Randomized study of doxorubicin-based chemotherapy regimens, with and without sildenafil, with analysis of intermediate cardiac markers

Andrew Poklepovic, Yuesheng Qu, Molly Dickinson, Michael C. Kontos, Maciej Kmieciak, Elizabeth Schultz, Dipankar Bandopadhyay, Xiaoyan Deng, Rakesh C. Kukreja

Doxorubicin chemotherapy is used across a range of adult and pediatric malignancies. Cardiac toxicity is common, and dysfunction develops over time in many patients. Biomarkers used for predicting late cardiac dysfunction following doxorubicin exposure have shown promise. Preclinical studies have demonstrated potential cardioprotective effects of sildenafil. We sought to confirm the safety of adding sildenafil to doxorubicin-based chemotherapy and assess N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) and high sensitivity cardiac troponin I (hsTnI) as early markers of anthracycline-induced cardiotoxicity. We randomized 27 patients (ages 31-77, 92.3% female) receiving doxorubicin chemotherapy using a blocked randomization scheme with randomly permuted block sizes to receive standard chemotherapy alone or with the addition of sildenafil. The study was not blinded. Sildenafil was dosed at 100 mg by mouth daily during therapy; patients took sildenafil three times daily on the day of doxorubicin. Doxorubicin dosing and schedule were dependent on the treatment regimen. Echocardiography was obtained prior to initiation of treatment and routinely thereafter up to 4 years. NT-proBNP and hsTnI were obtained with each cycle before, 1-3 h after, and 24 h after doxorubicin. Fourteen patients were randomized to receive standard doxorubicin chemotherapy alone (14 treated and analyzed), while 13 patients were randomized to the experimental doxorubicin and sildenafil arm (10 treated and analyzed). No toxicity signal was seen with the addition of sildenafil to doxorubicin-based regimens. There was no statistical difference between the treatment arms in relation to the change of mean left ventricular ejection fraction (LVEF) between the first and last evaluation. In both arms, hsTnI levels increased over time; however, elevated hsTnI was not associated with declines in LVEF. Adding sildenafil was safe, but did not offer cardioprotection following doxorubicin treatment. Increases in hsTnI levels were observed over time, but elevations during therapy did not correlate with subsequent decreases in LVEF. This clinical trial (NCT01375699) was registered at www.clinicaltrials.gov on June 17, 2011.