Prevention of Left Ventricular Dysfunction During Chemotherapy (OVERCOME)
The investigators' objective is to assess the efficacy of the combined treatment with enalapril and carvedilol in the prevention of left ventricular systolic dysfunction in patients with hematological malignancies submitted to intensive chemotherapy with potential cardiotoxicity.
The hypothesis is that these drugs administered during chemotherapy may prevent left ventricular systolic dysfunction.
Acute Myeloid Leukemia
Precursor-cell Lymphoblastic Leukemia-Lymphoma
Autologous Hematopoietic Stem Cell Transplantation
Drug: Enalapril and carvedilol
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
|Official Title:||Prevention of Left Ventricular Dysfunction With Enalapril and Carvedilol in Patients Submitted to Intensive Chemotherapy for the Treatment of Malignant Hemopathies|
- Change from baseline in left ventricular ejection fraction (LVEF) measured by echocardiography and by cardiac magnetic resonance imaging (CMR). [ Time Frame: 6 months after randomization ] [ Designated as safety issue: No ]
- Incidence of death, heart failure or LV systolic disfunction (LVEF<45%) [ Time Frame: 6 months after randomization ] [ Designated as safety issue: No ]
- Assessment of genetic polymorphisms involved in chemotherapy-induced cardiotoxicity [ Time Frame: Baseline ] [ Designated as safety issue: No ]
- Prognostic value for cardiac toxicity of troponin I and BNP [ Time Frame: up to 3 months ] [ Designated as safety issue: No ]
- Right and left ventricular volumes measured by CMR [ Time Frame: 6 months after randomization ] [ Designated as safety issue: No ]
- Subgroup analysis by diagnosis (acute leukemia vs. other malignant hemopathies submitted to autologous peripheral blood stem cell transplantation), and positive biomarkers (TnI, BNP). [ Time Frame: 6 months after randomization ] [ Designated as safety issue: No ]
- Incidence of an absolute decrease in LVEF>10 percent units associated with a decline below its normal limit of 50% [ Time Frame: 6 months after randomization ] [ Designated as safety issue: No ]
- Serious adverse events [ Time Frame: 6 months after randomization ] [ Designated as safety issue: Yes ]
- the incidence of LV dysfunction as assessed by the measurement of the LV strain, and of diastolic dysfunction measured by echo-Doppler [ Time Frame: 6 months after randomization ] [ Designated as safety issue: No ]
|Study Start Date:||April 2008|
|Study Completion Date:||March 2012|
|Primary Completion Date:||December 2011 (Final data collection date for primary outcome measure)|
Experimental: Enalapril and carvedilol
Enalapril 2.5 to 10 mg BID plus Carvedilol 6.25 to 25 mg BID
Drug: Enalapril and carvedilol
Enalapril 2.5 to 10 mg BID Carvedilol 6.25 to 25 mg BID
No Intervention: Control
Control arm without intervention
The prognosis of patients with hematological malignancies has greatly improved in the last years with the use of new chemotherapeutic drugs and regimens at the cost of significant adverse events such as cardiac toxicity. Asymptomatic left ventricular systolic dysfunction limits the specific treatment of the patients and their long-term survival, since a significant proportion of them will relapse within 5 years after front-line therapy and will require further salvage treatment, including hematopoietic stem-cell transplantation in most instances.
Angiotensin-converting enzyme inhibitors (ACEIs) have showed to have preventive effects against chemotherapy-induced cardiotoxicity in animal models, and in patients with early cardiotoxicity. Carvedilol prevent free radical release, mitochondrial dysfunction, apoptosis, and dilated cardiomyopathy in animals treated with anthracyclines, and have shown promising results in preventing chemotherapy-induced left ventricular dysfunction in patients.
As demonstrated in post-infarction patients, the combined treatment with an ACEI and carvedilol could have additive effects to prevent LV dysfunction in patients with hematological malignancies at high risk of cardiac toxicity. Therefore, we designed the OVERCOME (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies) study, a prospective, randomized trial to evaluate the combined effect of enalapril and carvedilol on the prevention of left ventricular dysfunction in patients with malignant hemopathies undergoing intensive chemotherapy.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01110824
|Barcelona, Catalunya, Spain, 08035|
|Barcelona, Catalunya, Spain, 08036|
|Study Chair:||Xavier Bosch, M.D., PhD.||Hospital Clinic, University of Barcelona|