Title: Preventing cardiac damage in patients treated for breast cancer: a phase 3 Randomised, Open label, blinded endpoint, superiority trial of enalapril to prevent Anthracycline-induced CardioToxicity (PROACT).
Funder: Department of Health and Social Care

Abstract: Background Over 50,000 new cases of breast cancer are diagnosed in the UK every year.1,2 Treatment often includes anthracycline-based chemotherapy, which is highly effective. However, anthracyclines cause immediate, irreversible, damage to cardiac cells (cardiotoxicity).3 This damage reduces cardiac contractility and impairs left ventricular (LV) systolic function in 9.7% of patients at one year; in the long-term heart failure occurs in approximately 5% of patients.4-7 Heart failure caused by anthracyclines has a particularly poor prognosis with a survival of just 40% at 2 years.8 Preventing cardiotoxicity is imperative in a patient group in whom 78% are alive 10-years after their cancer diagnosis.1,9 Angiotensin converting enzyme inhibitors (ACEI) are of proven benefit in cardiovascular medicine, and are widely and safely used. ACEI reduce the production of the reactive oxygen species responsible for anthracycline toxicity and prevent anthracycline cardiotoxicity in animal models.10-14 ACEI have not been robustly tested as a preventative therapy for cardiotoxicity in a randomised controlled trial (RCT). Meta-analyses and systematic reviews identify a lack of high quality evidence to guide clinical decision making.15-17 No preventative agents are in routine use. Anthracycline cardiotoxicity is identified by detection of cardiac troponin; a highly sensitive and specific marker of cardiac cell death, and stongly correlated to later LV dysfunction.3,18,19 A negative troponin result during and at one month post chemotherapy excludes cardiotoxicity.18 Data from 36 patients at the Freeman Hospital, Newcastle, showed a positive troponin T in 47% of patients who received >300mg/m2 of the anthracycline epirubicin. To inform practice, the effectiveness of ACEI to prevent anthracycline cardiotoxicity in patients with breast cancer requires rigorous evaluation. Aims PROACT will establish the effectiveness of angiotensin-converting enzyme inhibitor (ACEI) enalapril maleate (enalapril) in preventing cardiotoxicity in patients with breast cancer undergoing adjuvant chemotherapy. The primary outcome is the presence or absence of cardiac troponin T (=14ng/L) release at any time during epirubicin treatment, and one month after the last dose of epirubicin. Secondary endpoints focus on important meaures of cardiac function and parameters which relate directly to patient outcomes. These will include: echocardiographic measures of cardiotoxicity including global longitudinal strain (GLS) and LV ejection fraction (LVEF); cardiac troponin I; adherence to enalapril; side effects of ACEI; and any anxiety/distress caused by trial participation. Plan of Investigation PROACT is a phase 3 randomised, open label, blinded endpoint, superiority trial of enalapril to prevent anthracycline-induced cardiotoxicity. Patients due to receive adjuvant anthracycline chemotherapy (planned epirubicin dose >300mg/m2) for breast cancer at four specialist centres in the North of England will be invited to participate. 170 eligible patients will be randomised in a 1:1 ratio, to either enalapril plus usual care or to usual care. Enalapril will be commenced prior to the first anthracycline dose, titrated to a maximum tolerated dose, and continued during chemotherapy. Chemotherapy will continue per usual care; typically six treatment cycles. Patients will have a blood test performed at the end of each chemotherapy cycle to measure cardiac troponin, and at one month following the last epirubicin dose. Investigators and patients will be blinded to the troponin results. Patients will have an echocardiogram at baseline and following their chemotherapy; they will be assessed in a blinded manner by a central Core Laboratory. Patient Impact There are currently no available relevant and robust randomised trials of ACEI in the prevention of anthracycline induced cardiotoxicity. PROACT will determine the effectivenss of enalapril in preventing cardiotoxicity in patients receiving epirubicin-based adjuvant chemotherapy for breast cancer. Given increasing breast cancer survival, the frequency and burden of cardiotoxicity, and the potential for a simple and cheap preventative treatment, PROACT is highly relevant and important for patients and the NHS.

Lay abstract: Many patients with early breast cancer receive anti-cancer (chemotherapy) drugs following surgery to remove their cancer. The most commonly used chemotherapy drugs are called anthracyclines. Unfortunately, anthracyclines also cause heart damage by killing heart muscle cells. Although heart damage is caused at the time of treatment, symptoms occur later. Heart damage affects the length and quality of peoples’ lives, and is expensive to treat. One in ten patients will have reduced heart function one year after chemotherapy but will not know; one in twenty patients later develop heart failure. This is important because three out of four patients who receive chemotherapy for breast cancer survive for ten years or more. Currently there is no treatment to prevent heart damage caused by anthracyclines in the UK. Drugs called ACE inhibitors are used commonly to treat high blood pressure and other heart conditions. Some early research suggests that these may prevent heart damage caused by anthracycline chemotherapy. Patients and doctors now need more information to show whether ACE inhibitors are effective at preventing heart damage. This trial will include 170 patients. Half will receive the ACE inhibitor enalapril during their chemotherapy, the other half will not. Enalapril tablets will be taken twice a day, beginning before chemotherapy starts, and finishing after it ends. All patients will have health checks during their chemotherapy that will be scheduled at the same time as their usual care wherever possible. These checks will include blood tests and two additional heart scans (echocardiograms) to look for heart damage. The study will compare heart damage between the two groups. The trial team includes heart and cancer doctors and researchers. The team have developed this trial with patients. Findings will tell us whether future patients should be given enalapril routinely when receiving anthracycline-based chemotherapy.

Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION;6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR;CANCER AND NEOPLASMS