Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Outcomes in subgroups of hypertensive patients treated with regimens based on valsartan and amlodipine: an analysis of findings from the VALUE trial Alberto Zanchetti a , Stevo Julius b , Sverre Kjeldsen b,c , Gordon T. McInnes d , Tsushung Hua e , Michael Weber f , John H. Laragh g , Francis Plat h , Edouard Battegay i , Cesar Calvo-Vargas j , Andrzej Cies ´lin ´ ski k , Jean Paul Degaute l , Nicolaas J. Holwerda m , Janna Kobalava n , Ole Lederballe Pedersen o , Faustinus P. Rudyatmoko p , Kostas C. Siamopoulos q and O ¨ yvind Sto ¨ rset r Background In the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial the primary outcome (cardiac morbidity and mortality) did not differ between valsartan and amlodipine-based treatment groups, although systolic blood pressure (SBP) and diastolic blood pressure reductions were significantly more pronounced with amlodipine. Stroke incidence was non-significantly, and myocardial infarction was significantly lower in the amlodipine-based regimen, whereas cardiac failure was non-significantly lower on valsartan. Objectives The study protocol specified additional analyses of the primary endpoint according to: sex; age; race; geographical region; smoking status; type 2 diabetes; total cholesterol; left ventricular hypertrophy; proteinuria; serum creatinine; a history of coronary heart disease; a history of stroke or transient ischemic attack; and a history of peripheral artery disease. Additional subgroups were isolated systolic hypertension and classes of antihypertensive agents used immediately before randomization. Methods The 15 245 hypertensive patients participating in VALUE were divided into subgroups according to baseline characteristics. Treatment by subgroup interaction analyses were carried out by a Cox proportional hazard model. Within each subgroup, treatment effects were assessed by hazard ratios and 95% confidence intervals. Results For cardiac mortality and morbidity, the only significant subgroup by treatment interaction was of sex (P U 0.016), with the hazard ratio indicating a relative excess of cardiac events with valsartan treatment in women but not in men, but SBP differences in favour of amlodipine were distinctly greater in women. No other subgroup showed a significant difference in the composite cardiac outcome between valsartan and amlodipine-based treatments. For secondary endpoints, a sex-related significant interaction was found for heart failure (P < 0.0001), with men but not women having a lower incidence of heart failure with valsartan. Conclusion As in the whole VALUE cohort, in no subgroup of patients were there differences in the incidence of the composite cardiac endpoint with valsartan and amlodipine- based treatments, despite a greater blood pressure decrease in the amlodipine group. The only exception was sex, in which the amlodipine-based regimen was more effective than valsartan in women, but not in men, whereas the valsartan regimen was more effective in preventing cardiac failure in men than in women. J Hypertens 24:2163– 2168 Q 2006 Lippincott Williams & Wilkins. Journal of Hypertension 2006, 24:2163–2168 Keywords: amlodipine, cardiac events, heart failure, sex, valsartan a Centro Interuniversitario di Fisiologia Clinica e Ipertensione, University of Milan, Istituto Auxologico Italiano and Ospedale Maggiore, Milan, Italy, b University of Michigan, Ann Arbor, Michigan, USA, c Ullevaal University Hospital, Oslo, Norway, d University of Glasgow, Glasgow, UK, e Novartis Pharma, East Hanover, New Jersey, f State University of New York, New York, g Cornell Medical Center, New York, New York, USA, h Novartis Pharma AG, Basel, i University Hospital, Basel, Switzerland, j Hospital Civil Juan I, Menchaca University of Guadalajara, Guadalajara, Mexico, k Karol Marcinkowski University, Poznan ˇ , Poland, l Ho ˆ pital Erasme, Brussels, Belgium, m Sint Elisabeth Ziekenhuis, Tilburg, The Netherlands, n Russian University of People Friendship, Moscow, Russia, o Viborg Hospital, Viborg, Denmark, p J.I. Sutorejo-Utara F. 24, Surabaya, Indonesia, q University of Ioannina, Ioannina, Greece and r Akershus University Hospital, Nordbyhagen, Norway Correspondence and requests for reprints to Prof. Alberto Zanchetti, Centro di Fisiologia Clinica e Ipertensione, Via F. Sforza, 35, 20122 Milano, Italy E-mail: alberto.zanchetti@unimi.it Received 30 March 2006 Accepted 27 June 2006 Introduction The Valsartan Antihypertensive Long-term Use Evalua- tion (VALUE) trial was designed to test the hypothesis that, for the same blood pressure control, the angiotensin receptor blocker, valsartan, would reduce cardiac morbi- dity and mortality (primary endpoint) more than the calcium antagonist, amlodipine, in hypertensive patients at high cardiovascular risk. The principal results of the trial have recently been reported [1]. In brief, after a mean follow-up of 4.2 years with randomized treatment, 1599 out of 15 245 hypertensive patients at high risk of cardiovascular events experienced a primary endpoint. Original article 2163 0263-6352 ß 2006 Lippincott Williams & Wilkins