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Cardiovascular outcomes in hypertensive patients: comparing single-agent therapy with combination therapy

Weber, Michael A.; Julius, Stevo; Kjeldsen, Sverre E.; Jia, Yan; Brunner, Hans R.; Zappe, Dion H.; Hua, Tsushung A.; McInnes, Gordon T.; Schork, Anthony; Mancia, Giuseppe; Zanchetti, Alberto

doi: 10.1097/HJH.0b013e3283582ed6
ORIGINAL PAPERS: Therapeutic aspects

Objectives: To determine whether blood pressure (BP) control in hypertensive patients achieved with combination drug therapy provides the same cardiovascular benefits as with single-agent therapy.

Background: Drug combinations, most often including hydrochlorothiazide (HCTZ), are now recommended for routine BP management, but their effects on cardiovascular event rates have not been compared with effective monotherapy.

Methods: We conducted retrospective analyses of the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) data. VALUE compared cardiovascular event rates of valsartan and amlodipine. Patients with BPs not controlled (<140/90 mmHg) by the single agents had HCTZ and, if required, additional drugs of different classes, added. Using data pooled from the two treatment arms, we have now divided patients into those controlled on monotherapy and those controlled or not controlled by combination therapy. The primary study endpoint was first occurrence of cardiovascular death or nonfatal myocardial infarction or stroke. Comparisons between groups were by Cox regression, adjusted for on-treatment BP, age, prior cardiovascular events and left ventricular hypertrophy; the comparison between the monotherapy and combination therapy controlled groups was based on events occurring after 3 months by when the decision to use monotherapy or combination therapy was made.

Results: The primary endpoint occurred in 505 of 5924 (8.5%) monotherapy and 511 of 4621 (11.1%) combination therapy controlled patients: hazard ratio was 0.80 [95% confidence interval (CI) 0.70–0.90]. If these two groups were matched for baseline BPs and all events included from study baseline, the hazard ratio was 0.76 (95% CI 0.67–0.86). The difference between combination controlled and uncontrolled [434 of 3390 (12.8%)] groups was not significant [hazard ratio 0.90 (95% CI 0.80–1.03], nor when they were matched for baseline BPs [hazard ratio 0.95 (95% CI 0.81–1.11)].

Conclusion: Independent of prior cardiovascular history or baseline BP, hypertensive patients requiring combination therapy, which includes a thiazide diuretic for BP control, have a poorer cardiovascular prognosis than those controlled by monotherapy and only a nonsignificantly lower event rate than noncontrolled patients.

aState University of New York, Downstate College of Medicine, Brooklyn, New York

bUniversity of Michigan, Ann Arbor, Michigan, USA

cUllevaal University Hospital, Oslo, Norway

dNovartis Pharmaceuticals, East Hanover, New Jersey, USA

eUniversity of Lausanne, Lausanne, Switzerland

fUniversity of Glasgow, Glasgow, UK

gUniversity of Milano-Bicocca, St Gerardo Hospital, Monza

hIstituto Auxologico Italiano, Università di Milano, Milan, Italy

Correspondence to Michael A. Weber, State University of New York Downstate College of Medicine, 450 Clarkson Avenue, Box 97, Brooklyn, NY 11203, USA. Tel: +1 714 815 7430; e-mail:

Abbreviations: BP, blood pressure; MI, myocardial infarction

Received 21 July, 2011

Revised 11 July, 2012

Accepted 16 July, 2012

Copyright © 2012 Wolters Kluwer Health, Inc. All rights reserved.