TORAFIC study protocol: torasemide prolonged release versus furosemide in patients with chronic heart failure

Abstract

Loop diuretics, such as torasemide and furosemide, are important agents in the treatment of chronic heart failure. Beneficial effects of torasemide immediate-release formulation beyond diuresis have been documented as the ability of this compound to inhibit myocardial synthesis and deposition of collagen type I in patients with chronic heart failure. In addition, torasemide-treated patients, but not furosemide-treated patients, showed decreased serum concentrations of the C-terminal propeptide of procollagen type I, a biochemical marker of myocardial fibrosis. The aim of the TORAFIC study is to test the efficacy of torasemide prolonged-release formulation (PR) in reducing myocardial fibrosis in chronic heart failure in a large, randomized clinical trial. Methods: This prospective, Phase IV, randomized, blinded end point, active-controlled clinical trial will randomize 142 patients with chronic heart failure in New York Heart Association functional class II–IV to 8 months treatment with either torasemide-PR (10–40 mg daily) or furosemide (40–160 mg daily). The primary objective is to test the hypothesis that torasemide-PR is superior to furosemide in reducing myocardial fibrosis. The primary outcome measure is the difference in the change of serum propeptide of procollagen type I concentration from the initial to the final visit between both study groups. Secondary outcome measures include all efficacy variables related to heart failure (signs and symptoms, ECG, echocardiogram and serum levels of N-terminal brain natriuretic propeptide). Secondary safety variables are heart rate, blood pressure, laboratory data, adverse events, cardiovascular events (hospital admission, emergency department visits) and quality of life (Minnesota questionnaire). Discussion: This trial will test whether torasemide-PR possesses antifibrotic properties, which may provide an additional benefit beyond diuresis in patients with chronic heart failure.

Keywords::

• chronic heart failure
• furosemide
• myocardial fibrosis
• torasemide

Acknowledgements

All authors are involved in the design and acquisition, analysis and interpretation of data. They have been involved in drafting the manuscript and revising it critically for important intellectual content and have given final approval of the version to be published.

Members of the TORAFIC Investigators Group: Eulàlia Roig, Hospital Clinic, Barcelona, Spain; Enrique Galve, Hospital da la Vall d’ Hebron, Barcelona, Spain; Josep Lupón, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain; Francisco Ridocci, Hospital General de Valencia, Valencia, Spain; Domingo Pascual, Hospital Virgen de la Arrixaca, Murcia, Spain; Pedro L Sánchez, Hospital Gregorio Marañón, Madrid, Spain; Cándido Martín, Hospital Universitario de Salamanca, Salamanca, Spain; Juan Ignacio Pérez-Calvo, Hospital Clínico Universitario, Zaragoza, Spain; Ramón Querejeta, Hospital de Donostia, San Sebastián, Spain; Manuel Jiménez-Navarro, Hospital Clínico, Málaga, Spain; Lorenzo Monserrat, Complejo Hospitalario Universitario de La Coruña, La Coruña, Spain; JR González-Juanatey, Hospital Clínico Universitario, Santiago de Compostela, Spain; Beatriz Díaz, Hospital Central de Asturias, Oviedo, Spain; Jesús Cebollada, Hospital San Jorge, Huesca, Spain; Julia Roure, Hospital Josep Trueta, Girona, Spain; Sonia Ruiz, Hospital Universitari del Mar, Barcelona, Spain; Isidro López Centro de Salud Begonte, Lugo, Spain; Manel Terns, CAP Remei, Vic, Barcelona, Spain; Silvia Narejos, CAP Centelles, Barcelona, Spain; Alex Rodríguez, CAP Alcover, Tarragona, Spain; Mar Rodríguez, ABS Canet de mar, Barcelona, Spain; and Pere Toran, EAP Mataró 6 (Gatassa), Barcelona, Spain.

Financial & competing interests disclosure

This trial received funding from Laboratorios Novag SA (Ferrer Internacional, Barcelona, Spain). Trial registration is EudraCT 2006-001446-14; FDA (Clinicaltrials.gov) NCT00409942. Erik Cobo is a consultant for Ferrer International and Medtronic (UK) and receives regular training fees from both institutions and Novartis (UK). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing assistance was utilized in the production of this manuscript. The authors would like to thank Marta Pulido, MD, and Content Ed Net for editing the manuscript and for editorial assistance; Rous de Castellar, MD, for protocol writing assistance; Marta Llorens, RN, and Ramón Dosantos, BSc, from Trial Form Support for protocol writing assistance and statistical analysis.