CardioPROTECTion with dapagliflozin in breast cancer patients treated with AnthrAcycline - PROTECTAA TRIAL: rationale and design

Even every third breast cancer patient receives anthracyclines as a part of treatment. Among adverse effects of anthracyclines dose-related cardiotoxicity is enumerated. Frequency of development of symptomatic heart failure is poorly known in this population because a lack of large prospective trials. However, in some long-term observational studies it is estimated to reach even 50%. In this context prevention of cancer therapeutics-related left ventricular dysfunction is a serious challenge, both on the individual and society levels. However, there is no evidence from large randomized trials supporting use of any drug in prevention of cardiotoxicity so far. Since 2019 new group of drugs in heart failure therapy emerged – sodium-glucose co-transporter type 2 inhibitors. Dapagliflozin showed cardioprotective properties in animal models of diabetes or ischemic heart disease by decreasing an apoptosis and necrosis of cardiomyocytes and slowing interstitial fibrosis. Given the known pathophysiology of post-anthracycline myocardial injurydapagliflozin holds promise as a potential cardioprotective drug. Up to date no drug from this group was tested in prevention of left ventricular dysfunction after anthracycline-based cancer therapy.

Main aim of the trial is an assessment of effect of dapagliflozin on occurrence of cancer therapy-related cardiac dysfunction 12 months after initiation of anthracycline-based chemotherapy. Secondary aims are assessment of diastolic function of the left ventricle, quality of life and change in biomarkers values across the trial.

PROTECTAA trial is multicenter, randomized, placebo-controled, double blinded study, which will evaluate effect of dapagliflozin on cardiotoxicity of anthracycline-based chemotherapy in breast cancer patients. 188 breast cancer patients before initiation of anthracycline-based chemotherapy who meet eligibility criteria are going to be enrolled and randomized in 1:1 fashion to therapy with 10 mg of dapagliflozin or a control group. First dose of dapagliflozin will be given 1-7 days before first anthracycline infusion. Dapagliflozin will be given for 12 months. Placebo in form of a tablet imitating study drug will be a comparator.

At baseline visit levels of troponin I and NT-proBNP will be determined and transthoracic echocardioraphy with ejection fraction and global longitudinal strain assessment will be performed. Follow-up will last 13 months with two major visits with blood tests and transthoracic echocardiography at 6 and 12 months after first dose of anthracyclines. Additional minor visits are scheduled after 1, 3, 9 and 13 months.

Primary endpoint is a composite one, constituted by development of symptomatic heart failure, asymptomatic decrease in ejection fraction, asymptomatic decrease in global longitudinal strain or asymptomatic new rise of cardiac biomarkers. Many other secondary efficacy and safety endpoints will also be assessed.