Prevention of Left Ventricular Dysfunction During Chemotherapy

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Prevention of Left Ventricular Dysfunction With Enalapril and Carvedilol in Patients Submitted to Intensive Chemotherapy for the Treatment of Malignant Hemopathies

Conditions
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Acute Myeloid Leukemia, Precursor-cell Lymphoblastic Leukemia-Lymphoma, Lymphoid Neoplasm, Multiple Myeloma, Lymphoma, Autologous Hematopoietic Stem Cell Transplantation

Intervention / Treatment
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* Drug: Enalapril and carvedilol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients 18-70 years old Sinus rhythm Normal LVEF (>=50%) Patients recently diagnosed of acute leukemia to be submitted to intensive chemotherapy or Patients with other hemopathies submitted to autologous peripheral blood stem cell transplantation Signed informed consent Exclusion Criteria: Congestive heart failure LVEF<50% Coronary artery disease, significant valvulopathy or myocardiopathy Renal failure (MDRD<30) Liver failure Ongoing or expected need to be treated with angiotensin-converting enzyme inhibitors (ACE-i),angiotensin II receptor blockers (ARB) or beta-blockers Prior allergy to ACEI or ARB Systolic blood pressure <90 mmHg Asthma Auriculoventricular (AV) block or sinus bradycardia (HR<60 bpm) Persistent atrial fibrillation Need to be treated with Class I antiarrhythmic drugs Pregnancy Inability or unwillingness to give unformed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Enalapril and carvedilol<br>Enalapril 2.5 to 10 mg BID plus Carvedilol 6.25 to 25 mg BID | Drug: Enalapril and carvedilol<br>* Enalapril 2.5 to 10 mg BID Carvedilol 6.25 to 25 mg BID<br>|
| No Intervention: Control<br>Control arm without intervention | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in left ventricular ejection fraction (LVEF) measured by echocardiography and by cardiac magnetic resonance imaging (CMR). |  | 6 months after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of death, heart failure or LV systolic disfunction (LVEF<45%) |  | 6 months after randomization | 
| Assessment of genetic polymorphisms involved in chemotherapy-induced cardiotoxicity |  | Baseline | 
| Prognostic value for cardiac toxicity of troponin I and BNP |  | up to 3 months | 
| Right and left ventricular volumes measured by CMR |  | 6 months after randomization | 
| Subgroup analysis by diagnosis (acute leukemia vs. other malignant hemopathies submitted to autologous peripheral blood stem cell transplantation), and positive biomarkers (TnI, BNP). |  | 6 months after randomization | 
| Incidence of an absolute decrease in LVEF>10 percent units associated with a decline below its normal limit of 50% |  | 6 months after randomization | 
| Serious adverse events |  | 6 months after randomization | 
| the incidence of LV dysfunction as assessed by the measurement of the LV strain, and of diastolic dysfunction measured by echo-Doppler |  | 6 months after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prevention, ventricular dysfunction, chemotherapy, acute myeloid leukemia, precursor-cell lymphoblastic leukemia, multiple myeloma, lymphoma, ejection fraction, Autologous hematopoietic stem cell transplantation