Cancer
Conditions
Keywords
Carvedilol, Anthracyclines, Cardiotoxicity, Chemotherapy
Brief summary
Neoplasia is the main cause of general death in the Brazilian population. In 2016, they were responsible for approximately 211,343 (16%) deaths, followed by cardiovascular diseases (12.6%). Despite the high mortality rate of neoplasia, oncological treatment have advanced substantially in recent decades improving the prognosis of patients. However, growing evidence suggest that some oncological agents may induce significant toxicity that may play a major role in the quality of life, morbidity and mortality. The cardiovascular system is often negatively affected with cancer therapy, predisposing several patients to stop appropriate treatments or to have cardiovascular events related to the cardiotoxicity. The most typical manifestation of cardiotoxicity and related consequences (heart failure) are related to the use of anthracyclines. Anthracyclines are part of the chemotherapy regimen for solid tumors and hematological neoplasms in children and adults, and are associated with an increase in life expectancy. Carvedilol is an α and β-blocker that also has antioxidant properties. Preliminary studies have shown that carvedilol and its metabolites prevent lipid peroxidation, inhibit the formation and inactivate free radicals, in addition to preventing the depletion of endogenous antioxidants, such as vitamin E. These effects would potentially prevent anthracycline injury but definitive evidence is still needed. This is a multi-center, double-blind, randomized, placebo-controlled study that aims to establish the efficacy of carvedilol for the primary prevention of left ventricular systolic dysfunction in cancer patients obtained with anthracycline chemotherapy, in different schedules and doses.
Interventions
DRUGCarvedilol
Carvedilol will be dispensed in a staggered and progressive manner, initially from 6.25 mg twice daily, then increased to 12.5 mg twice daily, until maximum dose of 25 mg twice daily or development of contraindications
DRUGPlacebo
Patients will receive placebo in a presumed staggered and progressive manner similar to the intervention group. The placebo will ideally be maintained for up to 30 days after the end of chemotherapy.
Sponsors
Ministry of Health, Brazil
Hospital Sirio-Libanes
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Masking description
Randomization will be in the proportion of 1: 1 (carvedilol x placebo). Both randomization and allocation of patients will be chosen in a veiled manner to patients and to assess. Data on randomization and allocation will be under custody of the Data analysis and safety committee.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* ≥18 years of age at the time of screening * Cancer patients that will receive chemotherapy with anthracyclines.
Exclusion criteria
* Inability to adequate asses left ventricular function * Previous symptoms (dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, and pulmonary and systemic congestion) suggestive of or a previous diagnosis of heart failure. * Previous history of any cardiomyopathy (eg.: valve disease, Chagas' disease, infiltrative cardiomyopathy) * LVEF \< 50% * Previous history of myocardial revascularization * Permanent tachyarrhythmia (flutter, atrial fibrillation, atrial tachycardia) * Congenital heart disease with left ventricular function impared * Contra-indication to the use of beta-blockers. * Pregnant or Breast-feeding females or women of childbearing age who intend to became pregnant. * On kidney replacement therapy * ECOG \>= 4 or Karnofsky \<=30 * Advanced hepatic failure (C score Child-Pugh and MELD \> 15); * Previous use of anthracycline * Have any serious concomitant systemic disease, condition, or disorder that, in the opinion of the investigator, should preclude participation in this study * Are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cardiac events within 12 months of starting treatment. | 12 months | Cardiac events such as death, resuscitated cardiac arrest, myocardial infarction, heart failure and cardiac arrhythmias |
| Drop in ejection fraction within 12 months of starting treatment. | 12 months | Drop in ejection fraction\> 10% to values less than 50% of the left ventricle |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Reduction in myocardial strain in 12 months from the start of treatment. | 12 months | Relative reduction of more than 15% in myocardial strain |
| Diastolic dysfunction within 12 months | 12 months | Development of diastolic dysfunction within 12 months |
| Drop in ejection fraction within 12 months. | 12 months | Drop in ejection fraction greater than 10% and values less than 55% |
| Elevation of biomarkers during chemotherapy and up to 12 months of follow-up | 12 months | Elevation of biomarkers (NT-pro BNP and troponin) during chemotherapy and up to 24 months of follow-up |
| Quality of life (EuroQol-5D). | 12 months | Quality of life measured by questionnaire in up to 12 months. |
| Cardiovascular complications in 12 months. | 12 months | Cardiovascular complications (death, resuscitated cardiac arrest, myocardial infarction, heart failure and cardiac arrhythmias) in 24 months. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Diagnosis of neoplasia within 12 months. | 12 months | Diagnosis of another neoplasia |
| Progression of oncological disease within 12 months. | 12 months | Progression of oncological disease |
| Tumor recurrence within 12 months. | 12 months. | Tumor recurrence |
Countries
Brazil
Contacts
Primary ContactAna Cecilia A Silva, MD, PhD
Backup ContactIsabela B dos Santos da Silva, MD, PhD
Outcome results
None listed