Vitamin K antagonist therapy such as warfarin has been demonstrated to decrease the incidence of stroke by approximately sixty percent in patients with atrial fibrillation (1). Unfortunately, warfarin is an agent with a narrow therapeutic index that is sensitive to drug-drug interactions, changes in diet and overall patient compliance. The incidence of warfarin-induced hemorrhage can be life-threatening and often requires emergent reversal. Historically, fresh frozen plasma (FFP) has been utilized to reverse the effects of warfarin but it requires cross-typing, thawing of frozen product and prolonged administration times due to significant volume. More recently, prothrombin complex concentrates (PCC) containing either three or four human clotting factors (II, IX, X or II, VII, IX, X respectively) provide hemostasis more rapidly in significantly smaller volumes of fluid than FFP (2-4). While immediate control of hemostasis is crucial, less data is available related to the impact of FFP or PCC on long-term functional outcomes.
Therefore, in patients requiring reversal of warfarin-induced intracranial hemorrhage, is there sufficient evidence to show prothrombin complex concentrate (PCC) results in more favorable long-term functional outcomes than fresh frozen plasma (FFP)?
Frederickson et al. first described neurological status in seventeen patients by examining the modified Rankin Scale (mRS) of survivors upon hospital discharge, finding a non-significant trend towards favorable mRS scores (0-3) in those treated with 3F-PCC (63% versus 20%, p value not provided) (5).
Two studies sought to establish the efficacy of institutional guidelines on warfarin-associated hemorrhage but there was little consistency in the long-term outcomes measured. Hanger et al. performed a single center study examining the Functional Independence Measure (FIM), a test to analyze the changes observed in neurorehabilitation cases such as stroke, as a secondary outcome. They followed patients up to 524 days after discharge on average but only tested FIM upon leaving the hospital. There were no differences between groups in overall FIM scores; however, the PCC group exhibited significantly larger FIM score gains than the FFP group (28.3 versus 12.3, p = 0.049) (6). In one Japanese study, 56 patients were examined for neurologic deterioration (defined by the authors as a decrease in two or more GCS points or limb power) and mRS scores at 90 days. This was a unique study as they looked at two populations (overall patients and a target group consisting of only those GCS > 8, not requiring immediate intubation/surgery) between pre- and post-warfarin reversal protocol implementation groups. Overall, 90 day favorable mRS scores (0-3) were similar (46.3 versus 54.5%, p = 0.737). In the target group, the use of PCC was associated with a significantly lower risk of deterioration on logistical regression (OR = 0.256, 95% CI 0.069-0.956; p = 0.043) but it should be noted the clinical importance of their definition may be questionable (7). In addition, the investigation by Huttner et al. included 55 patients, evaluating one-year mRS scores. PCC was shown to decrease hematoma expansion but its use did not influence long-term outcomes (mRS 4-6 in 78% versus 83%, p = 0.86) suggesting early, rapid hemostasis may result in similarly dismal functional status.
When viewed as a whole, these four studies appear for the most part, homogenous. Some variability exists between in trial design but they all share the disadvantages of being small, single-site, non-randomized retrospective studies. To date, two prospective studies were found for the purpose of this review, each of which drew different conclusions (8).
Frontera et al. conducted a prospective albeit observational trial of 3F-PCC, FFP or both, and the effects of these interventions on multiple 90 day functional outcome variables including the mRS, Barthel Index and the Telephone Interview of Cognitive Status. While they did not find a difference in time to INR correction, sixty-nine percent of patients were dead or severely disabled (mRS 4-6) at 90 days with no differences between groups. 3-PCC alone or with FFP was associated with a lower risk of death or disability (adjusted OR 0.02, 95 % CI 0.001–0.8, p = 0.039) while FFP alone was associated with risk of increased rate of death or severe disability (adjusted OR 51.6, 95 % CI 1.2–2163.1, p = 0.039) (9).
In February 2016, preliminary results of the INCH trial were published. This is the first multicenter, prospective, randomized trial comparing 4F-PCC versus FFP to date. Fifteen- and 90-day functional outcomes such as mRS, NIHSS, Barthel Index and extended Glasgow Outcome Scale were measured. While 4F-PCC was more effective at attaining the primary endpoint (INR < 1.2 in 3 hours, OR 30.6 95% CI 4.7-197.9 p = 0.0003), there were no significant improvements in any functional outcomes at 15 or 90 days. The authors noted the use of 4F-PCC as a “rescue therapy” for FFP group patients that did not achieve an INR of less than 1.2 within three hours. Eighty-three percent of patients in the FFP group received PCC for this indication; however, it is difficult to evaluate the impact these doses may have had, given that this study was not powered to assess secondary functional outcomes (10).
In summary, the available evidence appears to suggest that the rapid reversal of vitamin K antagonist-associated intracranial hemorrhage does not improve long-term functional outcomes. However, some considerations must be kept in mind first. Historically, studies evaluating such outcomes have consisted of small, retrospective single center trials wherein the outcomes of interest to us were secondary. Additionally, the doses of FFP utilized and functional outcomes measured vary significantly between studies. The INCH trial, while unquestionably the strongest methodologically, does not add much to the current body of evidence regarding functional outcomes given the potentially confounding use of 4F-PCC in the majority of FFP group patients.
Matthew Bilhimer, PharmD (@MBNYPharmD)
PGY-2 Emergency Medicine Pharmacy Resident
University of Rochester Medical Center
Rochester, New York
Peer reviewed by Craig Cocchio, PharmD, BCPS (@iEMPharmD) and Nadia Awad, PharmD, BCPS (@Nadia_EMPharmD)
References:
- Hart RG, Benavente O, McBride R et al. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Annals of Internal Medicine1999;131:492–501.
- Karaca MA, Erbil B, Ozmen MM. Use and effectiveness of prothrombin complex concentrates vs fresh frozen plasma in gastrointestinal hemorrhage due to warfarin usage in the ED. American Journal of Emergency Medicine 2014; 32: 660-664.
- Sarode R, Milling TJ, Refaai MA et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding. Circulation 2013; 128: 1234-1243.
- Goldstein JN, Refaai MA, Milling TJ et al. Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial. Lancet 2015; 385: 2077-2087.
- Fredriksson K, Norrving B, Stromblad LG. Emergency reversal of anticoagulation after intracerebral hemorrhage. Stroke 1992; 23: 972-977.
- Hanger HC, Geddes AA, Wilkinson TJ et al. Warfarin-related intracerebral haemorrhage: better outcomes when reversal includes prothrombin complex concentrates. Internal Medicine Journal 2012; 43: 308-316.
- Fong WC, Lo WT, Ng YW et al. The benefit of prothrombin complex concentrate in decreasing neurological deterioration in patients with warfarin-associated intracerebral haemorrhage. Hong Kong Medical Journal 2014; 20: 486-494.
- Huttner HB, Schellinger PD, Hartmann M, et al. Hematoma Growth and Outcome in Treated Neurocritical Care Patients With Intracerebral Hemorrhage Related to Oral Anticoagulant Therapy. Stroke 2006; 37:1465-1470.
- Frontera JA, Gordon E, Zach Vet al. Reversal of coagulopathy using prothrombin complex concentrates is associated with improved outcome compared to fresh frozen plasma in warfarin-associated intracranial hemorrhage. Neurocrtical Care 2014; 21: 397-406.
- Steiner T, Poli S, Griebe S, et al. International normalized ratio Normalisation in patients with Coumarin-related intracranial Hemorrhages – randomized controlled multicenter trial to compare safety and preliminary efficacy of fresh frozen plasma and prothrombin complex. Preliminary results presented at the 2016 International Stroke Conference, Los Angeles.
EM PharmD 