Efficacy and safety of Prothrombin Complex Concentrates Weight-Based Dosing for Reversal of Warfarin Anticoagulation

Background: Prothrombin complex concentrates (PCCs) are widely used for correcting elevated international normalized ratio (INR) levels in patients anticoagulated with warfarin requiring an urgent reversal. However, the optimal dosing regimen has yet to be defined. In 2008, the Canadian National Advisory Committee (NAC) on blood product utilization recommended a single dose of 1000 IU for all adults over 18 years of age, irrespective of INR levels, and suggested further consultation with a Hematologist if extremes in weight or INR were observed. A revision in 2011, suggested dosing based on the INR elevation as an option and in 2014 the recommendation was updated to include a possible algorithm including both INR and weight. Currently there is insufficient evidence to suggest that one approach is more efficacious than another. Our institution has been using a novel weight-based dosing protocol for PCCs since 2009, which dispenses to a maximum of 3000 IU for adults weighing over 100kg. Herein, we sought to determine the efficacy of our weight-based dosing nomogram.

Methods: We conducted a retrospective cohort study of all consecutive adult patients (age > 18 years) who received PCCs using our weight based dosing regimen between April 30, 2009 and December 31, 2010. All patients were anticoagulated with warfarin. Clinical and laboratory information was obtained through chart review. The weight based regimen consisted of 1000 IU for weight less than 40kg, 1500IU for 41 to 60kg, 2000 IU for 61 to 80kg, 2500 IU for 81 to 100kg, and 3000 IU for > 100kg. Doses of PCCs were based on the concentration of factor IX. PCCs utilized at this centre were Octaplex and Beriplex. The primary outcome was reversal of warfarin anticoagulation, as defined by an INR of 1.5 or less to achieve a clinical response within 6 hours. Statistical analysis was done using descriptive statistics and chi squared analysis.

Results: A total of 227 charts were included in the study from April 30, 2009 to December 31, 2010. The median age was 74 years old (range 40-95), the median weight was 76kg (range 44-200), and 56% of patients were male. Medical indications for warfarin anticoagulation included atrial fibrillation (68%), DVT (32%) and stroke (21%). The most common indication for PCCs was active bleeding (44%: 13% intracranial, 12% gastrointestinal, 4% trauma, 15% other), reversal for a procedure (22%) and reversal for surgery (30%). Prior to receiving PCCs, 29% of patients were taking Aspirin and 4% were taking Clopidogrel. The percentages of patients treated with each dose were: 1000IU (1.3%), 1500IU (17.6%), 2000IU (41.0%), 2500IU (24.2%), 3000IU (15.9%). A second dose of PCC was given to 0.4% of patients. FFP was given to 7% of patients prior to PCCs administration and 14% of patients post PCCs administration. 63% of patients received vitamin K. Seventy-nine percent of patients achieved an INR of 1.5 or less within 6 hours of PCC administration. There was a statistically significant difference in response based on pre-PCC INRs (see table 1). The median baseline INR was 2.9 (range 1.5- >10) and decreased to a median of 1.3 (range 1.0-3.7) post-PCCs administration. Planned procedures were completed in 93% of 60 patients, and planned surgeries were completed in 94% of 70 patients within 24 hours of receiving PCCs. Four patients (2%) developed a deep vein thrombosis within 30 days of receiving PCCs.

Conclusion: Our study demonstrates that weight based dosing is effective in reversal of anticoagulation in patients on warfarin. Laboratory response rates are similar to other studies (Wozniak et al). Although the majority of patients in our study (99%) received doses over 1000IU; rates of thrombosis are low. Future studies comparing different strategies are needed.

*1.5-3 vs 3.1-4.5

**1.5-3 vs >4.5