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Use of Prothrombin Complex Concentrate for Vitamin K Antagonist Reversal before Surgical Treatment of Intracranial Hemorrhage.

ABSTRACT: BACKGROUND:Oral anticoagulant therapy (OAT) is used to prevent/treat thromboembolism. Major bleeding is common in patients on OAT; eg, warfarin increases intracranial hemorrhage (ICH) risk. CASE:A 71-year-old male on warfarin (to reduce stroke risk) presented at Accident and Emergency Minor Injuries Unit with headache after reportedly sounding 'drunk'. On triage, the patient appeared lucid and well. However, International Normalized Ratio (INR) was 4.1. Head computed tomography (CT) indicated a large right-sided subdural hematoma. Prothrombin complex concentrate (PCC; Beriplex(®) P/N, CSL Behring) with vitamin K normalized the INR within minutes of administration. The patient underwent neurosurgery without complications, and was discharged after 5 days, with no residual neurological symptoms. CONCLUSIONS:ICH patients can present with no neurological signs. In OAT patients with headache, INR must be established; if ?3.0, normalization of INR and head CT are essential. PCC is the best option to rapidly reverse anticoagulation and correct INR pre-surgery.

SUBMITTER: Wong Y

PROVIDER: S-EPMC3096433 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Use of Prothrombin Complex Concentrate for Vitamin K Antagonist Reversal before Surgical Treatment of Intracranial Hemorrhage.

Wong Yun Y

Clinical medicine insights. Case reports 20110112

<h4>Background</h4>Oral anticoagulant therapy (OAT) is used to prevent/treat thromboembolism. Major bleeding is common in patients on OAT; eg, warfarin increases intracranial hemorrhage (ICH) risk.<h4>Case</h4>A 71-year-old male on warfarin (to reduce stroke risk) presented at Accident and Emergency Minor Injuries Unit with headache after reportedly sounding 'drunk'. On triage, the patient appeared lucid and well. However, International Normalized Ratio (INR) was 4.1. Head computed tomography (C ...[more]

PMID: 21769259

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Project description:Background: Mortality of oral anticoagulation-associated ICH is around 60%, with oral anticoagulation increasing the risk of ICH seven to ten-fold compared to no anticoagulation. Current guidelines recommend DOACs (direct oral anticoagulants) as first-line therapy in the treatment of VTE (Venous Thromboembolism) due to their more favorable safety profile. There are two agents available for DOAC reversal, Coagulation Factor Xa (recombinant), inactivated-zhzo (andexanet alfa, Andexxa®) and 4-factor prothrombin complex concentrate (4FPCC). There is little data comparing the two agents in real-life clinical settings.ObjectiveThe primary objective of this study was to determine if there was a difference in hemostatic efficacy of andexanet alfa and 4FPCC in patients with a factor Xa inhibitor-related intracranial hemorrhage.MethodsThis was a retrospective, single-center study conducted in adult patients admitted at a quaternary academic medical center from September 2017 to March 2021. Adults with a diagnosis of intracranial hemorrhage (ICH) were included if they received either 4FPCC or andexanet alfa for reversal of apixaban or rivaroxaban. In addition to hemostatic efficacy per imaging, we assessed disposition location, cerebral performance score, blood product consumption, and the development of a new thrombus.ResultsA total of 46 patients were included in this study, 15 received 4FPCC (32%) and 31 received andexanet alfa (68%). There was no difference in the proportion of patients with excellent (4FPCC 9 [60%] vs. andexanet alfa 16 [51.6%], p = 0.61), good (4FPCC 2 [13.3%] vs. andexanet alfa 7 [22.6%]), or poor (4FPCC 1 [6.7%] vs. andexanet alfa 5 [16.1%]) hemostasis after administration of each agent. There were no significant differences in any secondary outcomes.Conclusion and relevanceOur study found no difference in hemostatic efficacy between andexanet alfa and 4FPCC. At this time, clinicians should choose an agent based on individual patient presentation and resource availability. Further research will help clarify the role of each agent in the management of DOAC-related intracranial hemorrhage.

Project description:Study objectiveWe evaluated thromboembolic events after vitamin K antagonist reversal in post hoc analyses of pooled data from 2 randomized trials comparing 4-factor prothrombin complex concentrate (4F-PCC) (Beriplex/Kcentra) with plasma.MethodsUnblinded investigators identified thromboembolic events, using standardized terms (such as "myocardial infarction," "deep vein thrombosis," "pulmonary embolism," and "ischemic stroke"). A blinded safety adjudication board reviewed serious thromboembolic events, as well as those referred by an independent unblinded data and safety monitoring board. We descriptively compared thromboembolic event and patient characteristics between treatment groups and included detailed patient-level outcome descriptions. We did not power the trials to assess safety.ResultsWe enrolled 388 patients (4F-PCC: n=191; plasma: n=197) in the trials. Thromboembolic events occurred in 14 of 191 patients (7.3%) in the 4F-PCC group and 14 of 197 (7.1%) in the plasma group (risk difference 0.2%; 95% confidence interval -5.5% to 6.0%). Investigators reported serious thromboembolic events in 16 patients (4F-PCC: n=8; plasma: n=8); the data and safety monitoring board referred 2 additional myocardial ischemia events (plasma group) to the safety adjudication board for review. The safety adjudication board judged serious thromboembolic events in 10 patients (4F-PCC: n=4; plasma: n=6) as possibly treatment related. There were 8 vascular thromboembolic events in the 4F-PCC group versus 4 in the plasma group, and 1 versus 6 cardiac events, respectively. Among patients with thromboembolic events, 3 deaths occurred in each treatment group. All-cause mortality for the pooled population was 13 per group. We observed no relationship between thromboembolic event occurrence and factor levels transiently above the upper limit of normal; there were no notable differences in median factor or proteins C and S levels up to 24 hours postinfusion start in patients with and without thromboembolic events.ConclusionThe incidence of thromboembolic events after vitamin K antagonist reversal with 4F-PCC or plasma was similar and independent of coagulation factor levels; small differences in the number of thromboembolic event subtypes were observed between treatment groups.

Project description:BackgroundAndexanet alfa is approved (FDA "accelerated approval"; EMA "conditional approval") as the first specific reversal agent for factor Xa (FXa) inhibitor-associated uncontrolled or life-threatening bleeding. Four-factor prothrombin complex concentrates (4F-PCC) are commonly used as an off-label, non-specific, factor replacement approach to manage FXa inhibitor-associated life-threatening bleeding. We evaluated the effectiveness and safety of andexanet alfa versus 4F-PCC for management of apixaban- or rivaroxaban-associated intracranial hemorrhage (ICH).MethodsThis two-cohort comparison study included andexanet alfa patients enrolled at US hospitals from 4/2015 to 3/2020 in the prospective, single-arm ANNEXA-4 study and a synthetic control arm of 4F-PCC patients admitted within a US healthcare system from 12/2016 to 8/2020. Adults with radiographically confirmed ICH who took their last dose of apixaban or rivaroxaban < 24 h prior to the bleed were included. Patients with a Glasgow Coma Scale (GCS) score < 7, hematoma volume > 60 mL, or planned surgery within 12 h were excluded. Outcomes were hemostatic effectiveness from index to repeat scan, mortality within 30 days, and thrombotic events within five days. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated using propensity score-overlap weighted logistic regression.ResultsThe study included 107 andexanet alfa (96.6% low dose) and 95 4F-PCC patients (79.3% receiving a 25 unit/kg dose). After propensity score-overlap weighting, mean age was 79 years, GCS was 14, time from initial scan to reversal initiation was 2.3 h, and time from reversal to repeat scan was 12.2 h in both arms. Atrial fibrillation was present in 86% of patients. Most ICHs were single compartment (78%), trauma-related (61%), and involved the intracerebral and/or intraventricular space(s) (53%). ICH size was ≥ 10 mL in volume (intracerebral and/or ventricular) or ≥ 10 mm in thickness (subdural or subarachnoid) in 22% of patients and infratentorial in 15%. Andexanet alfa was associated with greater odds of achieving hemostatic effectiveness (85.8% vs. 68.1%; OR 2.73; 95% CI 1.16-6.42) and decreased odds of mortality (7.9% vs. 19.6%; OR 0.36; 95% CI 0.13-0.98) versus 4F-PCC. Two thrombotic events occurred with andexanet alfa and none with 4F-PCC.ConclusionsIn this indirect comparison of patients with an apixaban- or rivaroxaban-associated ICH, andexanet alfa was associated with better hemostatic effectiveness and improved survival compared to 4F-PCC. Trial registration NCT02329327; registration date: December 31, 2014.

Project description:BackgroundRapid reversal of vitamin K antagonist (VKA)-induced anticoagulation is often necessary for patients needing urgent surgical or invasive procedures. The optimum means of VKA reversal has not been established in comparative clinical trials. We compared the efficacy and safety of four-factor prothrombin complex concentrate (4F-PCC) with that of plasma in VKA-treated patients needing urgent surgical or invasive procedures.MethodsIn a multicentre, open-label, phase 3b randomised trial we enrolled patients aged 18 years or older needing rapid VKA reversal before an urgent surgical or invasive procedure. We randomly assigned patients in a 1:1 ratio to receive vitamin K concomitant with a single dose of either 4F-PCC (Beriplex/Kcentra/Confidex; CSL Behring, Marburg, Germany) or plasma, with dosing based on international normalised ratio (INR) and weight. The primary endpoint was effective haemostasis, and the co-primary endpoint was rapid INR reduction (≤1·3 at 0·5 h after infusion end). The analyses were intended to evaluate, in a hierarchical fashion, first non-inferiority (lower limit 95% CI greater than -10% for group difference) for both endpoints, then superiority (lower limit 95% CI >0%) if non-inferiority was achieved. Adverse events and serious adverse events were reported to days 10 and 45, respectively. This trial is registered at ClinicalTrials.gov, number NCT00803101.Findings181 patients were randomised (4F-PCC n=90; plasma n=91). The intention-to-treat efficacy population comprised 168 patients (4F-PCC, n=87; plasma, n=81). Effective haemostasis was achieved in 78 (90%) patients in the 4F-PCC group compared with 61 (75%) patients in the plasma group, demonstrating both non-inferiority and superiority of 4F-PCC over plasma (difference 14·3%, 95% CI 2·8-25·8). Rapid INR reduction was achieved in 48 (55%) patients in the 4F-PCC group compared with eight (10%) patients in the plasma group, demonstrating both non-inferiority and superiority of 4F-PCC over plasma (difference 45·3%, 95% CI 31·9-56·4). The safety profile of 4F-PCC was generally similar to that of plasma; 49 (56%) patients receiving 4F-PCC had adverse events compared with 53 (60%) patients receiving plasma. Adverse events of interest were thromboembolic adverse events (six [7%] patients receiving 4F-PCC vs seven [8%] patients receiving plasma), fluid overload or similar cardiac events (three [3%] patients vs 11 [13%] patients), and late bleeding events (three [3%] patients vs four [5%] patients).Interpretation4F-PCC is non-inferior and superior to plasma for rapid INR reversal and effective haemostasis in patients needing VKA reversal for urgent surgical or invasive procedures.FundingCSL Behring.

Project description:OBJECTIVES:Clinicians often need to rapidly reverse vitamin K antagonists (VKAs) in the setting of major hemorrhage or urgent need for surgery. Little is known about the safety profile of the traditional reversal agent, plasma, or the newly approved agent, four-factor prothrombin complex concentrate (4F-PCC), in a randomized setting. This is an integrated analysis of safety data from two clinical trials that evaluated 4F-PCC versus plasma for the treatment of patients requiring rapid VKA reversal for acute major bleeding or prior to an urgent surgical/invasive procedure. METHODS:This descriptive analysis comprised adverse event (AE) data from two phase IIIb, randomized, controlled trials. The bleeding and surgical studies were performed across 36 and 33 sites, respectively, in nine countries, with the integrated analysis comprising 388 patients (4F-PCC, n = 191; plasma, n = 197) aged ? 18 years, who required VKA reversal due to major bleeding or prior to an urgent surgical/invasive procedure. Patients received either 4F-PCC, containing nonactivated factors II, VII, IX, and X and proteins C and S (Beriplex/Kcentra, CSL Behring) or plasma, both dosed according to baseline international normalized ratio and body weight. Patients were also to receive vitamin K1. AEs and serious AEs (SAEs) were assessed up to days 10 and 45, respectively. RESULTS:The proportion of patients with AEs (4F-PCC, 115/191 [60.2%]; plasma, 124/197 [62.9%]) and SAEs (4F-PCC, 54/191 [28.3%]; plasma, 49/197 [24.9%]) was similar between groups. The proportion of patients with thromboembolic events was also similar between groups (4F-PCC, 14/191 [7.3%]; plasma, 14/197 [7.1%]). There were 13 (6.8%) deaths in the 4F-PCC group and 13 (6.6%) in the plasma group. Fluid overload events occurred in more patients in the plasma group than the 4F-PCC group (25 [12.7%] and 9 [4.7%], respectively). CONCLUSIONS:These safety data represent the largest controlled assessment of a 4F-PCC to date. For patients requiring urgent VKA reversal, 4F-PCC had a safety profile similar to that of plasma (AEs, SAEs, thromboembolic events, and deaths), but was associated with fewer fluid overload events.

Dataset Information

Use of Prothrombin Complex Concentrate for Vitamin K Antagonist Reversal before Surgical Treatment of Intracranial Hemorrhage.

Publications

Use of Prothrombin Complex Concentrate for Vitamin K Antagonist Reversal before Surgical Treatment of Intracranial Hemorrhage.

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