ACE inhibitor, beta blocker may thwart cardiotoxicity from chemotherapy: Pilot study

Barcelona, Spain - Lasting cardiac damage from chemotherapy is a tragedy: cancer patients are cured of one life-threatening disease, only to succumb to another—heart failure—as a result of the treatment.

Current clinical practice is to stop chemotherapy if cardiac problems develop, but this means that the heart has already been damaged. A better strategy would be to prevent the damage in the first place, say the authors of a pilot study published online April 10, 2013 in the Journal of the American College of Cardiology [1].

Dr Xavier Bosch (Thorax Institute, Hospital Clinic, Barcelona, Spain) and colleagues report that cardiovascular drugs administered to cancer patients while they undergo intensive chemotherapy may protect their hearts from lasting damage. The treatment, a combination of the ACE inhibitor enalapril and the beta-blocker carvedilol, appeared to prevent the reduction in left ventricular ejection fraction (LVEF) seen in control patients, after both groups had undergone intensive chemotherapy for their cancer.

These results could "have important implications, since each year millions of patients with cancer are treated with chemotherapy worldwide and are surviving the disease in great numbers," Bosch and colleagues comment. However, they add that this prevention strategy "should be confirmed in larger future studies."

In an accompanying editorial [2], Dr Otto Smiseth (Oslo University Hospital, Norway) and colleagues say that large multicenter trials are needed, pointing out several limitations to the current study, and they also lament on the slow progress in this field.

"It is striking that it has taken 15 years" to go from general heart failure, where these drugs have markedly reduced mortality, "to testing this strategy in cancer patients at risk from heart failure," they comment. There needs to be a better and faster translation of knowledge between cardiology and oncology, and the recently created specialty of cardioncology is a step in the right direction, they add.

OVERCOME Trial

The study, known as Prevention of Left Ventricular Dysfunction With Enalapril and Carvedilol in Patients Submitted to Intensive Chemotherapy for the Treatment of Malignant Hemopathies (OVERCOME), was conducted in 90 patients with various hematological malignancies. Thirty-six patients had recently been diagnosed with acute leukemia; the remaining 54 patients (22 with multiple myeloma, 23 with Hodgkin's disease, nine with non-Hodgkin's lymphoma) were undergoing autologous hematopoietic stem-cell transplantation.

All patients received intensive high-dose chemotherapy: the regimens were not specified in the paper, but the authors mention that the patients with acute leukemia received anthracyclines, which are notoriously cardiotoxic, while the other patients did not.

Half of the patients (n=45) were randomly assigned to receive enalapril and carvedilol, while the other half served as controls. LVEF was measured before and after chemotherapy by both cardiac magnetic resonance (CMR) and echocardiography.

The authors report that after six months, LVEF had not changed in the patients who had received enalapril plus carvedilol, but it had decreased significantly in the controls, resulting in a -3.1% absolute difference by echocardiography (p=0.035) and a -3.4% absolute difference by CMR (p=0.09).

However, the editorialists point out that a follow-up CMR was performed in only 59 of the 90 patients, and the difference between the treated and control patients was "only marginally significant." But follow-up echocardiography was carried out in 79 of 90 patients, and this showed a significant difference, they add.

The apparent protective effect of enalapril plus carvedilol was more pronounced in the subgroup of 36 patients with acute leukemia, who received the more cardiotoxic chemotherapy regimens, the authors note. In this subgroup, the absolute difference in LVEF between treated patients and controls was -6.38%.

However, there was little difference in the LVEF among the remaining 54 patients with other hematologic malignancies (absolute difference -1%).

Effects on mortality?

The results suggest that patients treated with enalapril and carvedilol fared better overall than controls and that they suffered from less cardiac damage. The treated patients had a lower incidence of the combined end point of death and heart failure (6.7% vs 22% in controls, p=0.036) and also had a lower incidence of the combined end point of death, heart failure, or final LVEF <45% (6.7 vs 24.4%, p=0.02).

However, the authors note that two-thirds of the deaths were related to infectious complications in the context of postchemotherapy neutropenia, and so "it is difficult to elucidate whether enalapril and carvedilol could have influenced mortality."

In their editorial, Smiseth and colleagues say the design of the trial "leaves many questions that need an answer." The trial was not blinded, did not compare the combination of ACE inhibitor and beta-blocker with single agents, and the means of detecting ventricular function "was to some degree inadequate."

Future studies should include assessment of LV function by strain imaging and should also assess diastolic function and correct hypertension in order to reduce the deleterious effects of chemotherapy on cardiac function, they suggest.

Source: www.theheart.org