Impact of a Pharmacist-Driven Prothrombin Complex Concentrate Protocol on Time to Administration in Patients With Warfarin-Associated Intracranial Hemorrhage

Jessica L. Corio, PharmD; Jonathan H. Sin, PharmD; Bryan D. Hayes, PharmD; Joshua N. Goldstein, MD, PhD; Lanting Fuh, PharmD


Western J Emerg Med. 2018;19(5):849-854. 

In This Article

Abstract and Introduction


Introduction: Advancements in the treatment of warfarin-associated intracranial hemorrhage (ICH) include the use of four-factor prothrombin complex concentrate (4F-PCC), which has demonstrated more rapid reversal of the international normalized ratio (INR) when compared with fresh frozen plasma. A pharmacist-driven protocol for 4F-PCC was implemented within our institution, which allows for pharmacist approval of 4F-PCC in patients diagnosed with warfarin-associated ICH and an INR ≥2. The pharmacist is responsible for determining the appropriate dose of 4F-PCC, preparation, bedside delivery, and order entry into the electronic medical record. Prior to implementation of the new protocol, the blood bank was responsible for 4F-PCC approval, dosing, product preparation, and arranging delivery with emergency department (ED) staff. The purpose of this study was to evaluate the impact of a pharmacist-driven protocol on time to 4F-PCC administration in warfarin-associated ICH.

Methods: We performed a retrospective review of consecutive patients who received 4F-PCC in a single ED from September 2015 through February 2017. Patients ≥18 years old were eligible for inclusion based on three criteria: confirmed diagnosis of ICH; confirmed warfarin use; and INR ≥2. Secondary outcomes included dose of 4F-PCC in concordance with INR and weight-based dosing recommendations and hospital protocol, as well as concomitant intravenous vitamin K administration.

Results: A total of 48 patients met inclusion criteria for the study with 24 patients in each protocol group. The median time to administration of 4F-PCC in the pharmacist-driven protocol group was 35 minutes (interquartile range [IQR] [25-62]; range, 11–133) compared with 70 minutes (IQR [34-89]; range, 14–244) in the pre-protocol group (p=0.034). We saw no differences for appropriate 4F-PCC dosing based on INR and patient weight between the two groups.

Conclusion: Implementation of a pharmacist-driven protocol for 4F-PCC in the ED at our institution significantly reduced time to administration in patients presenting with warfarin-associated ICH.


Warfarin is a commonly prescribed oral anticoagulant indicated for prevention and treatment of venous thromboembolism and prevention of ischemic stroke in atrial fibrillation.[1] One potential adverse effect of anticoagulation is bleeding, including intracranial hemorrhage (ICH).

Until recently, warfarin-associated ICH in the United States was typically treated with fresh frozen plasma (FFP) and intravenous (IV) vitamin K.[2] However, a four-factor prothrombin complex concentrate (4F-PCC) was approved by the U.S. Food and Drug Administration (FDA) in 2013 and has since become widely available for reversal of vitamin K antagonists, such as warfarin.[3–5] The reversal effects of 4F-PCC occur through exogenous replacement of inactivated coagulation factors II, VII, IX, and X. The use of 4F-PCC has demonstrated a more rapid reversal of anticoagulation and the international normalized ratio (INR) compared with FFP.[6,7]

Clinical practice guidelines recommend prompt correction of the INR as soon as possible in patients with warfarin-associated ICH.[3,4,8,9] Delays in administration of 4F-PCC for life-threatening bleeding have been recognized in several institutions, prompting review of hospital protocols. In a survey of United Kingdom (UK) stroke physicians, specific delays identified included time to hematology approval for 4F-PCC use, time to receive INR results, time to 4F-PCC delivery to the emergency department (ED), and time to infusion start.[10] Solutions implemented within one healthcare system, based on survey results, included expanding approval privileges to include stroke physicians, purchasing point-of-care INR devices for bedside results, and moving 4F-PCC to be stored in the ED.

A second UK hospital observed a large delay in 4F-PCC administration with a median time of approximately five hours from initial presentation and almost two hours after vitamin K administration.[11] Investigators also identified relocating 4F-PCC to the ED, incorporating point-of-care INR testing, and eliminating mandatory hematology consultations as future directions for reducing delays to administration. Bordeleau and colleagues evaluated administration delays of 4F-PCC prior to implementing a flowchart and new delivery process to improve communication between ED staff and the hospital blood bank.[12] Use of the flowchart decreased time to obtain the product from the blood bank, and reduced time to 4F-PCC administration by almost half.

At our institution, the 4F-PCC was initially stored in the blood bank. To obtain the agent, ED clinicians contacted the blood bank for approval, and then ordered it via handwritten, paper slips that were delivered to the blood bank by pneumatic tube. The product was then prepared and delivered to the clinical nurse for infusion. To optimize 4F-PCC management, a new system was implemented in 2016 that led to product storage in the ED automated-dispensing cabinet and a revised protocol involving pharmacists physically present in the ED. Clinicians requesting 4F-PCC for warfarin-associated ICH contacted the ED pharmacist for dosing, preparation, bedside delivery, and order entry into the electronic medical record (EMR). The use of 4F-PCC for indications other than warfarin-associated ICH required approval from the on-call hematologist.

The purpose of this study was to assess the impact of the pharmacist-driven protocol on time to 4F-PCC administration in the ED for patients presenting with warfarin-associated ICH.