Prevention of Left Ventricular Dysfunction During Chemotherapy

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.

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