Prophylactic Lisinopril to Prevent Anthracycline Cardiomyopathy.
brief summary
The intent of the study is to show the potential benefits of angiotensin converting enzyme inhibitors in preventing anthracycline induced cardiotoxicity. This is a prospective, randomized, blinded and placebo-controlled clinical trial that will enroll patients who are to be treated with anthracycline chemotherapy (doxorubicin, epirubicin, idrarubicin, or mitoxantone) to either lisinopril or placebo group. The study will be performed at the Genesys Hurley Cancer Institute. The treating oncologist who intends to start the patient on anthracycline chemotherapeutic agent will provide the patient with a recruitment flyer and informed consent form and then referred to the research nurse. Subjects interested in participation, that do not meet any of the exclusion criteria, will be consented and enrolled by the research nurse prior to their first treatment with chemotherapy. Over a period of 1 to 3 weeks the study medication will be titrated in a stepwise fashion to a target of 20 mg daily, maintaining a systolic blood pressure greater than 90 mmHg. A baseline echocardiogram with strain and strain rate imaging will be obtained prior to initiation of anthracycline chemotherapy. Subsequent echocardiograms with strain and strain rate imaging will be performed every 3 months for a total of 12 months. Patients will be followed for a total of 12 months, starting on the day of enrollment. We intend to recruit a total of 200 patients. The primary endpoint of this study is a change in change in strain and strain rate parameters prior to, during, and after anthracycline chemotherapy compared to placebo. Study data will be collected and managed using the Ascension installation of REDCap (Research Electronic Data Capture). REDCap is a secure, web application designed to support data capture for research studies, providing user-friendly web-based case report forms, real-time data entry validation (e.g. for data types and range checks), audit trails and a de-identified data export mechanism to common statistical packages. Echocardiographic data will be stored in cine-loop format on a private, password protected echocardiogram viewing software and analyzed by a separate blinded cardiologist. Patients will be evaluated according to the standard oncologic evaluation. The treating oncologist will make decisions on their treatment based on their personal standards and clinical judgement.
detailed description
To date anthracycline chemotherapy regimens still play a major role in many cancer treatments, approximately 32% of breast cancer patients, 57-70% of elderly lymphoma patients, and 50-60% of childhood cancers survivors are treated with an anthracycline regimen.
Of these patients, approximately 9-24%% of patients on anthracycline chemotherapy will develop anthracycline cardiomyopathy and the majority will present with signs and/or symptoms within the first 12 months of starting chemotherapy. The onset of anthracycline cardiomyopathy, even asymptomatic, not only negatively impacts the cardiac outcome of cancer patients, but also limits their therapeutic opportunities to less aggressive and, consequently, less effective therapies
There is limited evidence based research for treatment of anthracycline induced cardiomyopathy and is mainly targeted towards standard heart failure therapy. In 2006, Cardinale et al. found early treatment of myocardial cell injury, as defined by a rise in troponin, with enalapril prevents left ventricular ejection fraction decrease as well as the occurrence of cardiac events. Subsequently in 2010, Cardinale et al. also found that treatment of anthracycline cardiomyopathy with standard heart failure therapy (enalapril, carvedilol) at the onset of cardiomyopathy, defined as ejection fraction of ≤ 45%, lead to complete recovery of left ventricular ejection fraction and improved cardiac outcomes. Indeed, much of the research has been focused on management of patients who develop early signs of left ventricular dysfunction. Unfortunately, despite this strategy up to 11% still go on to develop New York Heart Association class 3 or 4 heart failure symptoms.
A crucial issue remains is whether or not, and eventually how, to treat patients still asymptomatic who do not yet demonstrate left ventricular dysfunction. Lisinopril use has been well studied in patients with systolic heart failure and is a class I indication in all patients with an ejection fraction of \<40 %. Randomized control trials have established their benefit in reducing morbidity and mortality in heart failure with reduced ejection fraction. Since anthracycline induced-cardiotoxicity has a significant impact on overall prognosis in cancer patients and despite treatment after the development of left ventricular dysfunction from anthracyclines will still result in a large amount of the patient population developing heart failure, there is an urgent need in prophylactic treatment in preventing anthracycline-induced left ventricular dysfunction.
Thus, the intent of our study is to show the potential benefits of angiotensin converting enzyme inhibitors in preventing anthracycline induced cardiotoxicity.
official title
Prophylactic Lisinopril to Prevent Anthracycline Induced Left Ventricular Systolic Dysfunction (PLAID) Study.