initial combination therapy with irbesartan/hydrochlorothiazide for hypertension: an analysis of the...

suppl. 5 VOl. 9 NO. 12 December 2007 THe JOurNal Of cliNical HyperTeNsiON 15

Hypertension treatment guidelines recommend initiating 2-drug therapy whenever blood pres-sure (BP) is ≥20 mm Hg systolic or ≥10 mm Hg diastolic above goal. This post hoc pooled analy-sis of 2 multicenter, randomized, double-blind, active-controlled forced-titration studies in 1235 patients with moderate and severe hypertension examined how baseline BP levels relate to the need for combination therapy by comparing the antihypertensive efficacy and tolerability of once-daily fixed-dose irbesartan/hydrochlorothiazide (HCTZ) 300/25 mg compared with irbesartan 300-mg or HCTZ 25-mg monotherapies. In study 1, patients with severe hypertension (seated dia-stolic BP [SeDBP] ≥110 mm Hg) were treated for 7 weeks with irbesartan or irbesartan/HCTZ combination therapy, with forced-titration after week 1. In study 2, patients with moderate hyper-tension (seated systolic BP [SeSBP] 160–180 mm Hg or SeDBP 100–110 mm Hg) were treated for 12 weeks with irbesartan/HCTZ, irbesartan monotherapy, or HCTZ monotherapy, with forced-titration after week 2. The relationship between baseline BP and the likelihood of achieving BP goals (SeSBP <140 mm Hg or SeDBP <90 mm Hg; SeSBP <130 mm Hg or SeDBP <80 mm Hg) as

well as the antihypertensive response was evaluated at week 7/8. The need for combination therapy increased with increasing baseline BP and lower BP goals across the range of BP levels studied, with a comparable adverse effect profile to mono-therapy. These results suggest that the likelihood of achieving an early BP goal for a given BP severity should be considered when choosing initial combi-nation therapy vs monotherapy. (J Clin Hypertens. 2007;9(12 suppl 5):15–22) ©2007 Le Jacq

Hypertension affects approximately one-third of the adult population.1 it is the most

prevalent modifiable risk factor for cardiovascular disease and the most common risk factor for death from any cause worldwide.2,3 lowering blood pressure (bp) can produce rapid reductions in vas-cular disease risk in people with hypertension.4–6 current hypertension treatment guidelines rec-ommend lowering bp to <140/90 mm Hg in the general population and to <130/80 mm Hg in per-sons with diabetes and renal disease.7–11 recently, the european society of Hypertension/european society of cardiology (esH/esc) 2007 guide-lines10 have broadened their lower bp (<130/80 mm Hg) target group to include patients with cerebrovascular disease and coronary heart dis-ease. similarly, the american Heart association (aHa) council for High blood pressure research and the councils on clinical cardiology and epidemiology and prevention11 recommend a lower goal bp (<130/80 mm Hg) for patients with coronary artery disease, coronary artery disease

O r i g i n a l P a p e r

Initial Combination Therapy With Irbesartan/Hydrochlorothiazide for Hypertension: An Analysis of the Relationship Between Baseline Blood Pressure and the Need for Combination Therapy

Stanley Franklin, MD;1 Pablo Lapuerta, MD;2 David Cox, PhD;2 Mark Donovan, PhD2

From the University of California, Irvine, CA;1 and Bristol-Myers Squibb, Princeton, NJ2

Address for correspondence: Stanley Franklin, MD, University of California, Irvine, 155 Barlock Avenue, Los Angeles, CA 90049E-mail: [email protected]

www.lejacq.com ID: 7808

The Journal of Clinical Hypertension® (ISSN 1524-6175) is published monthly 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 [email protected] or 781-388-8511.

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THe JOurNal Of cliNical HyperTeNsiON suppl. 5 VOl. 9 NO. 12 December 200716

risk equivalents, carotid artery disease (carotid bruit or abnormal findings on carotid ultra-sound or angiography), peripheral arterial disease, abdominal aortic aneurysm, and a high cardiovas-cular risk (10-year framingham risk score >10%). Despite these guidelines, a significant percentage of patients are not being treated to bp goal.2,12

patients at high cardiovascular risk, such as patients with moderate and severe (≥160/100 mm Hg) hypertension, defined as stage 2 hyperten-sion by the seventh report of the Joint National committee on prevention, Detection, evaluation, and Treatment of High blood pressure (JNc 7)7 and grade 2 or 3 hypertension by the 2007 esH/esc guidelines,10 benefit from early and aggres-sive antihypertensive treatment to reduce their bp as quickly as possible.5,6 Hypertension treat-ment guidelines recommend initiating treatment with 2-drug therapy whenever bp is ≥20 mm Hg systolic or ≥10 mm Hg diastolic above the rec-ommended goal.7–11 The most widely used drug combinations include an angiotensin receptor blocker (arb), angiotensin-converting enzyme inhibitor, or b-blocker all with hydrochlorothi-azide (HcTZ), a thiazide diuretic. recent clini-cal studies in moderate and severe hypertension show that a combination of the arb irbesartan with HcTZ is safe and effective in patients irre-spective of baseline bp level, age, obesity, race, diabetic status, and the metabolic syndrome13–24 and has a significantly greater dose-dependent bp-lowering effect than either agent alone.13–16 adequate dosages of irbesartan monotherapy, however, have also been associated with high bp control rates in hypertensive individuals,25–28 which raises the question of which baseline bp level would warrant the need for irbesartan com-bination therapy vs monotherapy. The us food and Drug administration and the cardiorenal advisory committee have recently suggested that physicians should be presented with efficacy data across a wide range of bp levels so that they can decide when to initiate treatment with combina-tion therapy instead of monotherapy. This strat-egy represents a new and important approach to the labeling of antihypertensive drugs.

The following post hoc analysis was designed to examine how baseline bp levels relate to the need for combination therapy compared with monotherapy. in this study, the treatment effects and tolerability of irbesartan monotherapy were compared with those of an irbesartan/HcTZ fixed-dose combination therapy across a range of baseline bp levels span-ning moderate to severe hypertension.

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Figure 3. Probability of achieving a seated systolic blood pressure (SeSBP) <130 mm Hg at weeks 7 (study 1) and 8 (study 2). HCTZ indicates hydrochlorothiazide.

Figure 1. Probability of achieving a seated systolic blood pressure (SeSBP) <140 mm Hg at weeks 7 (study 1) and 8 (study 2). In this probability curve, patients without blood pressure measurements at week 7/8 were counted as not reaching goal. HCTZ indicates hydrochlorothiazide.

Figure 2. Probability of achieving a seated diastolic blood pressure (SeDBP) <90 mm Hg at weeks 7 (study 1) and 8 (study 2). HCTZ indicates hydrochlorothiazide.


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MeTHodsstudy designThis was a pooled post hoc analysis of 2 multi-center, randomized, double-blind, active-controlled forced-titration studies assessing the antihyperten-sive efficacy and tolerability of once-daily fixed-dose irbesartan/HcTZ 300/25 mg vs irbesartan 300-mg monotherapy in patients with moderate or severe hypertension (bp ≥20 mm Hg above the JNc 7–recommended systolic bp [sbp]/diastolic bp [Dbp] goals7). full details of the individual studies have previously been published.29,30 briefly:•Study1wasa7-weektrialinpatientswithsevere

hypertension (seated Dbp [seDbp] ≥110 mm Hg), conducted at 250 study centers in North america, europe, and asia. eligible patients entered a 7-day single-blind placebo lead-in period. patients with seDbp ≥110 mm Hg at 2 consecutive visits during the lead-in period were randomized in a 2:1 ratio to irbesartan/HcTZ 150/12.5-mg fixed-dose combination therapy force-titrated to 300/25 mg after week 1 or irbe-sartan 150-mg monotherapy force-titrated to 300 mg after week 1.

•Study2wasa12-weektrialinpatientswithmod-erate hypertension (seated sbp [sesbp] 160–180 mm Hg or seDbp 100–110 mm Hg), conducted at 150 study centers in North america, europe, and asia. eligible patients entered a 21-day single-blind placebo wash-out period before ran-domization in a 3:1:1 ratio to irbesartan/HcTZ 150/12.5-mg fixed-dose combination therapy force-titrated to 300/25 mg after week 2, irbe-sartan 150-mg monotherapy force-titrated to 300 mg after week 2, or HcTZ 12.5-mg mono-therapy force-titrated to 25 mg after week 2.patients were not eligible for either of the 2 stud-

ies if they had sesbp ≥220 mm Hg, seDbp ≥130 mm Hg, known or suspected secondary hyperten-sion, or any condition that required more immedi-ate bp lowering. in both studies, all patients gave a detailed medical history and underwent a complete physical examination at study entry, including 12-lead electrocardiography. During active treat-ment, average seated bp was measured, followed by standing trough bp (24±3 hours postdose) and heart rate. all study medication was taken once daily between 6 am and 11 am, except on the morning of a study visit.

baseline demographics (other than baseline bp level) and the absolute amount by which sbp was lowered were similar in the 2 studies, hence justi-fying pooling patient data in a post hoc analysis. Together, the patient populations spanned the

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Figure 6. Probability of achieving a seated diastolic blood pressure (SeDBP) <90 mm Hg at week 7/8. HCTZ indicates hydrochlorothiazide.

Figure 4. Probability of achieving a seated diastolic blood pressure (SeDBP) <80 mm Hg at weeks 7 (study 1) and 8 (study 2). HCTZ indicates hydrochlorothiazide.

Figure 5. Probability of achieving a seated systolic blood pressure (SeSBP) <140 mm Hg at week 7/8. In this probability curve, patients without blood pressure measurements at week 7/8 were counted as not reach-ing goal. HCTZ indicates hydrochlorothiazide.


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range of stage 2 (JNc 7 guidelines7) and grade 2 or 3 hypertension (esH/esc 2007 guidelines10).

a post hoc pooled analysis of studies 1 and 2 was carried out to examine the relationship between baseline bp level and the likelihood of achieving bp goals (sesbp <140 mm Hg or seDbp <90 mm Hg; sesbp <130 mm Hg or seDbp <80 mm Hg) with irbesartan/HcTZ combination ther-apy compared with irbesartan monotherapy and HcTZ monotherapy at week 7/8 using a logistic regression model. The relationship between base-line bp level and the magnitude of antihypertensive response, together with the tolerability of com-bination therapy vs irbesartan monotherapy and HcTZ monotherapy, was also evaluated.

statisticsin both studies, efficacy evaluations were conduct-ed on the intent-to-treat population, and safety evaluations were conducted on all randomized patients who took at least 1 dose of double-blind study medication. patients who had a missing postbaseline sesbp (or seDbp) reading at week 7/8 were defined as not meeting their sesbp (or seDbp) target. logistic regression curves were generated for each study using a model of separate slopes between treatment arms to assess the rela-tionship between baseline bp and the probability of achieving the following goals:• <140mmHgSeSBPvsbaselineSeSBP• <130mmHgSeSBPvsbaselineSeSBP• <90mmHgSeDBPvsbaselineSeDBP• <80mmHgSeDBPvsbaselineSeDBP

in addition to the analyses by study and treatment arm, data from the 2 studies were combined at the individual patient level. bp changes from baseline and the probability of achieving goal bp were assessed. patients with a baseline sesbp of 140 to <220 mm Hg were used for the sesbp analyses, and patients with a baseline seDbp of 90 to <130 mm Hg were used for seDbp analyses. These ranges were selected based on patients whose bp level was above target at baseline and within protocol-specified limits for the upper range of bp. logistic regression curves were generated for the combined studies using either a common slope model or a separate slope model to assess the relation-ship between baseline bp and the probability of achiev-ing these goals. The determination of the common/separate slope models was carried out using differences in model likelihood (chi-squared test with 2 df).

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Figure 7. Probability of achieving a seated systolic blood pressure (SeSBP) <130 mm Hg at week 7/8. HCTZ indicates hydrochlorothiazide.

Table I. Baseline Characteristics for the Pooled Analysis Safety PopulationIrbesartan/HCTZ (n=796) Irbesartan (n=335) HCTZa (n=104)

Age (range), y 53.4 (23–87) 53.7 (25–87) 56.0 (21–83)Male sex, % 57.6 51.6 59.6White race, % 83.7 85.6 82.7Black race, % 14.7 12.8 14.4Weight (range), kg 88.8 (46.0–164.3) 90.7 (44.0–151.5) 88.4 (55.0–146.1)Baseline DBP (range), mm Hg 106.8 (66.0–131.6) 108.4 (74.3–135.0) 97.6 (74.7–110.7)Baseline SBP (range), mm Hg 167.5 (127.7–221.7) 168.4 (135.7–220.7) 162.0 (136.0–180.0)Baseline heart rate (range), bpm 76.6 (48.0–111.0) 76.2 (52.0–117.0) 76.6 (50.0–108.0)Medical history, %

Diabetes 12.4 13.1 12.5Hyperlipidemia 38.2 36.7 35.6Stable angina pectoris 2.3 4.2 1.0Stroke or transient ischemic attack 1.5 2.1 1.0Myocardial infarction 1.4 1.2 1.9Previous antihypertensive therapy 52.0 56.7 45.2

aStudy 2 (patients with moderate blood pressure) only. Abbreviations: bpm, beats per minute; DBP, diastolic blood pressure; HCTZ, hydrochlorothiazide; SBP, systolic blood pressure.


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ResulTsamong the 1235 patients enrolled in the 2 studies, 796 were randomized to receive irbesartan/HcTZ combination therapy, 335 to irbesartan mono-therapy, and 104 (all with moderate hypertension) to HcTZ monotherapy. Of these, 1093 patients (88%) completed the study: 707 participants in the combination therapy group, 295 in the irbe-sartan monotherapy group, and 91 in the HcTZ monotherapy group. The most common reasons for study discontinuation were unresponsiveness to therapy and adverse events (aes).

patient characteristics were similar in each of the pooled treatment groups (Table i). most patients were middle-aged (mean age, 54 years); approximately one-half (56%) were men, and 84% were white. at baseline, the mean diastolic and systolic bp levels were 106.95 mm Hg and 167.28 mm Hg, respectively. Overall, 464 patients (37.6%) had hyperlipidemia, while 156 (12.6%) had diabetes mellitus. in total, 52.0%, 56.7%, and 45.2% of patients in the irbesartan/HcTZ, irbesartan, and HcTZ groups, respectively, had previously received antihypertensive therapy.

The mean ± se treatment-related changes from baseline to week 7/8 in seDbp and sesbp and the mean changes in sesbp, according to baseline bp strata, are given in Table ii. results of the logistic regression model by study are presented in figure 1, figure 2, figure 3, and figure 4. These graphs have been incorporated into the irbesartan/HcTZ us product label. a total of 1195 patients had baseline sesbp values from 140 to <220 mm Hg, and 1141 had baseline seDbp values from 90 to <130 mm Hg. in terms of the model selection for the pooled analyses, the common slope model was supported for sesbp (P=.25 for target sesbp <140 mm Hg; P=.49 for target sesbp <130 mm Hg), while the separate slope model was used for seDbp (P=.02 for target seDbp <90 mm Hg; P=.11 for target seDbp <80 mm Hg). The resulting logistic

regression curves are shown in figure 5, figure 6, figure 7, and figure 8.

irbesartan/HcTZ was generally associated with a greater likelihood of achieving an sesbp <140 mm Hg (figure 1 and figure 5) or seDbp <90 mm Hg (figure 2 and figure 6) relative to irbesartan or HcTZ monotherapies across the range of bp levels studied. in the separate slope models by study, the difference between the irbesartan/HcTZ and irbesartan arms in the likelihood of achieving a bp target tended to be smaller in patients with very high baseline bp levels (figure 1 and figure 2). in all cases, the likelihood of achieving bp goals increased as baseline bp decreased for all groups. for example, the probability of achieving a post-treatment value of <140 mm Hg for a patient with a baseline sesbp of 185 mm Hg is approximately 30% with irbesartan/HcTZ and 16% with irbe-sartan monotherapy (figure 5). for patients with a baseline sesbp of 160 mm Hg, the respective probabilities are 66% and 48% and only 35% for patients receiving HcTZ monotherapy.

Table II. Mean Changes from Baseline to Study End in SeSBP by Baseline SeSBP Strata (Primary Analysis Population)Irbesartan/HCTZ Irbesartan HCTZ

No.Mean Change (SE), mm Hg No.

Mean Change (SE), mm Hg No.

Mean Change(SE), mm Hg

Baseline SeSBP, mm Hg140–159 180 –22.1 (0.91) 74 –14.3 (1.41)160–179 406 –30.4 (0.69) 161 –23.2 (1.16)>180 120 –42.9 (1.68) 56 –30.6 (2.70)Overall 706 –29.9 (0.59) 291 –21.7 (0.97) 104 –15.7 (1.53)

Baseline SeDBP, mm HgOverall 706 –20.4 (0.38) 291 –17.3 (0.63) 104 –7.2 (0.75)

Abbreviations: HCTZ, hydrochlorothiazide; SeSBP, seated systolic blood pressure.

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similar results were obtained for a variety of tar-get goals, including sesbp <130 mm Hg (figure 3 and figure 7) or seDbp <80 mm Hg (figure 4 and figure 8), although the proportions of patients in whom target bp was reached decreased as the goal bp was lowered. for example, among patients with a baseline sesbp of 160 mm Hg, a goal bp <130 mm Hg was achieved in only 35% of those treated with combination therapy, 17% of those treated with irbesartan monotherapy, and 8% of those treated with HcTZ monotherapy (figure 7). although combination therapy remained insufficient for the majority of patients with severely elevated baseline bp and/or lower bp goals, substantially greater bp reductions were achieved with combination therapy than with irbesartan monotherapy across all base-line sesbp levels (Table ii). This suggests that add-ing a third agent to combination therapy would be more effective for achieving bp goals than adding a second agent to monotherapy.

The types and rates of aes experienced by patients treated with irbesartan/HcTZ were com-parable to those reported by patients treated with irbesartan or HcTZ monotherapy (Table iii). Overall, aes were experienced by 37% of patients treated with combination therapy, 39% of those treated with irbesartan monotherapy, and 39.4% of those treated with HcTZ monotherapy. Treatment-related aes were reported by 12.5%,

10.5%, and 7.7% of patients in each of the respec-tive treatment groups. Only 0.9%, 0.3%, and 2.9% of patients, respectively, experienced serious aes, and there were no deaths in any of the treat-ment groups.

dIsCussIoNin this pooled analysis of 2 randomized, double-blind active-controlled trials, irbesartan/HcTZ combina-tion therapy was associated with a greater degree of bp-lowering and a greater likelihood of achiev-ing goal bp after 7/8 weeks than was irbesartan or HcTZ monotherapy, across the range of bp levels studied. These results are consistent with those from previous studies in which irbesartan/HcTZ combina-tion therapy effectively lowered bp to goal in patients with difficult-to-treat hypertension.14,19,23,29,30

Our study suggests that although a goal bp of <140/90 mm Hg can be reached in the majority of patients with sbp <160 mm Hg with irbesartan monotherapy, most patients with moderate to severe (stage 27 or grade 2 or 310) hypertension (baseline sbp ≥160 mm Hg) require combination therapy for bp goal to be reached (figure 1, figure 3, figure 5, and figure 7). This observation is consistent with the current hypertension treatment guidelines that state that the majority of patients with hypertension require at least 2 drugs with different mechanisms of action for bp control to be attained and that the treatment of stage 2 hypertension should be initi-ated with combination therapy.4,7,8,10,11 Our study also shows that although combination therapy is effective in patients with stage 2 hypertension (in the pooled analysis, the mean reduction in sesbp in patients with baseline sbp ≥180 mm Hg was 43 mm Hg [Table ii]), baseline bp is so far above goal in many of these patients that a third or even a fourth antihypertensive agent may be required to achieve effective bp control.

in addition to a greater need for combination therapy in patients with higher baseline bp levels, more aggressive therapy is also required in patients with lower bp goals. in the pooled analysis, the proportions of patients with a baseline sbp of 160 mm Hg in whom a goal bp <140 mm Hg was achieved with combination therapy, irbesartan monotherapy, and HcTZ monotherapy were 66%, 48%, and 35%, respectively (figure 5) compared with 35%, 17%, and 8% of those in whom a goal bp <130 mm Hg was reached (figure 7). Given that the 2007 esH/esc10 and aHa hypertension treatment guidelines11 recommend reducing bp to the lower goal of <130/80 mm Hg in a wider patient group than previously suggested, more

Table III. AEs Associated With Irbesartan/HCTZ Combination Therapy, Irbesartan Monotherapy, and HCTZ Monotherapy % of Patients

Irbesartan/

HCTZ (n=796)Irbesartan

(n=333)aHCTZ (n=104)

Total AEs 37.0 39.0 39.4Treatment-related

AEs12.5 10.5 7.7

Treatment discontinuations due to AEs

3.5 2.7 4.8

Serious AEs 0.9 0.3 2.9Deaths 0 0 0AEs of special

interest9.6 9.9 6.7

Dizziness 3.4 1.5 1.0Headache 4.8 5.7 4.8Hyperkalemia 0.6 0 1.0Hypokalemia 0.7 0.3 0Hypotension 0.7 0 0Syncope 0 0 1.0

aTwo patients discontinued the study before receiving therapy. Abbreviations: AE, adverse event; HCTZ, hydrochlorothiazide.


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patients than ever are likely to require combination therapy rather than monotherapy.

previous studies have shown that the individual components of combination therapies can be given in a low-dose range that is more likely to be free of adverse effects than the higher doses of monotherapies that might be required to achieve the same bp goal.31 furthermore, some antihypertensive agents have the potential to attenuate the aes caused by other drugs. for example, diuretic-induced alterations in potas-sium, serum cholesterol, and fasting glucose values can be offset by the concomitant administration of an angiotensin-converting enzyme inhibitor or an arb.16 The types and incidences of aes reported in this study by patients treated with irbesartan/HcTZ were comparable to the ae profile for patients treated with irbesartan or HcTZ monotherapy. moreover, combination therapy reduced the risk of headache compared with irbesartan monotherapy and did not result in an increased incidence of hypotension, syn-cope, or dizziness—effects that might be expected to occur if bp is reduced too quickly.

Given the results of this analysis, it would be appropriate to initiate antihypertensive treatment in patients with stage 2 hypertension using arb/HcTZ combination therapy, to titrate to the maximum dose, if required, and to add a third medication within weeks if bp control is still not achieved. antihypertensive treatment strategies, however, should be selected according to the needs of each individual patient. in addition to hyperten-sion, some patients may have additional cardiovas-cular risk factors, such as diabetes, which suggest a greater urgency for quicker bp control. These patients may benefit from first-step combination therapy even if their bp level is in a range that might be effectively reduced using monotherapy. Other patients may have special safety concerns, such as risk factors for hypotension, and may ben-efit from initial monotherapy even if their bp level is relatively high. Thus, while the initial level of hypertension and goal bp are important consider-ations when deciding whether to initiate treatment using combination therapy or monotherapy, addi-tional risk factors must also be considered.

CoNClusIoNsThe results of this post hoc pooled analysis are consistent with those of previous studies in which first-step treatment using irbesartan/HcTZ combination therapy was well tolerated and more effective than irbesartan or HcTZ monotherapy in lowering bp to goal level in patients with a wide range of bp levels spanning moderate to severe (stage 27 or grade 2 or 310) hypertension.14,23,30,32

Our finding that the need for combination therapy increases with increasing baseline bp supports the current hypertension treatment guidelines, which recommend initiating treatment using combination therapy in patients with moderate to severe hyper-tension and using monotherapy in those whose bp level is closer to goal.7,10

Disclosures: Dr Franklin is a member of the Speakers’ Bureaus for Boehringer Ingelheim, Bristol-Myers Squibb, and Merck and is a consultant for AtCor Medical and Bristol-Myers Squibb. Drs Lapuerta, Cox, and Donovan conducted this work as employees of Bristol-Myers Squibb.

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20 Neutel Jm, saunders e, bakris Gl, et al. The efficacy and safety of low- and high-dose fixed combinations of irbe-sartan/hydrochlorothiazide in patients with uncontrolled systolic blood pressure on monotherapy: the iNclusiVe trial. J Clin Hypertens (Greenwich). 2005;7(10):578–586.

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30 Neutel Jm, franklin ss, lapuerta p, et al. a comparison of the efficacy and safety of irbesartan/HcTZ combination therapy with irbesartan and HcTZ monotherapy in the treatment of moderate hypertension. J Hum Hypertens. 2007 Oct 11;[epub ahead of print].

31 law mr, Wald NJ, morris JK, et al. Value of low dose com-bination treatment with blood pressure lowering drugs: anal-ysis of 354 randomised trials. BMJ. 2003;326(7404):1427.

32 Weir m, Neutel J, bhaumik a, et al. irbesartan/hydrochlo-rothiazide fixed-dose combination is effective and well tol-erated in moderate to severe (stage 2) hypertensive patients with and without advanced age, obesity, and/or type 2 dia-betes. presented at: 22nd meeting of the american society of Hypertension; may 19–22, 2007; chicago, il.


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