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Lancet. 2009 Nov 28;374(9704):1840-8. doi: 10.1016/S0140-6736(09)61913-9. Epub 2009 Nov 16.

Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial.

Collaborators (293)

Konstam MA, Poole-Wilson PA, Dickstein K, Drexler H, Komajda M, Martinez FA, Neaton JD, Riegger GA, Dargie H, Francis G, Kuebler W, Wedel H, Zannad F, Loeys T, Soler-Soler J, Hassenfuss G, Romo M, Manes C, Gibbs JS, Justice S, Delaplace D, Vala M, Capece R, Tansley G, Malbecq W, Smith RD, Charlier F, Henry PH, Vanhaecke J, Van Mieghem W, Soares GF, Rassi S, Lanas F, Paredes AI, Cai NS, Chen JZ, Chen Y, Fan WH, Guo J, Hu D, Huang D, Huang J, Ke Y, Li Y, Liao Y, Lu G, Ma H, Wang L, Wei M, Wu S, Zhang Y, Zheng X, Zhou S, Zhu W, Garcia M, Jaramillo CJ, Urina MA, Velez S, Padovan M, Plavljanic D, Pocanic D, Smalcelj A, Awwad OS, Taher MA, Zaki AM, Komajda M, Bassand JP, Benazza N, Bouchlaghem K, Boudhane A, Chati Z, Coisne D, Delahaye F, Denolle T, Drawin T, Dujardin JJ, Funck F, Gibelin P, Hittinger L, Khaldi E, Komajda M, Mallion JM, Martelet M, Trochu JN, Adelberger V, Adler J, Albrecht C, Al-Zoebi A, Baar M, Bohm G, Boscher D, Bouzo H, Brattström A, Deissner M, Dichmann R, Droese K, Dursch M, Ebert HH, Erdmann E, Frick HM, Gadow J, Gartner J, Guha M, Gunther H, Hassler N, Haustein G, Heinemann S, Heinz GU, Henke R, Himpel-Bonninghoff A, Hohensee H, Horacek T, Jahnke N, Kindermann P, Klein C, Klepzig H, Kordish I, Krezdorn HG, Lange R, Leicht M, Mobius-Winkler S, Oelker M, Overhoff U, Pieske B, Proskynitopolous N, Rouwen AJ, Sachs H, Schafer T, Schax U, Schmidt E, Schmidt-Rauch EM, Schreckenberg A, Sohn HY, Spitzer SG, Stahl HD, Steffens C, Stohring R, Tammen A, Troger S, Turk W, Unverdorben M, Walter J, Weissbrodt M, Weppner G, Wunderlich J, Adamopoulos S, Adamopoulou E, Kremastinos D, Manolis A, Nanas I, Tse HF, Yu CM, Ambrosio G, Branzi A, Brunelli C, D'Angelo G, Deicas L, Di Cioccio L, Ferrari R, Grassi V, Grieco A, Inserra V, Lembo G, Pedrinelli R, Purrello F, Tavazzi L, Terrosu P, Trimarco B, Volpe M, Zuccaro SM, Jeon ES, Kim JJ, Abchee A, Kassab R, Rebeiz A, Chew DS, Sim KH, Yusof Z, Marquez M, Meaney E, Benomar M, Srairi JE, El Akil R, Bouchara L, van den Berg BJ, van der Burgh PH, De Milliano PA, Gevers RM, Gobel EJ, Linssen GC, Kragten JA, Veldkamp RF, van Veldhuisen DJ, van Woerkens LJ, Aaser E, Dickstein K, Gullestad L, Hofsøy K, Hole T, Otterstad JE, Skogsholm A, Westheim A, Noriega ME, Osores JJ, Medina F, Segura L, Abola MT, Dans AM, Morales D, Ramos E, Rogelio G, Sy R, Adamus J, Bakun J, Gaciong Z, Kocon S, Kubik L, Rynkiewicz A, Sokolowski K, Wojciechowski D, Aroutiounov GP, Mareyev VY, Sidorenko BA, Kwok BW, Keber I, Medvescek NR, Mocnik FS, Doubell AF, Lloyd E, Marx JD, Naidoo DP, Pulpon LA, Anguita-Sanchez MP, Fernandez FA, Barrios-Alonso V, Fernandez JR, Bertomeu-Martinez V, Galvan Ede T, Santos AE, Ferreira-Montero I, Ligorit Adel R, Galve-Basilio E, Gomez-Sanchez MA, Gonzalez-Juanatey JR, Luengo CM, Melero-Pita A, Munoz-Aguilera R, Poyedo VR, Rodriguez-Garcia MA, Minguell ME, Sainz-Cusi L, Sanz AS, Toral BS, Chavarri MV, Tudela VV, Chen CH, Chou HT, Hou JY, Liu CP, Wu D, Caglar N, Kes S, Koylan N, Kozan O, Brack M, Brookes C, Bruce D, Davies J, Dunn F, Dutka DP, Gough N, Groves P, Haq I, Kadr HH, Keeling PJ, Kyle C, Lloyd GW, MacFadyen RJ, McLay J, Mehrzad A, Murdoch DL, Petrie M, Ray SG, Saeed B, Saltissi S, Senior R, Squire IB, Tilley J, Travill C, Walsh J, Wiles I, Wilson I, Wijnberg A.

Erratum in

  • Lancet. 2009 Dec 5;374(9705):1888.

Abstract

BACKGROUND:

Angiotensin-receptor blockers (ARBs) are effective treatments for patients with heart failure, but the relation between dose and clinical outcomes has not been explored. We compared the effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure.

METHODS:

This double-blind trial was undertaken in 255 sites in 30 countries. 3846 patients with heart failure of New York Heart Association class II-IV, left-ventricular ejection fraction 40% or less, and intolerance to angiotensin-converting-enzyme (ACE) inhibitors were randomly assigned to losartan 150 mg (n=1927) or 50 mg daily (n=1919). Allocation was by block randomisation stratified by centre and presence or absence of beta-blocker therapy, and all patients and investigators were masked to assignment. The primary endpoint was death or admission for heart failure. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00090259.

FINDINGS:

Six patients in each group were excluded because of poor data quality. With 4.7-year median follow-up in each group (IQR 3.7-5.5 for losartan 150 mg; 3.4-5.5 for losartan 50 mg), 828 (43%) patients in the 150 mg group versus 889 (46%) in the 50 mg group died or were admitted for heart failure (hazard ratio [HR] 0.90, 95% CI 0.82-0.99; p=0.027). For the two primary endpoint components, 635 patients in the 150 mg group versus 665 in the 50 mg group died (HR 0.94, 95% CI 0.84-1.04; p=0.24), and 450 versus 503 patients were admitted for heart failure (0.87, 0.76-0.98; p=0.025). Renal impairment (n=454 vs 317), hypotension (203 vs 145), and hyperkalaemia (195 vs 131) were more common in the 150 mg group than in the 50 mg group, but these adverse events did not lead to significantly more treatment discontinuations in the 150 mg group.

INTERPRETATION:

Losartan 150 mg daily reduced the rate of death or admission for heart failure in patients with heart failure, reduced left-ventricular ejection fraction, and intolerance to ACE inhibitors compared with losartan 50 mg daily. These findings show the value of up-titrating ARB doses to confer clinical benefit.

FUNDING:

Merck (USA).

PMID:
19922995
[PubMed - indexed for MEDLINE]
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