304 Comparative Thromboembolic Risk of 3-Factor Versus 4-Factor Prothrombin Complex Concentrate for Emergent Warfarin Reversal

Abstract

Prothrombin complex concentrates (PCCs) rapidly reverse anticoagulant-associated coagulopathy; however, thromboembolic complications (TECs) are a known risk. Studies designed to evaluate thromboembolic risk between 3-factor and 4-factor PCC have not been performed. The purpose of this study was to evaluate the risk of TEC between 3-factor and 4-factor PCC for warfarin reversal. This single center, multi-campus, retrospective cohort study included adult patients on warfarin who received at least one dose of 3-factor or 4-factor PCC for emergent warfarin reversal from December 1, 2011 to September 30, 2018. Hemophiliacs, pregnancy, incarcerated, and concomitant administration of recombinant FVIIa were excluded. The primary outcome was comparison of early TECs between 3-factor and 4-factor PCC for emergent warfarin reversal. Early TEC was defined as an acute deep venous thrombosis, pulmonary embolism, myocardial infarction, transient ischemic attack, or stroke within 14 days of PCC. Statistical analysis was performed with Fisher’s exact test and Student’s t-test as appropriate. Two-hundred and fifty patients were included with 125 patients in each group. Median age was 68 (IQR 59,80) years. Patients were most often anticoagulated for atrial fibrillation in both 4-factor and 3-factor PCC groups (70% vs 59%, p=0.11). The most common indication for reversal in both groups was intracerebral hemorrhage (50% vs 62%, p=0.098). TECs occurred in 26 patients (10.4%), with a median time to TEC of 6.5 (IQR 2,9.75) vs 4 (IQR 1.5,7.25) days (p=0.3). There was no difference in the rate of early TEC with 4-factor compared to 3-factor PCC (11.2% vs 9.6%, p=0.84). Arterial TECs trended towards being more common with 4-factor PCC (57.1% vs 16.7%, p=0.051). Risk factors for TECs present in >50% of the total TEC population included cardiovascular disease (88%) and concomitant administration of blood and/or reversal agents (81%). Of the 100 patients started on venous thromboembolism (VTE) prophylaxis, there was a trend towards delay of VTE prophylaxis initiation in patients who developed TECs (3.65 vs 2.70 days; 95% CI -0.39 to 2.29, p=0.16). In the 82 patients who had anticoagulation re-initiated, there was significant delay in time to re-initiation in patients experiencing TECs (9.07 vs 3.98 days; 95% CI 2.89 to 7.69, p<0.01). Patients had a lower median INR after receiving 4-factor PCC (1.4 vs 1.5 p<0.001) and greater frequency of achieving an INR <1.4 (45.2% vs 27.3%, p<0.01). Mean hospital length of stay trended towards being longer with 4-factor PCC (10.28 vs 8.96 days, p=0.23), while overall mortality was lower compared to 3-factor PCC (15.2% vs 26.4%, p=0.043). There was no difference in the early TEC rate between 3-factor and 4-factor PCC when administered for emergent warfarin reversal; however, this may be the first study to identify a trend towards greater risk of arterial thrombus with 4-factor PCC. It is prudent to assess patient-specific risk factors for development of TECs prior to warfarin reversal. Additionally, early re-initiation of anticoagulation may decrease the risk of TECs. The risk-benefit of anticoagulation re-initiation must be considered in all patients, especially those at risk for development of an arterial TEC.