SHOULD KCENTRA BE ADDED FOR TREATMENT IN EMERGENCY REVERSAL? Joyce Oh, MS, PharmD Candidate; Maryia Tsitarava, BS, PharmD Candidate; Feng-Hua Loh, BPharm, PhD, MBA Touro College of Pharmacy, New York, NY, USA Introduction Warfarin is the most commonly used oral anticoagulant in North America and has been the preferred agent for more than half a century.1 Warfarin was approved by the FDA in 1954 for treatment and prevention of atrial fibrillation, thromboembolism, and cardio embolic stroke. It is also used off-label as secondary prevention of recurrent stroke and myocardial infarction.1, 2 Despite the benefit of lower cost, patients treated with vitamin K antagonists like warfarin have a high risk of bleeding and have high rates of morbidity and mortality.5 Due to serious adverse effects of warfarin, there was a development of prothrombin complex concentrate (PCC) in 2013 and Kcentra® is the only drug in this class in United States 11. The U.S. FDA has approved Kcentra, which is manufactured by CSL Behring AG, for the urgent reversal of VKAs anticoagulation in adults with acute major bleeding and surgical procedures.12

Kcentra is a 4-factor product (II, VII, IX and X).6 It contains inhibitors such as heparin, , protein C and protein S which allows for more balanced replacement of procoagulants factors and anticoagulants proteins. PCC’s are free of leukocytes and less likely to cause adverse effects of infusion reactions.13 Kcentra has rapid action and INR declines within 10 minutes of administration.12 Kcentra may become “a must drug” on formulary for many hospitals. Objective To determine whether prothrombin complex concentrate should be added for treatment in Emergency Warfarin reversal.

Methods • Databases: PubMed, Embase, CINAHL, and Google Scholar • Keywords: 'prothrombin complex concentrate' or 'Kcentra' including clinical trials, controlled clinical trials, randomized controlled trials, case reports, and observational human studies published in English between 2008 to 2018. • The 53 articles were selected • Inclusion and exclusion criteria: (1) Kcentra or PCC is used for treatment of warfarin reversal, (2) study design is either clinical trial, controlled clinical trial, randomized controlled trial, case report/series, observational human study, or cost-effectiveness analysis, (2) published between 2008 to 2018, and (3) full texts available in English.

Results • Eleven articles were included in this study. Source/ Study Duration of Follow-up • 8 studies found Kcentra to have a positive outcome, 5 1 study found it to be neutral, and 2 studies found it Stratton et.al.; 2018 5 days to have both positive and neutral outcomes. Hedges et.al.; 201511 9.7 days • Four-factor prothrombin complex concentrate (PCC- 15 4), which includes Kcentra, was shown to be non- Sarode et. al.; 2013 45 inferior in 5 studies and superior in 6 studies Goldstein et. al.; 201516 90 compared to Fresh Frozen Plasma (FFP). 17 • Refaai et. al. found significantly shorter median Berndtson et. al.; 2015 51 infusion time (P < 0.0001), median infusion volume Kushimoto et. al.; 201718 45 (P < 0.0001), and median time from study treatment 19 initiation to first procedure (P = 0.037) in PCC-4 Clearly et. al.; 2016 up to 45 days group compared to plasma. A study done in U.K. Martin et. al.; 201620 28 days found Kcentra to be cost-effective in emergency 21 treatment of Warfarin reversal. Jones; 2016 7 days

Conclusion • Kcentra is effective for treatment in Emergency Warfarin reversal and may also be non-inferior or even superior to FFP. • Further studies with a long-term follow-up is needed to determine the safety, efficacy, and cost effectiveness of prothrombin complex concentrate. • Limitations included: non-retrieval follow-up data for long-term effects.

References

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