A Single Center Retrospective Analysis of Outcomes Following the Use of 4-Factor Prothrombin Complex Concentrate for Warfarin Reversal in Real-Life Settings

Introduction

Reversal of vitamin K antagonists (VKA) is required in patients presenting with acute major bleeding or requiring urgent surgery. Recent clinical trials lead to FDA approval of a 4 Factor-PCC (4F-PCC, Kcentra) for urgent VKA reversal. The thromboembolic events (TEE) are most concerning side effects of PCC; these studies showed similar TEE as compared to plasma. However, clinical trials had many exclusion criteria that would not apply in real-life practice. Therefore, we performed a retrospective analysis of real-life patients undergoing urgent VKA reversal with 4F-PCC to evaluate TEE and all-cause mortality.

Methods

A retrospective chart review was performed for patients who received 4F-PCC between April 2013 to July 2014 at 3 UT Southwestern hospitals to look for TEE and deaths. Patients were identified from pharmacy and transfusion services information systems. We recorded patients’ demographics, indications for VKA and PCC, and coagulation parameters before and after PCC administration. TEE was defined as any arterial or venous event detected by imaging, elevation in cardiac biomarkers, and clinical documentation.

Results

Fifty-two patients (age 27-89, 32 males) received PCC for VKA reversal for acute major bleeding or prior to urgent surgical procedure. Thirty-four (65.4%) patients had acute bleeding and 18 (34.6%) patients required urgent surgery. The median length of hospital stay was 8.5 days. The median time from pre-PCC INR to PCC administration was 2 h and 48 min. The median PCC dose was 33 IU/kg. Median pre-PCC INR was 3.1 (range 1.5-14), post-PCC INR was 1.3 (range 0.9-1.9), and at 24 hours 24h-INR was 1.2 (range 0.9-3.5). Vitamin K was given to 46/52 patients (mean dose 6.5 mg; 30 IV, 9 oral and 3 subcutaneous).

There were 2 TEE (3.8%). One occurred in a patient with antiphospholipid antibody syndrome who presented with gastro-intestinal bleed. Exploratory laparotomy on day 2 post-PCC revealed necrotic bowel. Repeat CT abdomen on day 3 showed a new occlusion of an accessory renal artery along with ischemic changes in the liver, spleen and colon. The patient was in septic shock and was made comfort measures; care was withdrawn 4 days post-PCC. This TEE was possibly related to PCC. The second patient had non-ischemic cardiomyopathy and mural thrombus and received 30.4 IU/kg of PCC for an INR of 1.5 prior to a heart transplant. She developed a lower extremity deep vein thrombosis 7 days post-PCC, while she was on heparin drip for intra-aortic balloon pump and thus was unrelated to PCC. Twelve patients died. Six died during the same hospitalization; 3 died within 3 days of PCC administration due to massive subdural hematomas, metastatic pancreatic cancer, and massive retroperitoneal hemorrhage complicated with septic shock and multi-organ failure. The remaining 3 died on post-PCC days 4, 5 and 48 due to septic shock resulting in multi-organ failure, hemorrhagic shock following cardiac surgery, and rejection of heart transplant, respectively. Six patients died following discharge; 4 in hospice care between 11 to 90 days post-PCC, 1 committed suicide at 9 days post-PCC, and 1 patient with multiple comorbidities died at home 3 months post-PCC.

Conclusion

This is the first retrospective analysis studying TEE and all-cause mortality following 4F-PCC for warfarin reversal in the real world setting. Our data show that 4F-PCC is safe for warfarin reversal when appropriately administered. Risks and benefits of using 4F-PCC should be addressed, especially in patients with a hypercoagulable state.