Combination therapy is superior to sequential monotherapy for the initial treatment of hypertension: A double-blind randomized controlled trial

Thomas M. MacDonald, Bryan Williams, David J. Webb, Steve Morant, Mark Caulfield, J. Kennedy Cruickshank, Ian Ford, Peter Sever, Isla S. Mackenzie, Sandosh Padmanabhan, Gerald P. McCann, Jackie Salsbury, Gordon McInnes, Morris J. Brown*, Anne Schumann, Jo Helmy, Carmela Maniero, Timothy J. Burton, Ursula Quinn, Lorraine HobbsJo Palmer, David Collier, Nirmala Markandu, Manish Saxena, Anne Zak, Enamuna Enobakhare, Judith Mackay, Simon A. McG Thom, Candida Coughlan, Alison R. McGinnis, Evelyn Findlay, Adrian G. Stanley, Christobelle White, Peter Lacy, Caroline J. Gardiner-Hill, Sheraz Nazir, Gordon T. McInnes, Scott Muir, Linsay McCallum, Vanessa Melville, Iain M. MacIntyre, Roger Brown, R. Simon, Handrean Soran, See Kwok, Karthirani Balakrishnan, Richard Hobbs, Rachel Iles, Khin Swe Myint, John Cannon, Sue Hood, Krzysztof Rutkowski, Andrew Webb, Una Martin, Sharon Kean, Robbie Wilson, Richard Papworth

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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.

Original languageEnglish
Article numbere006986
JournalJournal of the American Heart Association
Issue number11
Early online date18 Nov 2017
Publication statusPublished - Nov 2017


  • Angiotensin II receptor blocker
  • Comparative effectiveness
  • Diuretics
  • Renin
  • Treatment effectiveness


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