Protective effects of nebivolol against anthracycline-induced cardiomyopathy: A randomized control study

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Abstract

Background

We aimed to evaluate the effect of prophylactic nebivolol use on prevention of antracycline-induced cardiotoxicity in breast cancer patients.

Methods

In this small, prospective, double-blind study, we randomly assigned 45 consecutive patients with breast cancer and planned chemotheraphy to receive nebivolol 5 mg daily (n = 27) or placebo (n = 18). Echocardiographic measurements and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels were obtained at baseline and at 6-month of chemotherapy.

Results

Both studied groups had comparable echocardiographic variables and NT-pro-BNP levels at baseline. At 6-month, the left ventricular (LV) end-systolic and end-diastolic diameters increased in the placebo group (LVESD: 29.7 ± 3.4 to 33.4 ± 4.5 mm; LVEDD: 47.2 ± 3.8 to 52.0 ± 4.6 mm, p = 0.01 for both) but remained unchanged in the nebivolol group (LVESD: 30.4 ± 3.5 to 31.0 ± 3.6 mm, p = 0.20; LVEDD: 47.0 ± 4.4 to 47.1 ± 4.0 mm, p = 0.93). The placebo group also had lower LVEF than the nebivolol group (57.5 ± 5.6% vs. 63.8 ± 3.9%, p = 0.01) at 6-month. NT-pro-BNP level remained static in the nebivolol group (147 ± 57 to 152 ± 69 pmol/l, p = 0.77) while it increased in the placebo group (144 ± 66 to 204 ± 73 pmol/l, p = 0.01).

Conclusions

Prophylactic use of nebivolol treatment may protect the myocardium against antracycline-induced cardiotoxicity in breast cancer patients.

Introduction

In cancer therapy, several cytotoxic drugs may cause cardiotoxicity which is associated with poor short- and long-term outcome. Anthracycline has long been demonstrated to improve survival in breast cancer patients. However, the development of dose-related, cumulative, and essentially irreversible cardiac toxicity undermines its long-term clinical benefits [1].

The proposed mechanisms of antracycline-induced cardiotoxicity (AIC) include the formation of free reactive oxygen radicals, direct DNA damage and/or interference with DNA repair, apoptosis, activation of immune reactions involving antigen-presenting cells in the heart, changes in calcium transport, histamine release and activation of coagulation system leading to coronary artery thrombosis [1], [2], [3], [4], [5], [6].

Free radical hypothesis has been suggested to be one of the major determinants for AIC [7], [8]. Animal experiments demonstrated that numerous agents could potentially counteract chemotherapy toxicity. Promising results have been reported in these animal studies involving angiotensin-converting enzyme inhibitors [9], telmisartan [10], carvedilol [11], nebivolol [12], erythropoietin [13], bosentan [14], carbon monoxide (CO) and bilirubin [15] on AIC. However, data are scant about their clinical use in humans.

Of them, nebivolol is a β1-selective (i.e. cardio-selective) adrenergic receptor antagonist (at doses up to 10 mg/d), with vasodilatory effects mediated by nitric oxide (NO) release, a mechanism possibly triggered by activation of β3-receptors [16], [17]. In this randomized, double-blind, placebo-controlled clinical study, we aimed to evaluate the effect of prophylactic nebivolol use on prevention of AIC in breast cancer patients receiving anthracycline-based chemotherapy.

Section snippets

Study population

From October 2007 to September 2008, 45 consecutive patients admitted to the medical oncology department of the Erciyes University Medical School for breast cancer and planned antracycline-based chemotheraphy were enrolled. All patients were female. Exclusion criteria included the presence of cardiomyopathy (dilated, restrictive or hypertrophic) detected by baseline echocardiography, coronary heart disease, moderate or severe aortic and/or mitral valve disease, prior chemotherapy or

Results

Patients received low dose nebivolol treatment did not experience any symptomatic hypotention or bradycardia. There were no heart failure hospitalization or death occurred during the study period. No patient from each group discontinued the nebivolol or placebo therapy because of their side effects.

Of the 45 consecutive patients enrolled in the study, 27 were randomized to oral nebivolol, and 18 were randomized to placebo. Baseline clinical and echocardiographic characteristics are listed in

Discussion

This small, randomized, placebo-controlled study demonstrated prophylactic nebivolol use may prevent LV enlargement and functional impairment caused by anthracycline therapy.

Anthracycline-induced cardiotoxicity (AIC) causes severe morbidity and even mortality in cancer patients. The fear of developing cardiotoxicity may also limit the dose of the drug to be used and leads to reduced tumour response. Cardiotoxicity is mainly caused by anthracyclines although a number of other chemotherapeutic

Acknowledgments

The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.

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    Conflict of Interest: None.

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