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Morbidity and mortality on combination versus monotherapy: a posthoc analysis of the Systolic Hypertension in Europe trial

Thijs, Lutgardea; Richart, Toma,b; de Leeuw, Peter Wc,d; Kuznetsova, Tatianaa; Grodzicki, Tomasze; Kawecka-Jaszcz, Kalinaf; O'Brien, Eoing; Redón, Joseph; Birkenhäger, Willem Hi; Fagard, Roberta; Staessen, Jan Aa,b


There is an error in the horizontal labels for Figures 4 and 5 of the paper by Thijs et al. [1]. The time periods for follow up should be years and not months.

Journal of Hypertension. 34(3):588, March 2016.

doi: 10.1097/HJH.0b013e32833627c9
Original Papers: Therapeutic trial

Background The current literature supports the immediate use of combinations of antihypertensive drugs in terms of ease of use and adherence, but the key issue whether combination therapy is more effective than monotherapy in the prevention of cardiovascular complications remains unproven.

Methods We analysed the double-blind (median follow-up 2.0 years) and open follow-up (6.0 years) phases of the Systolic Hypertension in Europe trial. Patients were 60 years or more with an entry systolic/diastolic blood pressure (BP) of 160–219/less than 95 mmHg. Antihypertensive treatment started immediately after randomization in the active-treatment group, but only after completion of the double-blind trial in control patients. Treatment consisted of nitrendipine (10–40 mg/day) with the possible addition of enalapril (5–20 mg/day). We adjusted our analyses for sex, age, history of cardiovascular complications, baseline systolic BP and previous antihypertensive treatment.

Results During the double-blind trial, adding enalapril to nitrendipine (n = 515), compared with the equivalent combination of placebos (n = 559), decreased systolic BP by a further 9.5 mmHg and reduced all cardiovascular events by 51% (P = 0.0035) and heart failure by 66% (P = 0.032), with similar trends for stroke (–51%; P = 0.066) and cardiac events (−44%; P = 0.075). Over the whole duration of follow-up, combination therapy (n = 871), compared with nitrendipine monotherapy (n = 1552), decreased systolic BP by 3.1 mmHg and reduced total mortality (−32%; P = 0.023), with similar trends for all cardiovascular events (−23%; P = 0.081) and stroke (−42%; P = 0.054).

Conclusion Despite the limitations of a posthoc analysis, but congruent with the stronger BP reduction, our results suggest that combination therapy with nitrendipine plus enalapril might improve outcome over and beyond the benefits seen with nitrendipine monotherapy.

aThe Studies Coordinating Centre, Division of Hypertension and Cardiovascular Rehabilitation, Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium

bDepartment of Epidemiology, The Netherlands

cCardiovascular Research Institute, The Netherlands

dDepartment of Internal Medicine, Maastricht University, Maastricht, The Netherlands

eDepartment of Internal Medicine and Gerontology, Poland

fFirst Department of Cardiology and Hypertension, Jagiellonian University Medical College, Kraków, Poland

gConway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland

hFundacion de Investigacion Hospital Clinico Valencia, University of Valencia, Valencia, Spain

iErasmus University, Rotterdam, The Netherlands

Received 23 September, 2009

Revised 1 December, 2009

Accepted 4 December, 2009

Correspondence to Jan A. Staessen, MD, PhD, FESC, FAHA, Studies Coordinating Centre, Laboratory of Hypertension, University of Leuven, Campus Sint Rafaël, Kapucijnenvoer 35, Block d Level 00, B-3000 Leuven, Belgium Tel: +32 16 34 7104; fax: +32 16 34 7106; e-mail: and

© 2010 Lippincott Williams & Wilkins, Inc.