Title: A multicentre prospective randomised open-label blinded end-point controlled trial of cardiac troponin I-guided combination angiotensin receptor blockade and beta blocker therapy to prevent cardiac toxicity in anthracycline treated breast cancer patients
Funder: Chief Scientist Office, Scotland

Abstract: Background: Anthracyclines are used in a wide range of cancers including breast and lymphoma. Anthracycline administration is associated with dose-related cardiomyocyte injury and death leading to left ventricular dysfunction and heart failure.1,2 Cohort studies indicate increasing heart failure prevalence 30 years after cancer treatment with 5% of patients receiving anthracycline developing symptomatic heart failure and up to 10% in those over the age of 64 years. The progression from heart muscle injury at the time of chemotherapy to development of clinical heart failure is not understood and no preventive treatments are available. Current practice relies on monitoring systolic cardiac function with serial scans to measure ejection fraction. Scans are conducted with ultrasound or radionuclide. These involve extra hospital visits and the latter requires a radiation dose which can be up to 30 mSv over a treatment course. Previous studies have used the circulating myocardial injury marker Troponin I (cTnI) to detect early muscle injury before systolic function is impaired4-6. One study using a contemporary assay found elevated cTnI levels in 80% of patients who developed systolic dysfunction4. Previous and ongoing clinical trials have investigated whether administration of medications established in the treatment of heart failure can prevent systolic dysfunction in patients receiving chemotherapy. These studies are limited by 1. An aim to treat all patients resulting in massive over-treatment and 2. Using either an angiotensin receptor blocker (ARB) or B-blocker rather than co-prescription which has the evidence base for improving function and survival in patients with established left ventricular dysfunction7. Research question and investigation plan: We will use surveillance with cTnI blood testing in patients receiving cardiotoxic systemic therapy to identify early myocardial injury enabling targeted protective treatment with ARB and B-blocker. Our group has validated the clinical application of a high-sensitivity cTnI assay. We demonstrated that this assay doubles the diagnosis of myocardial infarction in women with chest pain by defining a lower gender-specific reference range8. We believe it will improve detection of heart muscle injury compared to previous studies with contemporary assays. Patients recruited into the study who exhibit an elevated cTnI concentration will be randomised to receive either carvedilol and candesartan (B-blocker and ARB), or continue with no treatment. The study will recruit 168 patients from several UK regional cancer centres. Participants will have cardiac function (ejection fraction) monitored with serial cardiac magnetic resonance imaging (MRI) scans. Cardiac MRI is the most precise measure of cardiac function and provides additional measures of systolic volume and cardiac strain that inform on early mechanisms of chemotherapy induced cardiac muscle injury. The endpoint will be the change in ejection fraction 6 months after chemotherapy. The hypothesis is that carvedilol and candesartan will prevent development of cardiac dysfunction in at-risk participants identified by elevated cTnI levels. Additional outcomes include treatment effect on ongoing cardiac injury (persistence of cTnI elevation), death and heart failure and a provisional health economic analysis of this selective intervention strategy to prevent chemotherapy related heart failure

Lay abstract: Background Breast cancer is common. The lifetime risk of women developing breast cancer in the UK is 1 in 8. Survival continues to improve. This improved survival is in part down to chemotherapy drugs called anthracyclines. This medication can cause the unwanted side effect of heart muscle injury. Breast cancer and lymphoma survivors have increased rates of heart problems including heart muscle failure. Research questions: We aim to test whether tablet medications called angiotensin receptor blockers (ARB) and B-blockers can prevent heart muscle injury related to chemotherapy. These medications are well established treatments for improving symptoms and survival in patients with heart failure. We will examine a blood test called cardiac troponin I which can detect very slight heart muscle injury. In the trial only patients with increased levels of this marker will be treated with ARB and B-blocker. What will happen to study patients? Breast cancer or non-Hodgkin lymphoma patients scheduled for anthracycline treatment will be approached to take part. If they give consent they will have a detailed magnetic resonance imaging (MRI) scan of their heart prior to starting chemotherapy. Patients receiving anthracycline have blood taken routinely before each cycle. Cardiac troponin I levels will be measured on these blood samples. Patients who have an elevation in cardiac troponin I will be allocated at random to treatment with a combination of ARB and B-blocker or standard care. What is measured in the study? The main measurement is whether ARB and B-blocker can prevent the decline in heart muscle function measured on MRI. We will follow-up patients to measure health events such as heart failure. The study will show whether a convenient blood test can detect those at risk of heart failure.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS;CARDIOVASCULAR