Angiotensin II antagonists for hypertension are there differences in efficacy

Angiotensin II Antagonists for Hypertension: Are There Differences in Ef?cacy?

Paul R.Conlin,J.David Spence,Bryan Williams,Arthur B.Ribeiro,Ikuo Saito,Claude Benedict, and Antonius M.G.Bunt

We compared the antihypertensive ef?cacy of available drugs in the new angiotensin-II-antagonist(AIIA)class.The antihypertensive

ef?cacy of losartan,valsartan,irbesartan,and candesartan was evaluated from randomized controlled trials(RCT)by performing a metaanalysis of43published RCT.These trials involved AIIA compared with placebo,other antihypertensive classes,and direct comparisons between AIIA.A weighted-average for diastolic and systolic blood pressure reduction with AIIA monotherapy,dose titration,and with addition of low-dose hydrochlorothiazide(HCTZ)were calculated.Weighted-average responder rates were also determined.The metaanalysis assessed a total of11,281patients.The absolute weighted-average reductions in diastolic(8.2to8.9mm Hg)and systolic(10.4to11.8mm Hg)blood pressure reductions(not placebo-corrected)for AIIA monotherapy were comparable for all AIIA.Responder rates for AIIA monotherapy were48% to55%.Dose titration resulted in slightly greater blood pressure reduction and an increase in responder rates to53%to63%.AIIA/hydrochloro-thiazide combinations produced substantially greater reduction in systolic(16.1to20.6mm Hg) and diastolic(9.9to13.6mm Hg)blood pressure reductions than AIIA monotherapy and responder rates for AIIA/HCTZ combinations were56%to 70%.This comprehensive analysis shows comparable antihypertensive ef?cacy within the AIIA class,a near-?at AIIA-dose response when titrating from starting to maximum recommended dose,and substantial potentiation of the antihypertensive effect with addition of HCTZ. Am J Hypertens2000;13:418–426?2000American Journal of Hypertension,Ltd.

KEY WORDS:Hypertension,randomized controlled trials,ef?cacy,review,angiotensin-II-antagonists.

A new class of antihypertensive drugs—an-

giotensin II antagonists(AIIA)—has

emerged during the past5years.These

agents speci?cally and selectively antago-nize the effects of angiotensin II(AII)at the angioten-sin type1(AT1)receptor.Prior clinical experience with angiotensin-converting enzyme inhibitors (ACE-I)suggested that this new class of drugs would be similarly effective for the treatment of hyperten-sion.

Received February26,1999.Accepted September17,1999. From the Endocrinology-Hypertension Division(PR),Brigham and Women’s Hospital and Harvard Medical School(JS),Boston, Massachusetts;Siebens-Drake/Robarts Research Institute,Univer-sity of Western Ontario,London,Ontario;Cardiovascular Research Institute(BW),University of Leicester,Leicester,United Kingdom; Nephrology Division(AR),UNIFESP-EPM,Sa?o Paulo,Brasil; Health Center(IS),Keio University,Tokyo,Japan;University of Texas Medical School(CB),Houston,Texas;and Merck&Co.Inc. (AMGB),Whitehouse Station,New Jersey.

This work was supported by grants from National Institutes of Health(HL57173)and Merck and Company,Inc.

Address correspondence and reprint requests to Paul R.Conlin, MD,Endocrinology-Hypertension Division,Brigham and Women’s Hospital,221Longwood Avenue,Boston,MA02115;e-mail: pconlin@271465c18bd63186bcebbcd0

AJH2000;13:418–426

?2000by the American Journal of Hypertension,Ltd.0895-7061/00/$20.00 Published by Elsevier Science,Inc.PII S0895-7061(99)00237-X

Losartan was the?rst of the AIIA to be approved for clinical use in hypertension,in1994.Since then,three other agents,valsartan,irbesartan,and candesartan, have been introduced for clinical use;many others are at various stages of development.Differences in the pharmacokinetic(PK)and pharmacodynamic(PD)pa-rameters of these agents,such as gastrointestinal ab-sorption,protein binding,volume of distribution,con-version of prodrug or active parent to active metabolite,oral bioavailability,competitive or non-competitive antagonism of AII at AT1receptors,re-ceptor binding af?nity,and elimination half-life,have been described.1–7

These differences have been cited as potentially im-portant causes of differential clinical ef?cacy within the AIIA class,particularly with regard to the magni-tude and duration of the antihypertensive response.In this regard,some recent publications have suggested differences in antihypertensive ef?cacy when AIIA were directly compared to each other in patients with hypertension.8–11This question of ef?cacy is poten-tially very important because if there are real and clinically meaningful differences in antihypertensive ef?cacy within the AIIA class,physicians would need to be aware of such differences to optimize therapeutic decisionmaking.

Independent interpretation of the available clinical data is confounded by the following problems:small trials,often conducted by the pharmaceutical manu-facturer with a study design potentially set up in its favor;differences in methodology in describing the blood pressure(BP)reduction that hamper or pre-clude comparisons across studies;and a lack of suf?-ciently large,well-designed,independent head-to-head comparative studies.In the absence of optimal studies,an alternative way to objectively assess the antihypertensive ef?cacy of AIIA is to pool all of the existing randomized clinical trial(RCT)data and con-duct a metaanalysis.We report the results of such an analysis and,in so doing,describe the antihyperten-sive ef?cacy of currently available AIIA from studies where these agents were compared with other classes of antihypertensive therapy and with each other.

MATERIALS AND METHODS

Data Sources This analysis examines the antihyper-tensive ef?cacy of four currently available AIIA—lo-sartan,valsartan,irbesartan,and candesartan—using Medline and Current Contents,through October1998, as sources of data.

Types of Data Three categories of peer-reviewed data were considered:randomized,double blind, placebo-controlled trials of the various AIIA;RCT comparing the various AIIA with other established classes of antihypertensive therapy,such as ACE-I,calcium channel blockers(CCB),?-blockers(BB),and combinations of AIIA with thiazide diuretics,mainly hydrochlorothiazide(HCTZ);and the limited number of RCT in which the antihypertensive ef?cacy of dif-ferent AIIA were compared directly with each other, so called“head-to-head”studies.The pooled data from all of the published RCT identi?ed in these cat-egories were subjected to a metaanalysis.

Study Selection The following criteria were used to determine the inclusion of a published RCT in the pooled metaanalysis:

Prospective,double-blind,randomized controlled methodology;

Placebo run-in period of4to5weeks;

Patient population de?ned as mild-to-moderate hy-pertension(DBP95to115mm Hg),with no concom-itant diseases;

Population representative of the overall hyperten-sive population;

Clinical measurement of blood pressure using sphygmomanometer and cuff,not studies using only ambulatory blood pressure monitoring(ABPM); Evaluated doses recommended in US,Japanese,and European product labels;

Treatment duration of at least4to6weeks with starting dose of AIIA before dose titration,then at least another4to6weeks until?nal assessment(total duration of double blind study was typically8to12 weeks);

Use of the following dosing regimens:titration as needed(or elective titration),either from starting dose to maximum dose of monotherapy or from starting dose of monotherapy to a combination of starting dose AIIA with low-dose HCTZ;parallel-group compari-sons of various doses as monotherapy or AIIA/HCTZ combinations;and forced titration of the dose. Trials were excluded if they examined use of AIIA after demonstration of lack of response with a drug from another class,or if they used a dose of AIIA not recommended in the product label.

Data Extraction To analyze the pooled data,we cor-rected for the size of the different studies by assigning a greater weight to the results in proportion to the size of the study.To calculate the mean blood pressure reduction with the different agents,the pooled data were weighted for the study size using the following formula:

The absolute,ie,non–placebo-corrected,weighted average BP reduction was:

??BP reduction(study1)?Number of patients(study1)?...??BP reduction(study n)?Number of patients(study n))] Total number of patients(study1?...?study n)

AJH–APRIL2000–VOL.13,NO.4,PART1ANTIHYPERTENSIVE EFFICACY OF AIIA419

Statistical Analyses Data are presented as mean val-ues with95%con?dence intervals(CI)calculated from the mean and standard deviation(SD)reported in the original publications.In publications where no SD was reported,we assumed an SD that was calculated from the weighted average of the same drug and dose. Comparisons of weighted average changes in blood pressure were compared using a t test with correction for multiple comparisons.

RESULTS

Pooled Metaanalysis of43Published RCT(N?11,281)The number of patients included in the pooled analysis(Tables1and2)was substantially larger for losartan than for the three other AIIA.The pooled analysis was grouped into three separate cat-egories:AIIA monotherapy at starting dose;AIIA monotherapy with elective or forced dose titration from the starting to the maximum dose;and starting dose AIIA/HCTZ combinations.Because of lack of suf?cient number of published trials,the higher dose AIIA/HCTZ combinations were not included. Diastolic Blood Pressure Reduction The absolute weighted average DBP reduction at trough(non–placebo-corrected)for the starting doses of AIIA was 8.2to8.9mm Hg(ie,maximum difference between individual AIIA was0.7mm Hg).The absolute weighted average DBP reduction at trough for AIIA monotherapy with dose titration was9.5to10.4mm Hg(ie,maximum difference between the individual AIIA was0.9mm Hg).AIIA monotherapy dose titra-tion resulted in a modest incremental DBP reduction compared to the starting dose of AIIA,which suggests a relatively?at dose response curve across the AIIA class.

Angiotensin II antagonists are frequently combined with low-dose diuretics to potentiate the antihyper-tensive effect.The absolute weighted average DBP reduction for AIIA at usual starting dose in combina-tion with12.5mg HCTZ was9.9to13.6mm Hg(ie,the maximum difference between individual AIIA/HCTZ was thus3.7mm Hg).However,these data were based on substantially smaller numbers of patients. The incremental DBP reduction between the starting doses of AIIA and the AIIA/HCTZ combinations was substantial,indicating that combination therapy is a more effective strategy than monotherapy dose titra-tion.

Systolic blood pressure reductions paralleled the DBP reductions.The absolute weighted average SBP reduction at trough for the starting doses of AIIA ranged from10.4to11.8mm Hg(ie,a maximum difference between AIIA of1.4mm Hg).The absolute weighted average SBP reduction for AIIA mono-therapy with dose titration was12.4to14.7mm Hg(ie,a maximum difference between agents of2.3mm Hg). AIIA monotherapy dose titration provided a modest incremental SBP reduction compared with the starting dose of AIIA.The absolute weighted average SBP reduction for AIIA/HCTZ combination therapy was 16.1to20.6mm Hg(ie,a maximum difference be-tween individual AIIA/HCTZ of4.5mm Hg).Once again,these data were based on fewer numbers of trials.The incremental SBP reduction between the starting doses of AIIA and the AIIA/HCTZ combina-tions was again more substantial.

Responder Rates The responder rate,de?ned as DBP less than90mm Hg or a DBP decrease of10mm Hg or more,was approximately50%for the recom-mended starting dose of all AIIA and increased to only55%after AIIA monotherapy dose titration.The AIIA/HCTZ combinations,however,showed re-sponder rates of approximately70%,con?rming the ef?cacy of this speci?c combination and the superior-ity of combination therapy when compared to mono-therapy dose titration.

There were no statistically signi?cant differences among the blood pressure responses of the four AIIA either as monotherapy or with dose titration for both systolic and diastolic blood pressures.Because there were fewer trials reporting responses to AIIA/HCTZ combinations,some of which did not report standard deviations,statistical comparisons could not be per-formed across this group.

The ranking of these four AIIA based on weighted average DBP and SBP reductions,and responder rates for monotherapy at starting dose,monotherapy titra-tion,and the combination of AIIA/HCTZ,appeared to be random,with each agent ranking as the best or worst in one category or another(data not shown). Averages across all studies of a given AIIA at a given dose without correction for sample size showed re-sults similar to the weighted averages presented here (data not shown).

DISCUSSION

This comprehensive analysis shows the comparable antihypertensive ef?cacy of losartan,valsartan,irbe-sartan,and candesartan when administered at their recommended doses.These four AIIA also show a near-?at dose-response curve when administered at doses recommended for the treatment of hyperten-sion,which suggests that monotherapy dose titration offers limited bene?t.As with other antihypertensive agents,combination of AIIA with low-dose diuretics signi?cantly potentiated the blood pressure reduction and responder rates.Importantly,the blood pressures used in this analysis are trough blood pressures mea-sured at the end of the24-h dosing interval.This also

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420CONLIN ET AL

TABLE1.FORTY-THREE PUBLICATIONS USED FOR THE INTEGRATED ANALYSIS OF AIIA

ANTIHYPERTENSIVE EFFICACY*

AIIA Dose First Author n

DBP(mm Hg)SBP(mm Hg)

Responders

(%) Mean SD95%CI Mean SD95%CI

Losartan50mg Trimarco4572?11.9 6.8(?13.5,?10.3)?14.611.8(?17.4,?11.8)

Gradman2279?10.17.0(?11.7,?8.5)?13.012.7(?15.8,?10.2)

Dahlof30132?9.07.7(?10.3,?7.7)?11.812.2(?13.9,?9.7)49

Weir46110?8.97.5(?10.3,?7.5)?9.613.0(?12.1,?7.1)

MacKay47138?8.87.6(?10.1,?7.5)?10.714.3(?13.1,?8.3)52

Chan2889?8.87.7(?10.4,?7.2)?12.613.8(?15.5,?9.7)56

Townsend27132?8.87.7(?10.1,?7.5)?8.613.8(?11.0,?6.2)

Roca-Cusachs48192?8.77.7(?9.8,?7.6)?12.013.8(?14.0,?10.0)56

Tikkanen25200?8.47.1(?9.4,?7.4)?10.613.0(?12.4,?8.8)51

Wilson2936?8.4 5.9(?10.4,?6.4)?10.09.2(?13.1,?6.9)

Oddou-Stock8534?8.07.7(?8.7,?7.3)?10.513.8(?11.7,?9.3)44

Ikeda49125?7.79.0(?9.3,?6.1)?9.213.8(?11.6,?6.8)46

Oparil5097?7.39.0(?9.1,?5.5)?6.114.4(?9.0,?3.2)

Mallion26109?7.0 6.6(?8.3,?5.7)?9.311.9(?11.6,?7.0)46

Byyny5129?6.77.8(?9.7,?3.7)?11.717.6(?18.4,?5.0)

Andersson983?6.68.7(?8.5,?4.7)?11.121.2(?15.7,?6.5)

Oparil11192?6.27.7(?7.3,?5.1)?8.313.8(?10.3,?6.3)44

Martina5210?4.07.2(?9.2,1.2)?7.08.2(?12.9,?1.1)

Valsartan80mg Hegner3682?13.47.7(?15.1,?11.7)?16.115.8(?19.6,?12.6)74 Mallion3494?13.27.6(?14.8,?11.6)?17.211.9(?19.6,?14.8)61

Corea3584?11.5 6.8(?13.0,?10.0)?13.114.8(?16.3,?9.9)67

Holwerda32136?9.5 6.2(?10.6,?8.4)?12.412.7(?14.5,?10.3)55

Oddou-Stock8545?8.312.0(?9.3,?7.3)?11.017.5(?12.5,?9.5)46

Oparil23150?7.214.6(?9.6,?4.9)?8.625.1(?12.6,?4.6)43

Black33364?7.114.7(?8.6,?5.6)?8.017.5(?9.8,?6.2)42 Irbesartan150mg Kassler-Taub10129?9.77.4(?11.0,?8.4)?12.113.1(?14.4,?9.8)60 Weber53124?9.77.2(?11.0,?8.4)?11.912.6(?14.1,?9.7)50

Fogari5453?8.37.9(?10.5,?6.1)?11.412.4(?14.8,?8.0)55

Guthrie5598?8.3 6.6(?9.6,?7.0)?9.112.1(?11.5,?6.7)53

Oparil11178?7.77.2(?8.8,?6.6)?11.112.6(?13.0,?9.2)50 Candesartan8mg Franke5668?10.59.9(?12.9,?8.1)69 Andersson977?9.013.0(?11.9,?6.1)?14.023.7(?19.4,?8.6)

Reif2460?8.78.5(?10.9,?6.5)?9.914.0(?13.5,?6.3)

Philipp44131?8.110.8(?10.0,?6.2)?11.420.1(?14.9,?7.9)47 Losartan50–100mg Chan2889?13.28.2(?14.9,?11.5)?17.214.7(?20.3,?14.1)69 Roca-Cusachs48192?11.58.2(?12.7,?10.3)?15.414.7(?17.5,?13.3)60

Tiebel57304?11.49.5(?12.5,?10.3)?16.916.2(?18.7,?15.1)

Dahlof58298?10.37.5(?11.2,?9.4)?13.613.7(?15.2,?12.0)60

Gradman2290?9.9 6.9(?11.3,?8.5)?8.913.6(?11.7,?6.1)

Oddou-Stock8534?9.78.2(?10.4,?9.0)?12.914.7(?14.2,?11.6)55

Byyny5128?9.67.6(?12.6,?6.6)?11.014.5(?16.6,?5.4)

Mallion26109?9.27.1(?10.5,?7.9)?9.514.0(?12.2,?6.8)51

Kassler-Taub10131?8.77.3(?10.0,?7.4)?11.313.0(?13.6,?9.0)56

Dahlof30132?8.68.8(?10.1,?7.1)?11.416.4(?14.2,?8.6)50

Ikeda49118?8.68.3(?10.1,?7.1)?9.414.7(?12.1,?6.7)52

Oparil11192?7.98.2(?9.1,?6.7)?11.714.7(?13.8,?9.6)54 Valsartan80–160mg Oddou-Stock8545?10.513.6(?11.6,?9.4)?13.824.0(?15.8,?11.8)62 Black33162?8.512.5(?10.4,?6.5)?10.921.9(?14.3,?7.5)46

Oparil23148?7.314.7(?9.7,?5.0)?9.026.0(?13.2,?4.7)44 Irbesartan150–300mg Kassler-Taub10134?11.77.4(?13.0,?10.4)?16.413.1(?18.6,?14.2)69 Pool2178?11.67.5(?13.3,?9.9)?13.011.7(?15.6,?10.4)67

Guthrie5598?10.58.0(?12.1,?8.9)?12.614.1(?15.4,?9.8)59

Oparil11178?10.27.6(?11.3,?9.1)?13.713.1(?15.6,?11.8)63

Kochar5943?10.27.6(?12.5,?7.9)49

Weir6079?7.77.6(?9.4,?6.0)?12.013.1(?14.9,?9.1)

AJH–APRIL2000–VOL.13,NO.4,PART1ANTIHYPERTENSIVE EFFICACY OF AIIA421

provides some information with regard to ef?cacy in relation to the recommended dose interval for the AIIA for the treatment of hypertension.

The current pooled data analysis from 43studies involving 11,281patients treated with AIIA showed that the weighted average DBP/SBP reductions and responder rates for all four AIIA were comparable.This conclusion applied to studies of starting doses of AIIA,monotherapy dose titration,and combination therapy with starting doses of AIIA plus low-dose HCTZ.The dose-response was similar for all the AIIA and the observed differences were not clinically mean-ingful.For all four AIIA under consideration,titration to the AIIA/HCTZ combination produced the greatest antihypertensive effect.

There have been four published studies in which losartan has been compared directly with valsartan,8irbesartan,10,11and candesartan.9Some of these trials have suggested differences in ef?cacy or responder rates between the agents tested.The results of the present metaanalysis show no difference in blood pressure ef?cacy or responder rates.Because these direct comparative studies contribute less than 20%of all the available evidence on blood pressure ef?cacy,a metaanalysis of the sort provided in this paper might be regarded as a stronger basis for understanding the comparative ef?cacy of drugs in this class.

It is possible that additional data that are perceived to be negative by commercial sponsors of speci?c therapies may not be published.By necessity,our pooled analysis of published trials would not be able to include the data from any such negative studies,which inevitably would introduce a publication bias.Nevertheless,the volume of data recorded in our anal-ysis strengthens the hypothesis that there are no clin-ically meaningful differences in antihypertensive ef?-cacy within the AIIA class.

Review articles on AIIA 1–7and separate pooled analyses for irbesartan 18,19and candesartan 6,20re-ported results consistent with the weighted average SBP/DBP reductions and response rates reported here.Man in ‘t Veld calculated placebo-corrected DBP reductions of 5mm Hg for 150mg irbesartan and 6mm Hg for 300mg irbesartan,and non–placebo-corrected DBP reductions of 9.2mm Hg for 150mg irbesartan and 10.3mm Hg for 300mg irbesartan.19

TABLE 1.CONTINUED.

AIIA Dose First Author n DBP (mm Hg)

SBP (mm Hg)

Responders

(%)

Mean

SD

95%CI

Mean

SD

95%CI

Candasartan 8–16mg

Philipp 44

36?10.310.0(?13.7,?6.9)?12.619.1(?19.1,?6.1)69

Andersson 980?10.013.2(?12.9,?7.1)?16.024.4(?21.4,?10.6)Meineke 61232?10.010.0(?11.3,?8.7)?17.119.1(?19.6,?14.6)Zuschke 6290?9.410.0(?11.5,?7.3)?11.119.1(?15.1,?7.1)McInnes 6396?8.77.2(?10.2,?7.2)?14.316.3(?17.6,?11.0)47Reif 24

59?7.88.8(?10.1,?5.5)?10.714.7(?14.5,?6.9)54Losartan 50mg Trimarco 4572?13.97.3(?15.6,?12.2)?17.412.2(?20.3,?14.5)HCTZ 12.5mg

MacKay 47135?13.2 6.6(?14.3,?12.1)?17.213.1(?19.4,?15.0)78Tiebel 57

310?13.27.7(?14.1,?12.3)?18.416.0(?20.2,?16.6)Critchley 64216?12.67.3(?13.6,?11.6)?21.514.1(?23.4,?19.6)71

Wilson 2931?11.9 5.4(?13.9,?9.9)?16.011.6(?20.3,?11.7)Weir 46110?11.67.6(?13.0,?10.2)?14.213.1(?16.7,?11.7)Dahlof 58300?11.47.1(?12.2,?10.6)?17.112.4(?18.5,?15.7)70Oparil 11192?10.87.3(?11.8,?9.8)?13.914.1(?15.9,?11.9)65

Oparil 50

97?10.48.0(?12.0,?8.8)?11.316.5(?14.6,?8.0)Townsend 27132?10.37.3(?11.6,?9.0)?11.314.1(?13.7,?8.9)Martina 5210?9.07.9(?14.7,?3.3)?13.014.8(?23.6,?2.4)Valsartan 80mg Mallion 3494?15.57.5(?17.0,?14.0)?19.712.2(?22.2,?17.2)

68HCTZ 12.5mg Black 6596?11.77.5(?13.2,?10.2)64Irbesartan 150mg Phillips 6657?13.27.5(?15.2,?11.2)69HCTZ 12.5mg Weber 53124?12.07.5(?13.3,?10.7)?16.114.3(?18.6,?13.6)65Candesartan 8mg Philipp 4461?10.29.4(?12.6,?7.8)?20.620.0(?25.7,?15.5)

56

HCTZ 12.5mg

McInnes 67

237

?9.89.4(?11.0,?8.6)

*Per agent at a given dose,the studies were ranked by DBP reduction.The results from the four direct,head-to-head comparative trials within the AIIA class are indicated in bold.The 95%con?dence intervals (95%CI)were calculated from the mean and standard deviation.For those studies,where no standard deviations (SD)were reported,we assumed the SD for the weighted average of the same drug and dose (SD underlined).AIIA,angiotensin II antagonists;DBP,diastolic blood pressure;HCTZ,hydrochlorothiazide.

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CONLIN ET AL

Elmfeldt et al reported placebo-corrected DBP reduc-tions of6mm Hg for8mg candesartan and8mm Hg for16mg candesartan.20Reductions in SBP and re-sponse rates were also comparable to the current in-tegrated analysis.

This analysis suggests that AIIA lower blood pres-sure with similar ef?cacy when administered at their usual recommended doses for the treatment of hyper-tension.At these recommended doses,the dose re-sponse for blood pressure reduction with all AIIA is relatively?at and,in general,ef?cacy is enhanced signi?cantly by adding low-dose(12.5mg)HCTZ to the initial dose of AIIA rather than escalating the dose of the AIIA.

ACKNOWLEDGMENTS

We gratefully acknowledge the assistance of Francois Harel at the Montreal Heart Institute for statistical support.

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TABLE2.SUMMARY OF WEIGHTED AVERAGE ANTIHYPERTENSIVE EFFICACY FROM43PUBLISHED DOUBLE-BLIND,RANDOMIZED CONTROLLED TRIALS WITH STARTING DOSE AIIA MONOTHERAPY, AIIA MONOTHERAPY DOSE TITRATION,OR AIIA/HCTZ COMBINATION THERAPY AND

CROSS ALL PRODUCTS*

N %of

Total

DBP

(mm Hg)95%CI

SBP

(mm Hg)95%CI

Responders

(%)

AIIA monotherapy starting dose

Losartan50mg235950%?8.2(?8.5,?7.9)?10.4(?10.9,?9.8)48 Valsartan80mg145531%?8.8(?9.4,?8.2)?10.9(?11.8,?10.0)49 Irbesartan150mg58212%?8.7(?9.3,?8.1)?11.2(?12.2,?10.2)53 Candesartan8mg3367%?8.9(?10.1,?7.7)?11.8(?14.0,?9.7)55 Across products4732100%?8.5?10.849.5 AIIA monotherapy titration

Losartan50–100mg221752%?10.0(?10.3,?9.6)?13.1(?13.7,?12.5)56 Valsartan80–160mg85520%?9.6(?10.5,?8.7)?12.4(?14.0,?10.8)56 Irbesartan150–300mg61014%?10.4(?11.0,?9.8)?13.8(?14.9,?12.8)63 Candesartan8–16mg59314%?9.5(?10.3,?8.7)?14.7(?16.2,?13.1)53 Across products4275100%?9.9?13.356.6 Starting dose AIIA/HCTZ

combination

Losartan50mg/HCTZ12.5mg160571%?12.0(?12.3,?11.6)?16.5(?17.2,?15.8)70 Valsartan80mg/HCTZ12.5mg1908%?13.6(?14.6,?12.5)?19.7(?21.4,?18.0)66 Irbesartan150mg/HCTZ12.5mg1818%?12.4(?13.5,?11.3)?16.1(?18.2,?14.0)66 Candesartan8mg/HCTZ12.5mg29813%?9.9(?11.0,?8.8)?20.6(?22.9,?18.3)56 Across products2274100%?11.9?17.368

*The95%con?dence intervals(95%CI)were calculated from the mean and standard deviation.Responder rates were typically the percent of treated patients who achieved a diastolic blood pressure?90mm Hg or had a decline in diastolic blood pressure by?10mm Hg.

Abbreviations as in Table1.

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