Abstract
BackgroundAnthracycline-induced cardiotoxicity (AIC), a condition associated with multiple mechanisms of damage, including oxidative stress, has been associated with poor clinical outcomes. Carvedilol, a β-blocker with unique antioxidant properties, emerged as a strategy to prevent AIC, but recent trials question its effectiveness. Some evidence suggests that the antioxidant, not the β-blocker effect, could prevent related cardiotoxicity. However, carvedilol’s antioxidant effects are probably not enough to prevent cardiotoxicity manifestations in certain cases. We hypothesize that breast cancer patients taking carvedilol as well as a non-hypoxic myocardial preconditioning based on docosahexaenoic acid (DHA), an enhancer of cardiac endogenous antioxidant capacity, will develop less subclinical cardiotoxicity manifestations than patients randomized to double placebo.Methods/designWe designed a pilot, randomized controlled, two-arm clinical trial with 32 patients to evaluate the effects of non-hypoxic cardiac preconditioning (DHA) plus carvedilol on subclinical cardiotoxicity in breast cancer patients undergoing anthracycline treatment. The trial includes four co-primary endpoints: changes in left ventricular ejection fraction (LVEF) determined by cardiac magnetic resonance (CMR); changes in global longitudinal strain (GLS) determined by two-dimensional echocardiography (ECHO); elevation in serum biomarkers (hs-cTnT and NT-ProBNP); and one electrocardiographic variable (QTc interval). Secondary endpoints include other imaging, biomarkers and the occurrence of major adverse cardiac events during follow-up. The enrollment and follow-up for clinical outcomes is ongoing.DiscussionWe expect a group of anthracycline-treated breast cancer patients exposed to carvedilol and non-hypoxic myocardial preconditioning with DHA to show less subclinical cardiotoxicity manifestations than a comparable group exposed to placebo.Trial registrationISRCTN registry, ID: ISRCTN69560410. Registered on 8 June 2016.
Highlights
Anthracycline-induced cardiotoxicity (AIC), a condition associated with multiple mechanisms of damage, including oxidative stress, has been associated with poor clinical outcomes
We expect a group of anthracycline-treated breast cancer patients exposed to carvedilol and nonhypoxic myocardial preconditioning with docosahexaenoic acid (DHA) to show less subclinical cardiotoxicity manifestations than a comparable group exposed to placebo
As AIC has been historically associated with left ventricular systolic dysfunction (LVSD), the incidence of AIC has been mainly expressed as a decline in different quantitative left ventricular ejection fraction (LVEF) criteria [3, 10]
Summary
CarDHA is a limited, academic, randomized, placebocontrolled, double-blind, two-arm clinical trial designed to evaluate the efficacy of the proposed strategy to inhibit or attenuate subclinical manifestations of anthracycline-induced cardiotoxicity (AIC). Notwithstanding, we maintain that beyond the use of CMR, the greatest contribution of this protocol is to evaluate a prophylactic strategy completely designed to attenuate the oxidative stress derived from AIC, with the inclusion of two different antioxidant strategies administered sequentially to enhance the effects. CarDHA is the first randomized trial designed to evaluate the potential cardioprotective effects of a dual antioxidant strategy comprising a nonischemic pharmacologic cardiac preconditioning based on DHA and carvedilol, designed to attenuate oxidative stress as a key factor in AIC development and progression.
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