Clinical trial NCT01110824: Prevention of Left Ventricular Dysfunction During Chemotherapy
Official title: Prevention of Left Ventricular Dysfunction With Enalapril and Carvedilol in Patients Submitted to Intensive Chemotherapy for the Treatment of Malignant Hemopathies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Myeloid Leukemia
Precursor-cell Lymphoblastic Leukemia-Lymphoma
Lymphoid Neoplasm
Multiple Myeloma
Lymphoma
Autologous Hematopoietic Stem Cell Transplantation
Keywords: Prevention
ventricular dysfunction
chemotherapy
acute myeloid leukemia
precursor-cell lymphoblastic leukemia
multiple myeloma
lymphoma
ejection fraction
Autologous hematopoietic stem cell transplantation
Lead sponsor: Hospital Clinic of Barcelona
Sponsor class: OTHER
Collaborators: name: Instituto de Salud Carlos III
name: European Union
First posted: 2010-04-27
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change from baseline in left ventricular ejection fraction (LVEF) measured by echocardiography and by cardiac magnetic resonance imaging (CMR).
timeFrame: 6 months after randomization
Secondary outcomes:
measure: Incidence of death, heart failure or LV systolic disfunction (LVEF<45%)
timeFrame: 6 months after randomization
measure: Assessment of genetic polymorphisms involved in chemotherapy-induced cardiotoxicity
timeFrame: Baseline
measure: Prognostic value for cardiac toxicity of troponin I and BNP
timeFrame: up to 3 months
measure: Right and left ventricular volumes measured by CMR
timeFrame: 6 months after randomization
measure: Subgroup analysis by diagnosis (acute leukemia vs. other malignant hemopathies submitted to autologous peripheral blood stem cell transplantation), and positive biomarkers (TnI, BNP).
timeFrame: 6 months after randomization
measure: Incidence of an absolute decrease in LVEF>10 percent units associated with a decline below its normal limit of 50%
timeFrame: 6 months after randomization
measure: Serious adverse events
timeFrame: 6 months after randomization
measure: the incidence of LV dysfunction as assessed by the measurement of the LV strain, and of diastolic dysfunction measured by echo-Doppler
timeFrame: 6 months after randomization
Other outcomes:
Locations:
city: Barcelona
country: Spain
facility: Hospital Clinic
state: Catalunya
city: Barcelona
country: Spain
facility: Hospital Clinic
state: Catalunya
Study officials:
affiliation: Hospital Clinic, University of Barcelona
name: Xavier Bosch, M.D., PhD.
role: STUDY_CHAIR
References:
citation: Bosch X, Esteve J, Sitges M, de Caralt TM, Domenech A, Ortiz JT, Monzo M, Morales-Ruiz M, Perea RJ, Rovira M. Prevention of chemotherapy-induced left ventricular dysfunction with enalapril and carvedilol: rationale and design of the OVERCOME trial. J Card Fail. 2011 Aug;17(8):643-8. doi: 10.1016/j.cardfail.2011.03.008. Epub 2011 May 6.
citation: Bosch X, Rovira M, Sitges M, Domenech A, Ortiz-Perez JT, de Caralt TM, Morales-Ruiz M, Perea RJ, Monzo M, Esteve J. Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies). J Am Coll Cardiol. 2013 Jun 11;61(23):2355-62. doi: 10.1016/j.jacc.2013.02.072. Epub 2013 Apr 10.