Prevention of Left Ventricular Dysfunction During Chemotherapy

Phase 3

Completed

• Conditions: Precursor-cell Lymphoblastic Leukemia-Lymphoma; Lymphoid Neoplasm; Lymphoma; Multiple Myeloma; Autologous Hematopoietic Stem Cell Transplantation; Acute Myeloid Leukemia
• Interventions: Drug: Enalapril and carvedilol

• Registration Number: NCT01110824
• Lead Sponsor: Hospital Clinic of Barcelona

Brief Summary

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

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.

Study Timeline

• Study Start: 2008-04
• Study First Submitted: 2010-04-23
• Study First Submitted QC: 2010-04-23
• Study First Posted: 2010-04-27
• Primary Completion: 2011-12
• Study Completion: 2012-03
• Status Verified: 2013-11
• Last Update Submitted: 2013-11-14
• Last Update Posted: 2013-11-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 90

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Enalapril and carvedilol	Enalapril and carvedilol	Enalapril 2.5 to 10 mg BID plus Carvedilol 6.25 to 25 mg BID

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
Prognostic value for cardiac toxicity of troponin I and BNP	up to 3 months
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
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

Trial Locations

Locations (1)

Hospital Clinic; 🇪🇸 Barcelona, Catalunya, Spain