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Higher cardiovascular risk and impaired benefit of antihypertensive treatment in hypertensive patients requiring additional drugs on top of randomized therapy: is adding drugs always beneficial?

Zhang, Yuqing; Zhang, Xuezhong; Liu, Lisheng; Wang, Yang; Tang, Xinran; Zanchetti, Albertofor the FEVER Study Group

doi: 10.1097/HJH.0b013e3283582eec
ORIGINAL PAPERS: Therapeutic aspects

Background: In antihypertensive treatment trials, when randomized therapies do not reach target, additional drugs are administered. However, patients requiring (add-on) or not requiring add-on therapy (no-add-on) may be at different cardiovascular risk and differently susceptible to benefits of antihypertensive treatment.

Methods and results: The Felodipine Event Reduction study included 9711 Chinese hypertensive patients receiving 12.5 mg/day hydrochlorothiazide and randomized to associating either felodipine (5 mg/day) or placebo. Within 6 months, add-on therapy (further diuretic and other drugs) was required by 2185 patients, whereas 7243 did not require it. Despite significant SBP/DBP reductions by add-on therapy, outcome incidence remained much lower in no-add-on than in add-on patients: hazard ratios for various outcomes, after adjusting for baseline variables and blood pressure (BP) at time of add-on decision, were 0.22–0.368 (P always <0.001) and remained substantially unchanged when further adjusted for the small SBP/DBP difference persisting during follow-up treatment (−2.4/−1.1 mmHg in no-add-on). When felodipine was compared to placebo, the benefit of a lower SBP/DBP caused by felodipine was evident in the no-add-on patients (hazard ratio 0.45–0.68, P always <0.001), but it was lost in the add-on group (hazard ratio 0.91–1.17).

Conclusion: Comparing patients more or less easily responding to antihypertensive treatment may identify patients at high risk of outcomes and less susceptible to benefits of a lower BP. It remains to be more directly investigated to what extent adding drugs to drugs is effective in reducing outcomes of patients in whom simple antihypertensive therapy does not achieve goal BP.

aDivisions of Hypertension and Biometrics, FuWai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences

bClinical Trials and Research Center, Beijing Hypertension League Institute, Beijing, China

cIstituto Auxologico Italiano and Centro di Fisiologia Clinica e Ipertensione, University of Milan, Milan, Italy

Correspondence to Professor Alberto Zanchetti, Direttore Scientifico, Istituto Auxologico Italiano, via Ludovico Ariosto 13, 20145 Milan, Italy. Tel: +39 02 619112237; fax: +39 02 619112901; e-mail:

Abbreviations: BP, blood pressure; CI, confidence interval; FEVER, Felodipine Event Reduction; LVH, left ventricular hypertrophy; ONTARGET, Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial; SCOPE, Study on Congnition and Prognosis in the Elderly; SystEur, Systolic Hypertension in Europe; TRANSCEND, Telmisartan Randomized Assessment Study in ACE-I Intolerant Subjects with Cardiovascular Disease; VALUE, Valsartan Antihypertensive Long-term Use Evaluation

Received 1 June, 2012

Revised 10 July, 2012

Accepted 16 July, 2012

The FEVER trial has been registered on, no. NCT01136863.

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