Analysis of the Safety Profile of Commonly Used Procoagulants Using the FDA Adverse Event Reporting System

Introduction: Though less commonly used than their anticoagulant counterparts, procoagulants have an important role in the reversal of anticoagulation. Four-factor prothrombin complex concentrate (4PCC) is now approved by the U.S. Food & Drug Administration (FDA) for the reversal of major bleeding associated with warfarin, and is often used off-label to reverse direct oral anticoagulants. Three-factor concentrate (3PCC) and off-label use of recombinant activated factor VII (rFVIIa) have filled this role in the past. Vitamin K is also used as a common antidote for warfarin-induced coagulopathy. Comparative data evaluating the safety profiles and relative thrombotic risks of the PCCs and rFVIIa is limited. In order to better evaluate their comparative safety we calculated the rate of adverse events reported to the FDA of each procoagulant. Methods: We evaluated the FDA Adverse Event Reporting System (FAERS) database, which compiles drug-related adverse events reported to the FDA from 1969 onwards, to assess the rate of adverse events reported with various procoagulants. Safety profiles were assessed using proportional reporting ratios (PRR) with the total number of reported cases as the denominator. Adverse events data for each drug (vitamin K, rFVIIa, 3PCC, 4PCC) was gathered from FAERS. Both generic and brand names were used to query the database. Adverse events data was filtered by including only events reported by healthcare professionals. Specific adverse events were chosen apriori based on hypothesized potential complications and included hemorrhagic and thrombotic complications. The PRR with 95% confidence interval was generated for each event, with a cut-off of 2 being used to identify associations. Results: As shown in Table 1 and Figure 1, rFVIIa was associated with increased reports of mortality while 4PCC was associated with ischemic stroke, and all but rFVIIa were associated with high INR. 3PCC displayed an increased association with reports of intracranial hemorrhage (ICH), although there was a low rate of reports for 3PCC. Lesser associations were found between rFVIIa and myocardial infarction (MI), 3PCC and deep-vein thrombosis (DVT), and 4PCC and DVT and ICH. In general, vitamin K had the weakest associations among adverse events. Conclusions: Our analysis found that the rate of reports of death and MI were higher with rFVIIa than other procoagulants, while reports of ischemic stroke and intracranial hemorrhage were more common with PCCs. rFVIIa has been associated with cardiovascular before, a finding reiterated by our study. There are notable limitations of this type of analysis, including the reliance on the accurate reporting of adverse events to the FDA, possibility of duplications of reports in the FAERS database, and the importance of not conflating correlation with causation as it relates to these events. The association between rFVIIa and increased death may be due to rFVIIa's history of off-label use in trauma patients and other patient groups at higher risk for mortality. While 4PCC may be the procoagulant of the present, it does not have a perfect safety profile, and further study is needed to better characterize the complications of 4PCC and ensure that it is used in such a way as to not under- or over-treat the condition. Disclosures No relevant conflicts of interest to declare.