Combination Therapy Is Superior to Sequential Monotherapy for the Initial Treatment of Hypertension: A Double-Blind Randomized Controlled Trial

TY - JOUR

T1 - Combination Therapy Is Superior to Sequential Monotherapy for the Initial Treatment of Hypertension

T2 - A Double-Blind Randomized Controlled Trial

AU - MacDonald, Thomas M.

AU - Williams, Bryan

AU - Webb, David J.

AU - Morant, Steve

AU - Caulfield, Mark

AU - Cruickshank, J. Kennedy

AU - Ford, Ian

AU - Sever, Peter

AU - Mackenzie, Isla S.

AU - Padmanabhan, Sandosh

AU - McCann, Gerald P.

AU - Salsbury, Jackie

AU - McInnes, Gordon

AU - Brown, Morris J.

AU - for The British Hypertension Society Programme of Prevention And Treatment of Hypertension With Algorithm‐based Therapy (PATHWAY)

N1 - The study was funded by a special project grant from the British Heart Foundation (number SP/08/002). Further funding was provided by National Institute of Health Research Comprehensive Local Research Networks. Williams, Sever, Caulfield and Brown are National Institute of Health Research Senior Investigators. Williams is supported by the National Institute of Health Research University College London Hospitals Biomedical Research Centre. Caulfield is supported by the National Institute of Health Research Cardiovascular Biomedical Research Unit at St Bartholomew's Hospital, London. McCann is supported by National Institute of Health Research Research Fellowship.

PY - 2017/11

Y1 - 2017/11

N2 - Background: Guidelines for hypertension vary in their preference for initial combination therapy or initial monotherapy, stratified by patient profile; therefore, we compared the efficacy and tolerability of these approaches.Methods and Results: We performed a 1-year, double-blind, randomized controlled trial in 605 untreated patients aged 18 to 79 years with systolic blood pressure (BP) ≥150 mm Hg or diastolic BP ≥95 mm Hg. In phase 1 (weeks 0-16), patients were randomly assigned to initial monotherapy (losartan 50-100 mg or hydrochlorothiazide 12.5-25 mg crossing over at 8 weeks), or initial combination (losartan 50-100 mg plus hydrochlorothiazide 12.5-25 mg). In phase 2 (weeks 17-32), all patients received losartan 100 mg and hydrochlorothiazide 12.5 to 25 mg. In phase 3 (weeks 33-52), amlodipine with or without doxazosin could be added to achieve target BP. Hierarchical primary outcomes were the difference from baseline in home systolic BP, averaged over phases 1 and 2 and, if significant, at 32 weeks. Secondary outcomes included adverse events, and difference in home systolic BP responses between tertiles of plasma renin. Home systolic BP after initial monotherapy fell 4.9 mm Hg (range: 3.7-6.0 mm Hg) less over 32 weeks (P<0.001) than after initial combination but caught up at 32 weeks (difference 1.2 mm Hg [range: -0.4 to 2.8 mm Hg], P=0.13). In phase 1, home systolic BP response to each monotherapy differed substantially between renin tertiles, whereas response to combination therapy was uniform and at least 5 mm Hg more than to monotherapy. There were no differences in withdrawals due to adverse events.Conclusions: Initial combination therapy can be recommended for patients with BP >150/95 mm Hg.Clinical Trial Registration URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00994617.

AB - Background: Guidelines for hypertension vary in their preference for initial combination therapy or initial monotherapy, stratified by patient profile; therefore, we compared the efficacy and tolerability of these approaches.Methods and Results: We performed a 1-year, double-blind, randomized controlled trial in 605 untreated patients aged 18 to 79 years with systolic blood pressure (BP) ≥150 mm Hg or diastolic BP ≥95 mm Hg. In phase 1 (weeks 0-16), patients were randomly assigned to initial monotherapy (losartan 50-100 mg or hydrochlorothiazide 12.5-25 mg crossing over at 8 weeks), or initial combination (losartan 50-100 mg plus hydrochlorothiazide 12.5-25 mg). In phase 2 (weeks 17-32), all patients received losartan 100 mg and hydrochlorothiazide 12.5 to 25 mg. In phase 3 (weeks 33-52), amlodipine with or without doxazosin could be added to achieve target BP. Hierarchical primary outcomes were the difference from baseline in home systolic BP, averaged over phases 1 and 2 and, if significant, at 32 weeks. Secondary outcomes included adverse events, and difference in home systolic BP responses between tertiles of plasma renin. Home systolic BP after initial monotherapy fell 4.9 mm Hg (range: 3.7-6.0 mm Hg) less over 32 weeks (P<0.001) than after initial combination but caught up at 32 weeks (difference 1.2 mm Hg [range: -0.4 to 2.8 mm Hg], P=0.13). In phase 1, home systolic BP response to each monotherapy differed substantially between renin tertiles, whereas response to combination therapy was uniform and at least 5 mm Hg more than to monotherapy. There were no differences in withdrawals due to adverse events.Conclusions: Initial combination therapy can be recommended for patients with BP >150/95 mm Hg.Clinical Trial Registration URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00994617.

KW - Angiotensin II receptor blocker

KW - Comparative effectiveness

KW - Diuretics

KW - Renin

KW - Treatment effectiveness

U2 - 10.1161/JAHA.117.006986

DO - 10.1161/JAHA.117.006986

M3 - Article

C2 - 29151036

SN - 2047-9980

VL - 6

SP - 1

EP - 28

JO - Journal of the American Heart Association Cardiovascular and Cerebrovascular Disease (JAHA)

JF - Journal of the American Heart Association Cardiovascular and Cerebrovascular Disease (JAHA)

IS - 11

M1 - e006986

ER -