ORLANDO, Fla. — In patients treated for early breast cancer, concomitant treatment with the angiotensin receptor blocker (ARB) candesartan may provide protection against early decline in global left ventricular function (LVF). Conversely, the beta-blocker metoprolol does not appear to help alleviate decline in global LVF, according to a new Norwegian study presented at the American Heart Association Scientific Sessions.

For some time now, investigators have been searching for agents that may help protect against cardiotoxicity associated with contemporary adjuvant therapy regimens for early breast cancer. These cancer regimens are associated with improved survival, but come with a high cost.

Studies have shown there is significant increased risk of cardiac dysfunction that may progress to clinical heart failure (HF) in women who receive adjuvant therapy regimens for early breast cancer.


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It has been theorized that a preventive neurohormonal blockade may have the potential to alleviate the decline in cardiac function. However, until now there have been no randomized, placebo-controlled, double-blind trials confirming any specific cardioprotective agents.

“Breast cancer is one of the most common cancers among women. Contemporary anti-cancer treatment has led to marked survival improvement, but cardiotoxicity is a major concern,” said Geeta Gulati, MD, of Akershus University Hospital, Lørenskog, Norway. “Previous studies suggesting a beneficial effect of beta-blockers or angiotensin inhibitors have been small, often included heterogeneous populations, and been non-blinded … In contrast to prior studies including breast cancer patients, in the current study we have used cardiac MRI as the imaging method, which is the gold standard for measuring left ventricular ejection fraction.”

Dr Gulati and colleagues tested the concomitant use of the beta-blocker metoprolol and/or ARB candesartan to see if either agent was protective against cardiotoxicity in patients receiving adjuvant treatment containing anthracyclines with or without trastuzumab and radiation for early breast cancer.

The PRADA  trial was a 2×2 factorial, randomized, placebo-controlled, double-blind clinical trial that evaluated the cardioprotective effect of metoprolol succinate and/or candesartan cilexetil compared to placebo administered in parallel with adjuvant therapy.

Dr Gulati presented data on 120 women (mean age, 50.7 years) with early breast cancer. All the patients were randomized at a single center between September 2011 and September 2014 and adjuvant therapy ranged from 10 to 61 weeks. In the treatment arms, the target dose was 100 mg daily for metoprolol and 32 mg daily for candesartan.

Researchers measured changes in left ventricular ejection fraction (LVEF) as determined by cardiac MRI from baseline to the completion of adjuvant therapy. They found no evidence of an interaction between assignment to candesartan and to metoprolol.

In the intention-to-treat analysis, researchers found that the overall decline in LVEF was 2.6 percentage points in the placebo group and 0.8 in the candesartan group. The investigators found no effect of metoprolol on the change in LVEF.

“In the PRADA-study anti-cancer treatment for breast cancer was associated with a modest decline in left ventricular function. Observational studies suggest that early minor decrements in cardiac function are associated increased risk of developing cardiac dysfunction,” Dr Gulati told Cardiology Advisor. “If sustained, long-term beneficial effects of early angiotensin inhibition can be confirmed in this and other, larger multicenter studies, preventive therapy may become indicated as standard care in these patients.”

In the current study, women were included if they were between the ages of 18 and 70, had serum creatinine <–1.6 mg/dL or eGFR ≥60 mL/min/1.73 m2, systolic blood pressure ≥110 mg Hg and <170 mm Hg, and LVEF ≥ 50%.

Women were excluded from the trial if they had prior malignancy requiring chemotherapy or chest radiotherapy, symptomatic HF, clinically significant coronary artery disease, valvular heart disease, significant arrhythmias, or conduction delays. Women were also excluded if they had been treated with an ACE-inhibitor, ARB, or beta-blocker within the last 4 weeks prior to study start.

“This is an important study for all clinicians who meet patients treated for breast cancer. It is important to be aware that these patients may have a cardiotoxic effect of their cancer treatment, and should be referred to a cardiologist if symptoms of heart failure occur,” said Dr Gulati.

Reference

Gulati G. LBCT.06—Novel Therapies for Common Problems. Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA): Primary Results of a Randomized, 2 x 2 Factorial, Placebo-Controlled, Double-Blind Clinical Trial. Presented at the American Heart Association Scientific Sessions; November 7-11, 2015; Orlando, FL.