate that hypertension (defined as systolic blood pressure [SBP] 140 mm Hg or diastolic blood pressure [DBP] 90 mm Hg or use of antihypertensive medication) affects approximately two thirds of individuals aged 60 years or older. In

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those aged 75 years or older, the percentage of individuals with hypertension rises to 68.1% in men and 84.0% in women.2 Elevated SBP, especially isolated systolic hypertension (SBP 140 mm Hg with DBP <90 mm Hg), is the predominant form of hypertension, affecting individuals aged 50 years and older.3 Furthermore, elevated SBP is a strong predictor of cardiovascular events, including stroke, myocardial infarction, peripheral vascular disease, heart failure, renal failure, and all-cause mortality.47

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The American Journal of Geriatric Cardiology (ISSN 1076-7460) is published bimonthly (Jan., March, May, July, Sept., Nov.) by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT 06484. Copyright 2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Ben Harkinson at BHarkinson@bos.blackwellpublishing.com or 781-388-8511.

Compelling data from clinical trials demonstrate the benefits of treating hypertension in the elderly.815 Current hypertension management guidelines, including the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7),16 identify SBP control as the primary objective of hypertension treatment in persons older than 50 years.17 Most patients in this age group will reach their DBP goal once the SBP goal is achieved. These blood pressure (BP) targets should be the same as for younger patients: <140/90 mm Hg in uncomplicated hypertension and <130/80 mm Hg in individuals with diabetes.16,17 A number of monotherapy and combination products are available for the treatment of elevated BP. Thiazide diuretics are recommended as the first-line monotherapy treatment option by JNC 7 in most hypertensive patients without a compelling indication for another therapeutic agent.16 In the majority of elderly patients with hypertension, 2 or more antihypertensive drugs will be required to achieve BP goal, however. JNC 7 also recommends that thiazide-type diuretics be included in most multidrug regimens, both because of the benefits of thiazides in outcome trials and because multidrug regimens that include a thiazide-type diuretic are generally more effective in lowering BP than those without a diuretic.16,1820 Singlepill, fixed-dose combination products containing appropriate doses of 2 separate drugs may be particularly desirable in elderly patients, as this helps reduce the overall pill burden and may improve drug adherence.2123 Furthermore, some combination products have improved tolerability when compared with the respective monotherapies.24 In clinical trials, the coadministration of irbesartan (an angiotensin receptor blocker [ARB]) and the diuretic hydrochlorothiazide (HCTZ), either as individual components or in a fixed-dose combination, provides greater reductions in BP compared with the respective monotherapies and is well tolerated.2530 The additive antihypertensive effects achieved with ARB/HCTZ combinations (also observed with angiotensin-converting enzyme [ACE] inhibitor/HCTZ combinations) is attributed to the blunting effect of ARBs (or ACE inhibitors) on the renin-angiotensin-aldosterone system, which may become activated by mild, diuretic-induced volume contraction.31 In addition, in elderly individuals (aged 6580 years), the pharmacokinetics of irbesartan are not significantly altered compared with in younger individuals. Therefore, no dosage adjustments are required.32

The pharmacokinetic profile of irbesartan and the lack of necessary dosage adjustments in special populations suggest that irbesartan is an appropriate antihypertensive medication to include in regimens for management of hypertension in elderly patients.32,33 The current subgroup analysis of the Irbesartan/ Hydrochlorothiazide Blood Pressure Reductions in Diverse Patient Populations (INCLUSIVE) trial aimed to evaluate the antihypertensive efficacy and safety of low- and high-dose irbesartan/HCTZ fixed combinations in patients older than 65 years whose SBP was uncontrolled with antihypertensive monotherapy.

MEtHOdS

Study design. This was a prespecified subgroup analysis of the INCLUSIVE trial, a multicenter, prospective, open-label single-arm study involving 119 sites across the United States between July 2003 and August 2004. Full details of the INCLUSIVE trial design and patient population have been published.34 Briefly, qualifying patients with uncontrolled SBP at screening (140159 mm Hg; 130159 mm Hg for patients with type 2 diabetes mellitus) discontinued previous antihypertensive monotherapy, which they had been receiving for at least 4 weeks, and entered a sequential 4-phase treatment period. At the end of a 4- to 5-week placebo run-in phase (baseline: week 0), patients received HCTZ 12.5 mg for 2 weeks (1 tablet once daily), followed at week 2 by irbesartan/HCTZ 150/12.5 mg for 8 weeks (1 fixed-dose combination tablet once daily) and at week 10 by irbesartan/HCTZ 300/25 mg for 8 weeks (2 irbesartan/HCTZ 150/12.5 mg fixeddose combination tablets once daily). Patients were seen 2 weeks after each change in dosage (at weeks 4 and 12) for safety reasons. Entry into each treatment period was dependent on BP criteria. For entry into the placebo, HCTZ 12.5-mg, and irbesartan/HCTZ 150/12.5-mg treatment periods, SBP had to be 140 to 179 mm Hg (130179 mm Hg for patients with type 2 diabetes mellitus). Treatment in patients whose SBP was 120 to 179 mm Hg after 8 weeks of irbesartan/ HCTZ 150/12.5-mg was titrated to irbesartan/ HCTZ 300/25 mg; treatment in patients whose SBP was <120 mm Hg was discontinued as a safety measure. Diastolic BP had to be 70 to 109 mm Hg throughout the study, irrespective of treatment period and diabetes status. Patients not meeting BP criteria at the start of each phase were withdrawn. Lack of qualification could arise either because BP goal was achieved in the patients or

28

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tHE aMErican JoUrnal of GEriatric cardioloGy 2008 Vol. 17 no. 1

The American Journal of Geriatric Cardiology (ISSN 1076-7460) is published bimonthly (Jan., March, May, July, Sept., Nov.) by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT 06484. Copyright 2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Ben Harkinson at BHarkinson@bos.blackwellpublishing.com or 781-388-8511.

because their BP level was higher than the safety criteria specified by the protocol. The study protocol was approved by the institutional review board/ethics committee of each participating site. Written informed consent was obtained from each patient. Patients. Participants were men and women aged 18 years and older with uncontrolled SBP at screening (ie, following at least 4 weeks of singledrug antihypertensive therapy and before administration of placebo). Fixed-dose HCTZ/triamterene combinations were considered monotherapy. Patients were excluded from the study if they had severe (SBP 180 mm Hg or DBP 110 mm Hg) or secondary hypertension; hypertensive encephalopathy, stroke or transient ischemic attack in the preceding year; myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft, or unstable angina pectoris in the preceding 6 months; symptomatic resting bradycardia; other significant cardiac, hepatic, renal, or gastrointestinal disease; systemic lupus erythematosus; malignancy in the previous 5 years (except localized skin carcinoma); drug or alcohol abuse in the preceding 5 years; hypersensitivity to irbesartan, other ARBs, HCTZ, or other thiazide diuretics; or an arm circumference >17 in (>43 cm). Also excluded were patients receiving insulin or drugs that might interfere with efficacy and safety evaluations and women who were pregnant, lactating, or of childbearing potential who were not using an approved method of contraception. dosing Instructions and BP Measurement. Patients were instructed to take their medication at 8:00 am ( 2 hours) except on the morning of a clinic visit, when medication was administered after BP had been measured. BP measurements were taken at trough (8:00 am 2 hours) in the participants dominant arm with patients in a seated position, with back supported, and with a validated automatic Omron measurement device (model: HEM 705CP; Omron Healthcare Inc, IL; device variance: 4 mm Hg).35 BP was determined from the mean of 3 readings obtained 2 minutes apart. Efficacy End Point Measures. The primary efficacy end point was mean change in SBP from baseline (week 0; end of placebo treatment) to the end of irbesartan/HCTZ 300/25-mg treatment (week 18; study end). Secondary end points included mean change in DBP from baseline to week 18 and mean changes

in SBP and DBP from baseline to the end of the irbesartan/HCTZ 150/12.5-mg treatment phase (week 10). BP goal attainment rates were also assessed at weeks 2, 10, and 18 according to the following definitions: SBP goal: <140 mm Hg; <130 mm Hg for patients with type 2 diabetes mellitus DBP goal: <90 mm Hg; <80 mm Hg for patients with type 2 diabetes mellitus Dual BP goal: <140/90 mm Hg; <130/80 mm Hg for patients with type 2 diabetes mellitus. These definitions of BP goals are consistent with current hypertension management guidelines, particularly JNC 7.16,3638 Safety Evaluations. Patients were monitored and questioned regarding signs and symptoms of adverse events, their severity, the date and time of onset, action taken, relationship to study medication, and outcome. Monitoring was initiated from the administration of the first dose of placebo until study end. Laboratory evaluations were conducted on blood and urine samples (chemistry panel [sodium, potassium, glucose, blood urea nitrogen, and creatinine], liver function tests [aspartate aminotransferase, alanine aminotransferase, and total bilirubin], fasting plasma glucose, hemoglobin A1c, high-sensitivity C-reactive protein, serum pregnancy [for women of childbearing potential only], hematology [hemoglobin, hematocrit, red blood cell count, white blood cell count, and platelet count], and routine urinalysis). Any changes in physical examination or laboratory findings considered by the investigators to be clinically significant were recorded on the case report form. Statistical Analyses. This prespecified subgroup analysis evaluated safety and efficacy parameters in patients enrolled in the INCLUSIVE trial according to age group (younger than 65 years and 65 years and older). To achieve a 95% confidence interval (CI) of width 2.5 mm Hg on the primary end point for each age group, at least 100 patients needed to be enrolled in each group. Efficacy data were analyzed for the intent-totreat (ITT) populations, which included patients with 1 or more valid SBP recording after taking at least 1 dose of irbesartan/HCTZ 150/12.5 mg. The last observation carried forward (ie, the last BP measurement before discontinuation) was used to calculate efficacy parameters for ITT patients whose BP was controlled or who withdrew from the study before week 18. All patients taking at least 1 dose of placebo were evaluated for safety.

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The American Journal of Geriatric Cardiology (ISSN 1076-7460) is published bimonthly (Jan., March, May, July, Sept., Nov.) by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT 06484. Copyright 2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Ben Harkinson at BHarkinson@bos.blackwellpublishing.com or 781-388-8511.

Mean, standard deviation, median, minimum, and maximum values were calculated for continuous variables; 95% CIs were calculated for point estimates of mean change scores in continuous variables. Mean changes in BP from baseline were tested using a paired t test for a normally distributed population. If sample data appeared to be selected from a population that was not normally distributed, the Wilcoxon signed rank test was employed. Goal attainment rates were expressed as frequency counts and percentages with 95% CIs. Alternative formulas from Fleiss39 were used to calculate the upper and lower limits of the interval if a point estimate was <0.1 or >0.9.

Table I. Flow of Elderly Participants (Aged 65 Years or Older) Through Each Phase of the INCLUSIVE Trial Reason foR Discontinuation DiD not Meet patients/ total no. aDveRse lost to pRotocol DiD not Meet inclusion/exclusion investigatoRs Week action DiscontinueD cRiteRia events folloW-up violation Decision Bp cRiteRia otheR 5 to 4a 260 Met inclusion criteria 48 3 2 3 1 13 25 1 and were assigned to placebo (safety population) 0 (baseline) 212 Elderly patients 12 3 1 8b assigned to HctZ 12.5 mg (enrolled population) 2 200 Elderly patients 37 5 3 5d 24e assigned to irb/HctZ 150/12.5 mgc 10 163 Elderly patients 23 5 2 1d 14b 1 assigned to irb/HctZ 300/25 mg 18 140 Elderly patients com pleted treatment with irb/ HctZ 300/25 mg a of 404 elderly patients screened; 144 did not qualify. ball had blood pressure (bP) levels below specified limits. c184 Elderly patients had 1 valid systolic bP measurement after taking 1 dose of irb/HctZ 150/12.5 mg (intent-to-treat population). dPatients decision. e23 Had bP levels below specified limits; 1 had bP level above predefined safety limits. abbreviations: HctZ, hydrochlorothiazide; inclUsiVE, irbesartan/Hydrochlorothiazide blood Pressure reductions in diverse Patient Populations; irb, irbesartan.
30
Efficacy of irbEsartan/HctZ in EldErly PatiEnts

RESUltS

Patient Population. A total of 404 of the 1568 patients screened in the INCLUSIVE trial were aged 65 years or older. The flow of these elderly patients through the sequential treatment phases is shown in Table I. The safety population comprised 260 patients aged 65 years or older and 745 patients younger than 65 years who met the inclusion criteria and commenced placebo treatment at week 4 or 5. Subsequently, 212 patients aged 65 years or older and 632 patients younger than 65 years were enrolled and started therapy with HCTZ 12.5 mg. Overall, 140 patients aged 65 years or older and 474 patients younger than 65 years completed the study. The predominant reason for discontinuation among elderly patients was that they did not meet BP qualification criteria at the start of a treatment period (n=71) because their BP was either above the protocol safety criteria or below qualification limits. Only 2 patients in the enrolled population discontinued active treatment because their BP exceeded that considered safe per protocol: one patient in the 65 years and older group (mean SBP, 193 mm Hg at week 4), and one patient younger than 65 years (mean DBP, 113 mm Hg at week 10); treatment with irbesartan/HCTZ 150/12.5 mg was discontinued in both. Baseline demographic characteristics of the enrolled patients were generally similar between age groups, although the metabolic syndrome was more common in participants younger than 65 years than in those aged 65 years or older, and a greater proportion of elderly participants were Caucasian (Table II). In the 65 years or older age group, mean SBP (156.510.6 mm Hg) at baseline was higher than in participants in the younger age group (153.210.0 mm Hg), and mean DBP (85.68.7 mm Hg) was lower than in participants in the younger age group (93.18.0 mm Hg).

tHE aMErican JoUrnal of GEriatric cardioloGy 2008 Vol. 17 no. 1

The American Journal of Geriatric Cardiology (ISSN 1076-7460) is published bimonthly (Jan., March, May, July, Sept., Nov.) by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT 06484. Copyright 2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Ben Harkinson at BHarkinson@bos.blackwellpublishing.com or 781-388-8511.

Table II. Demographics of Enrolled Population at Baseline (Week 0; End of Placebo Phase)
chaRacteRistic YoungeR than 65 YeaRs YeaRs oR olDeR (n=212) Mean age at screening, y 52.5 71.6 Women, no. (%) 328 (52) 108 (51) Men, no. (%) 304 (48) 104 (49) race/ethnic group, no. (%)a caucasian 364 (58) 151 (71) african american 163 (26) 28 (13) Hispanic/latino 91 (14) 28 (13) asian 11 (2) 3 (1) other 5 (1) 2 (1) Previous antihypertensive monotherapy, no. (%)b b-blocker 71 (11) 26 (12) a-blocker 4 (1) 7 (3) calcium channel blocker 128 (20) 40 (19) angiotensin receptor blocker 121 (19) 45 (21) angiotensin-converting enzyme inhibitor 208 (33) 75 (35) diuretic 89 (14) 25 (12) other 10 (2) 0 type 2 diabetes mellitus, no. (%) 188 (30) 66 (31) Metabolic syndrome, no. (%) 313 (50) 73 (34) Vital signs, mean sd sbP, mm Hg 153.210.0 156.510.6 dbP, mm Hg 93.18.0 85.68.7 Pulse rate, beats per min 74.110.9 73.010.2 Weight, mean sd, kg 90.019.4 82.016.0 creatinine clearance, mean sd, ml/min 65.811.7 47.811.7 a two patients self-identified into more than 1 race/ethnic group. bEight patients were categorized into more than 1 antihypertensive drug class; data was missing for 3 patients. abbreviations: sbP, systolic blood pressure; dbP, diastolic blood pressure. age gRoup (n=632) 65

Mean Changes in BP Parameters. Mean changes in SBP and DBP from baseline to week 2, week 10, and week 18 were calculated separately for the 184 patients in the ITT population who were aged 65 years or older and the 552 patients who were younger than 65 years of age (Figure). The mean change from baseline to week 18 for patients aged 65 years or older age was 23.013.3 mm Hg (P<.001) in SBP and 10.97.7 mm Hg (P<.001) in DBP For . patients younger than 65 years, the mean change in SBP was 21.014.6 mm Hg (P<.001) and 10.28.9 mm Hg (P<.001) in DBP The magnitude of these . reductions at week 18 was not significantly different between patients younger than 65 years and those aged 65 years or older. Mean SBP level at study end was 134.014.7 mm Hg, and mean DBP level was 75.18.4 mm Hg among patients aged 65 years or older vs a mean SBP level of 132.613.5 mm Hg and a mean DBP level of 83.09.3 mm Hg among those younger than 65 years.

As reported previously,34 the mean SBP change from baseline to week 18 in the total INCLUSIVE ITT population (n=736) was 21.514.3 mm Hg (P<.001) and the mean DBP change was 10.48.7 mm Hg (P<.001). Goal Attainment Rates. The SBP and DBP goal attainment rates at weeks 2, 10, and 18 were determined for participants aged 65 years or older and those younger than 65 years (Table III). Over the 18-week study period, SBP goal was achieved in 73% (95% CI, 67%80%) of participants aged 65 years or older compared with 79% (95% CI, 75%82%) of those younger than 65 years (no significant difference between age groups). DBP goal was achieved in significantly more patients aged 65 years or older at week 18 (96%; 95% CI, 92%98%) than those younger than 65 years (78%; 95% CI, 75%82%; P=.001). The dual SBP and DBP goal attainment rate was 72% (95% CI,

Efficacy of irbEsartan/HctZ in EldErly PatiEnts

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The American Journal of Geriatric Cardiology (ISSN 1076-7460) is published bimonthly (Jan., March, May, July, Sept., Nov.) by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT 06484. Copyright 2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Ben Harkinson at BHarkinson@bos.blackwellpublishing.com or 781-388-8511.

Figure. Mean change from baseline in systolic blood pressure (SBP) (A) and diastolic blood pressure (DBP) (B) at the end of each treatment period for patients younger than 65 years and those aged 65 years or older (intent-to-treat population). Week 2 was the end of hydrochlorothiazide (HCTZ) 12.5 mg treatment; week 10 was the end of irbesartan/HCTZ 150/12.5 mg treatment; and week 18 was the end of irbesartan/HCTZ 300/25 mg treatment. The last observation carried forward was used for week 18 data. CI indicates confidence interval.

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Efficacy of irbEsartan/HctZ in EldErly PatiEnts

tHE aMErican JoUrnal of GEriatric cardioloGy 2008 Vol. 17 no. 1

The American Journal of Geriatric Cardiology (ISSN 1076-7460) is published bimonthly (Jan., March, May, July, Sept., Nov.) by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT 06484. Copyright 2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Ben Harkinson at BHarkinson@bos.blackwellpublishing.com or 781-388-8511.

Table III. Patients in Whom SBP and/or DBP Goal Was Reached at the End of HCTZ 12.5 mg (week 2), Irbesartan/HCTZ 150/12.5 mg (week 10), and Irbesartan/HCTZ 300/25 mg (week 18) Treatment by Age Group (ITT population) age gRoup YoungeR than 65 YeaRs 65 YeaRs oR olDeR sbP goal, no. (%) at week 2 14 (3) 7 (4) at week 10 315 (57) 96 (52) at week 18 434 (79) 135 (73) 95% ci for baseline to week 18, % 7582 6780 dbP goal, no. (%) at week 2 151 (27) 115 (63)a at week 10 361 (65) 158 (86)a at week 18 433 (78) 177 (96)b 95% ci for baseline to week 18, % 7582 9298 sbP and dbP goal, no. (%) at week 2 9 (2) 6 (3) at week 10 264 (48) 90 (49) at week 18 375 (68) 132 (72) 95% ci for baseline to week 18, % 6472 6578 a P<.05 for the comparison between age groups. bP<.001 for the comparison between age groups. systolic blood pressure (sbP) goal, <140 mm Hg; <130 mm Hg in patients with type 2 diabetes mellitus. diastolic blood pressure (dbP) goal, <90 mm Hg; <80 mm Hg in patients with type 2 diabetes mellitus. abbreviations: ci, confidence interval; HctZ, hydrochlorothiazide. 65%78%) in the 65 years and older age group vs 68% (95% CI, 64%72%) in the younger than 65 years age group (no significant difference between age groups). For comparison, goal attainment rates at week 18 in the total INCLUSIVE patient population were 77% (95% CI, 74%80%) for SBP, 83% (95% CI, 80%86%) for DBP, and 69% (95% CI, 66%72%) for dual SBP/DBP control.34 Safety. The safety population comprised 260 patients aged 65 years or older and 745 of those younger than 65 years who took at least 1 dose of placebo. Adverse events were experienced by 57% of patients younger than 65 years and 50% of patients aged 65 years or older. Most were of mild or moderate intensity, transient in duration, and considered unrelated to study medication (Table IV). Dizziness was the most common adverse event, occurring in 5% of patients in each age group. Twenty-five patients experienced a serious adverse event; 5 of these were in the 65 years and older age group (1.9% of the safety population) and 20 were in the younger than 65 years age group (2.7% of the safety population). All serious adverse events were judged to be unrelated to study medication, except for 1 incidence of hypotension, which occurred in a 56-year-old man and was considered to probably be related to study medication (irbesartan/HCTZ 150/12.5 mg). There were 2 deaths during the study. One 86-year-old man experienced a fatal myocardial infarction during placebo treatment (last recorded BP level, 154/73 mm Hg), and one 52-year-old man had a fatal motor vehicle accident during study treatment with irbesartan/HCTZ 150/12.5 mg. In addition, one 84-year-old woman died after signing the written informed consent form but before receiving any study treatment, and she was not included in the safety population. None of the deaths were considered to be related to study medication. Changes in levels of blood urea nitrogen, creatinine, and potassium during the treatment period were significant but not clinically relevant (Table V).

dISCUSSIOn

This subgroup analysis of the INCLUSIVE trial showed that treatment with irbesartan/HCTZ produced significant reductions in both SBP and DBP in the majority of patients with SBP uncontrolled with previous antihypertensive monotherapy, regardless of whether the patients were aged 65 years or older or were younger than 65 years. The SBP and DBP reductions observed over the 18-week treatment period were of a similar magnitude in the 2 age

Efficacy of irbEsartan/HctZ in EldErly PatiEnts

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The American Journal of Geriatric Cardiology (ISSN 1076-7460) is published bimonthly (Jan., March, May, July, Sept., Nov.) by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT 06484. Copyright 2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Ben Harkinson at BHarkinson@bos.blackwellpublishing.com or 781-388-8511.

Table IV. Adverse Events Occurring at a Frequency of 2% During Irbesartan/HCTZ 150/12.5 mg or

Irbesartan/HCTZ 300/25 mg Treatment by Age Group (Safety Population) tReatMent peRioD iRBesaRtan/hctZ 150/12.5 Mg placeBo hctZ 12.5 Mg younger than 65 years safety population, no. 745 632 584 total with an adverse event, no. (%) 187 (25) 110 (17) 157 (27) 9 (1) 4 (1) 12 (2) dizziness, no. (%)a 65 years or older safety population, no. 260 212 198 total with an adverse event, no. (%) 53 (20) 34 (16) 55 (28) 1 (0.4) 5 (2) 4 (2) dizziness, no. (%)a a Most frequent adverse event. abbreviation: HctZ, hydrochlorothiazide. iRBesaRtan/hctZ 300/25 Mg 530 138 (26) 13 (2) 163 40 (25) 5 (3)

total 745 421 (57) 36 (5) 260 130 (50) 14 (5)

Table V. Change in Laboratory Measurements of Renal Function and Serum Potassium During the Treatment
Period (Baseline to Week 18) by Age Group (Intent-to-Treat Population) age gRoup YoungeR than 65 YeaRs 65 YeaRs oR olDeR blood urea nitrogen, mg/dl 2.594.59 4.654.96 serum creatinine, mg/dl 0.040.12 0.070.12 serum potassium, mmol/l 0.120.40 0.070.49 Values are mean sd. P<.0001 for all changes from baseline to week 18 in both age groups.

groups and to the overall patient population,34 suggesting that BP control can be achieved in relatively resistant groups of patients, such as older patients with systolic hypertension uncontrolled by monotherapy, through the provision of irbesartan/HCTZ combination therapy. SBP goal was achieved in a slightly higher proportion of younger patients than older patients, despite a 2-mm Hg greater SBP reduction in the 65 years or older age group than in the younger than 65 years age group, although neither of these differences was statistically significant. This finding is apparently due to the higher baseline SBP level in the older patients. Nevertheless, SBP goal was achieved in more than 7 out of 10 patients aged 65 years or older, which is clinically important given the high prevalence of elevated SBP among older individuals and the strong association between SBP and cardiovascular risk.47 In addition, since elderly patients tend to have greater elevations in SBP than DBP, in most patients in the 65 years and older age group in whom SBP goal was achieved, DBP goal was also achieved. The study drugs appeared to be well tolerated. Adverse events were consistent with previous studies, indicating that the proven tolerability profile of irbesartan is maintained when administered in combination with HCTZ.2530,40 There was no excess of adverse events, including orthostatic hypotension

symptoms, in patients aged 65 years or older compared with those younger than 65 years, and there was no increase in rates of adverse events as treatment was titrated from low- to high-dose irbesartan/ HCTZ. Although the frequency of adverse events was greater during treatment with irbesartan/HCTZ than with HCTZ alone in both age groups, this may be explained by the longer irbesartan/HCTZ treatment period (8 weeks for each dose) vs HCTZ 12.5 mg (2 weeks), and there were few adverse events attributed to study medications. Poor compliance with the antihypertensive treatment regimen is an important cause of failure to reach BP goal in patients with hypertension.41,42 Treatment efficacy, tolerability, and the complexity of the dosing regimen are potentially important factors that influence compliance in older individuals, especially in the setting of hypertension, in which multiple drugs will be needed for most patients to reach their BP target.16,18 Careful selection of drugs that are effective and well tolerated when used in combination, such as those used in the current study, can help patients adhere to the treatment regimen by minimizing the impact of medication-related adverse effects. Of patients aged 65 years or older in the INCLUSIVE trial, only 10 discontinued irbesartan/HCTZ treatment because of adverse events. Fixed-dose combination products, such as irbesartan/HCTZ, can also

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Efficacy of irbEsartan/HctZ in EldErly PatiEnts

tHE aMErican JoUrnal of GEriatric cardioloGy 2008 Vol. 17 no. 1

The American Journal of Geriatric Cardiology (ISSN 1076-7460) is published bimonthly (Jan., March, May, July, Sept., Nov.) by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT 06484. Copyright 2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Ben Harkinson at BHarkinson@bos.blackwellpublishing.com or 781-388-8511.

encourage therapy compliance by simplifying the dosing regimen and reducing the pill burden. This is of particular relevance in older individuals, who are more likely to be taking additional medications for comorbidities and in whom forgetfulness may be a problem. Achieving BP goal soon after the initiation of therapy may also promote longterm compliance because the patient will develop confidence in the efficacy of the treatment regimen and understand its benefit.43 The filter study design of the INCLUSIVE trial allowed selection of patients whose SBP was uncontrolled by single-agent therapy with a low dose of HCTZ. The study enabled direct evaluation of the therapeutic benefit of add-on irbesartan 150 mg to HCTZ 12.5 mg in fixed-dose combination and of up-titration to irbesartan/HCTZ 300/25 mg in patients aged 65 years or older. This study design also mimics the stepped-care approach to hypertension management that is usually applied in clinical practice and is consistent with current labeling for the drug40 and with JNC 7 recommendations for the treatment of the elderly.16 The JNC 7 guidelines advocate the initial use of a thiazide-type diuretic in most patients with hypertension and use of combination therapy, usually including a thiazidetype diuretic, when a patients BP is uncontrolled by monotherapy or is >20 mm Hg above the SBP goal or >10 mm Hg above the DBP goal.16 Because elderly patients may be more vulnerable to an acute fall in BP, however, drug treatment should be initiated carefully, with a low dose of drug that has a safe profile of adverse events. A number of factors may limit the interpretation of the results of this study and have been discussed previously.34 Briefly, the relatively short active treatment period allowed only short-term evaluation of efficacy and tolerability; the 2-week HCTZ monotherapy treatment period may have been insufficient in duration or dose of HCTZ (12.5 mg) to allow maximal antihypertensive efficacy of a thiazide-type diuretic; a control group was not included; the study was open-label; and patients were not randomized to treatment. The initial placebo and HCTZ phases, and the measurement of BP with a validated automatic manometer, should have minimized potential sources of bias and regression to the mean. It is acknowledged that although the elderly population examined in this subgroup analysis included minorities, patients with type 2 diabetes mellitus, and those with metabolic syndrome, the extensive exclusion criteria eliminated many of the comorbidities typically seen in some practices.

COnClUSIOnS

Hypertension is not a benign aging phenomenon; it increases the risk of both fatal and nonfatal cardiovascular events. These risks are markedly reduced when careful attention is given to achievement of BP goals. Treatment should be with appropriate antihypertensive agents, with persistent dose titration or addition of medications until the BP goal is met. In many patients, this will necessitate the use of 2 or more drugs from different classes. This subgroup analysis of the INCLUSIVE trial suggests that irbesartan/HCTZ combination therapy is safe and effective in achieving BP goal in more than 7 out of 10 patients aged 65 years or older with previously uncontrolled SBP on monotherapy.
Acknowledgments: In addition to the authors, the INCLUSIVE Investigators are as follows: L. Altschul, Z. Ansari, P Arcuri, . H. Bays, H. Biermann, N. Bittar, J. Bloom, K. Bordenave, D. Brautigam, P Buchanan, A. Carr, J. Champlin, D. Cheung, S. . Chrysant, J. Clower III, G. Collins, M. DeBruin, E. Denoia, V . Desai, M. Dewan, M. El Shahawy, A. Elkind, R. D. Ferrera, J. Fidelholtz, N. Fraser, L. Gidday, L. Gilderman, R. Ginsburg, E. Hare, D. Hassman, M. Heitbrink, M. Henriquez, J. Herron, G. Hilliard, P Hughes, H. Ibrahim, T. Isakov, W. Jacobs, J. . Jernigan, L. Judy, D. Kereiakes, B. Kerzner, L. Koehler, M. Koren, M. Kozinn, E. Kunst, G. Lankin, A. Lewin, T. Littlejohn III, B. Lubin, R. Marple, J. Mersey, F Messerli, N. Messina . III, M. Mollen, P Narayan, S. Nesbitt, S. Ong, S. Oparil, . R. Owens, C. Patel, M. Peshimam, F Pettyjohn, A. Phillips, . I. Plisco, M. Pohl, J. Quesada, G. Raad, B. Rankin, D. Riff, S. Rosansky, E. Roth, G. Ruoff, J. Sandoval, J. Saponaro, S. Shahzad, K. Sheehan, T. Sherraden, D. Sica, J. Siemienczuk, N. Singh, G. Smith, W. Smith, J. Soufar, W. Starling, K. Stone, C. Strout, R. Strzinek, D. Sugimoto, G. Szenkiel, R. Tidman, M. Tonkon, M. S. Touger, H. Underwood, C. Uy, J. Wadleigh, V Wassily, J. Wayne, V Weber, R. Weiss, N. Winer, D. Young, . . and J. Zebrack.

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The American Journal of Geriatric Cardiology (ISSN 1076-7460) is published bimonthly (Jan., March, May, July, Sept., Nov.) by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT 06484. Copyright 2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Ben Harkinson at BHarkinson@bos.blackwellpublishing.com or 781-388-8511.

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Efficacy of irbEsartan/HctZ in EldErly PatiEnts

tHE aMErican JoUrnal of GEriatric cardioloGy 2008 Vol. 17 no. 1

The American Journal of Geriatric Cardiology (ISSN 1076-7460) is published bimonthly (Jan., March, May, July, Sept., Nov.) by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT 06484. Copyright 2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Ben Harkinson at BHarkinson@bos.blackwellpublishing.com or 781-388-8511.