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Safety and Efficacy of Warfarin Reversal with Four-Factor Prothrombin Complex Concentrate for Subtherapeutic Inr in Intracerebral Hemorrhage
Rivosecchi RM, Durkin J, Okonkwo DO, et al. Neurocrit Care. 2016;25:359-64.
Study Question: Is there a difference in safety and efficacy in the administration of four-factor prothrombin complex concentrate (4F-PCC) for warfarin reversal in patients with intracerebral hemorrhage (ICH) and subtherapeutic international normalized ratios (INRs), compared to INRs greater than 2?
Study Description: This was a single-center, retrospective, observational study that included all 4F-PCC medication administrations occurring from September 2013 to July 2015. The 4F-PCC must have been used to reverse elevated INRs secondary to warfarin usage in traumatic or spontaneous ICH with a presenting INR between 1.4 and 3.9. These patients were then divided into two groups based on their initial INR: 1.4-1.9 and 2-3.9. The initial INR was defined as the one immediately preceding administration of 4F-PCC while the follow-up INR was the first INR after administration. Venous thromboembolic events were determined via Doppler ultrasound or computerized tomography (CT) angiogram. The primary outcomes were the difference between the two groups in achievement of a follow-up INR ≤ 1.3 after and the development of thromboembolic events after administration of 4F-PCC, within the first occurrence of the following: 7 days after administration, hospital discharge or death.
Results: A total of 131 patients met inclusion criteria: INR 1.4-1.9 (n = 30) and INR 2-3.9 (n = 101). Baseline demographics were similar between the two groups except a higher number of patients in the lower INR group had a history of thromboembolism (70% vs. 47.5%). The mean age was 74 years and most were receiving anticoagulation for atrial fibrillation. The mean initial INR in the lower INR group was 1.8 ±0.1 and 2.7 ±0.5 in the higher INR group. Significantly more patients in the lower INR group achieved an INR ≤ 1.3 (79.3 vs. 51%; p = 0.03). There was no difference in the number of patients experiencing a probable or definite thrombotic event (lower INR: 6.7% vs. higher INR: 10%; p = 0.73).
Conclusion(s): The administration of 4F-PCC appears to be safe and effective for reversing INR elevations in patients with spontaneous and traumatic ICH presenting with subtherapeutic INRs.
Perspective: Vitamin K antagonist (VKA) therapy in the setting of ICH is an independent risk factor for the expansion of hematoma and increased mortality, therefore, current guidelines support the use of 4F-PCC for the urgent reversal of anticoagulation and correction of INR. Currently, the degree of INR elevation that requires reversal and the extent of INR correction is less clear. The thrombotic risk of reversing ICH secondary to VKA therapy in patients with lower INRs is also unknown. This retrospective study evaluated patients with ICH and subtherapeutic INRs (1.4-1.9) and concluded that 4F-PCC is safe and effective in this patient population. This study is not without limitations which include its retrospective nature, small sample size, 4F-PCC administered based on physician preference, a lack of standardized thrombosis screening protocol, and lastly, INR reversal extrapolation to hemostasis efficacy. Future randomized controlled trials should focus on the development of a standardized thromboembolic screening protocol and measurable hemostasis using other coagulation markers such as ROTEM.