Effects of carvedilol on the prevention of cardiotoxicity induced by anthracyclines: Design and rationale of the CARDIOTOX trial

Background Patients with cancer undergoing chemotherapy with an anthracycline-based regimen are at increased risk of cardiotoxicity, predisposing to heart failure, arrhythmias and death. Whether carvedilol may confer benefit to prevent anthracycline-induced cardiotoxicity remains to be determined. Design CARDIOTOX is a double-blind, placebo controlled randomized clinical trial that plan to enroll 1,018 patients across 25 study sites in Brazil. Patients with active cancer scheduled to undergo an anthracycline-based chemotherapy regimen are eligible. Patients with prior HF or cardiomyopathy are excluded. Patients are randomized in 1:1 ratio to carvedilol (starting dose 6.25mg BID up titrated to 25mg BID or maximum tolerated dose) or placebo, stratified by site and use of reninangiotensin blockers at baseline. Study drug is administered through the duration of chemotherapy and up to 30 days after the last dose of anthracycline. Patients are scheduled to undergo echocardiographic evaluations at baseline and at 3, 6, and 12 months. The study primary endpoint is the composite of new left ventricle ejection fraction (LVEF) reduction by at least 10% leading to an LVEF < 50%, cardiovascular death, myocardial infarction, urgent care visit or hospitalization for heart failure, or clinically significant arrhythmias at 12 months. Echocardiographic images will be analyzed by a central core lab, clinical outcomes will be adjudicated, and safety endpoints include serious adverse events and adverse events of special interest (symptomatic bradycardia, hypotension, syncope and bronchospasm). Summary The CARDIOTOX trial is the largest trial to date analyzing the potential role of beta-blockers as prophylactic therapy to prevent cardiotoxicity induced by anthracyclines.