Acute Myeloid Leukemia, Autologous Hematopoietic Stem Cell Transplantation, Lymphoid Neoplasm, Lymphoma, Multiple Myeloma, Precursor-cell Lymphoblastic Leukemia-Lymphoma
Conditions
Keywords
Prevention, ventricular dysfunction, chemotherapy, acute myeloid leukemia, precursor-cell lymphoblastic leukemia, multiple myeloma, lymphoma, ejection fraction, Autologous hematopoietic stem cell transplantation
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.
Interventions
DRUGEnalapril and carvedilol
Enalapril 2.5 to 10 mg BID Carvedilol 6.25 to 25 mg BID
Sponsors
Instituto de Salud Carlos III
European Union
Hospital Clinic of Barcelona
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | 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
| Measure | Time frame |
|---|---|
| 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 |
| Incidence of death, heart failure or LV systolic disfunction (LVEF<45%) | 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 |
| 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 |
Countries
Spain
Outcome results
None listed