A Meta-Analysis Evaluating the Risk of Bleeding-Related Adverse Events with Defibrotide Treatment

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<h3>Introduction</h3> Defibrotide (DF) is approved for adult and pediatric patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) with renal or pulmonary dysfunction after hematopoietic cell transplantation (HCT) in the United States. The recommended dose is 6.25 mg/kg every 6 hours given as a 2-hour intravenous (IV) infusion. <i>In vitro</i>, DF reduces activation of endothelial cells, promotes fibrinolytic enzymes, and exhibits antithrombotic properties. Post-HCT patients with VOD/SOS are often at a high risk for bleeding events. <h3>Objectives</h3> To broaden our understanding of the potential risk of bleeding events with DF treatment, this meta-analysis assessed the incidence and risk of bleeding-related AEs with DF outside of the VOD/SOS and HCT setting, using published literature. <h3>Methods</h3> PubMed and Embase were searched through July 24, 2018 for studies using DF. Studies of patients with VOD/SOS or HCT, case reports with <10 patients, and reviews were excluded. Publications containing data on bleeding-related events were included. Overall bleeding rate and risk ratio of bleeding were calculated from studies that used IV DF. The Freeman-Tukey double arcsine transformation and random-effects modeling (Stata Software) and the Mantel-Haenszel method and random-effects modeling (RevMan 5.3 Software) were used for overall bleeding rate and risk ratio, respectively. <h3>Results</h3> A total of 1,857 records were identified; 125 studies reported on DF and 23 contained data on bleeding and were included in the analysis. Most studies (17 of 23) had 2 treatment arms; among these, heparin was the most common comparator (14 of 17). Overall, 14 of 23 studies used IV DF; the most commonly administered dose was 800 mg daily and IV DF was used to treat deep vein thrombosis (10 studies), acute myocardial infarction (2 studies), thrombosis (1 study), and "other" (1 study). The bleeding rate and risk ratio of bleeding were calculated using data from the 14 IV DF studies only. Rates of bleeding events from the 14 studies with IV DF ranged from 0% to 10% in individual studies; the estimated overall bleeding rate was 1% (95% confidence interval [CI]: 0.00-0.02). Among 10 studies with available data on IV DF and controls (8 calcium heparin, 1 urokinase, 1 conventional supportive treatment), the risk ratio for bleeding events with IV DF versus controls was 0.36 (95% CI: 0.24-0.52; <i>P</i> <0.00001; Figure). <h3>Conclusion</h3> This meta-analysis showed that the risk of bleeding with DF was low in patients outside of the VOD/SOS setting, and there is comparable risk of bleeding with DF treatment versus controls such as heparin or urokinase. Limitations of this analysis include variations in AE reporting across studies and the use of a DF dose that is lower than the currently approved recommended dose.