Warfarin‐related intracerebral haemorrhage: better outcomes when reversal includes prothrombin complex concentrates

Hanger, H. C.; Geddes, John A.; Wilkinson, Tim; Lee, Martin; Baker, Alice

doi:10.1111/imj.12034

Cited by 47 publications

(31 citation statements)

References 34 publications

(94 reference statements)

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“…A recent German observational study on VKA‐OAC (n = 1,176), published after the submission of our study, suggested that rapid reversal of INR is associated with less ICH expansion and lower in‐hospital mortality, but was not powered to compare reversal therapies due to a uniform national practice of using PCC 24. Previous observational studies comparing treatments have been small (17–181 patients), with variable results with regard to case fatality,14, 25, 26 functional outcome,27, 28 and hematoma expansion 29. These studies also combined patients receiving FFP with either PCC26, 29 or no reversal,14, 23, 27 precluding direct comparison of specific reversal strategies.…”

Section: Discussionmentioning

confidence: 92%

Reversal strategies for vitamin K antagonists in acute intracerebral hemorrhage

Parry‐Jones

Napoli²,

Goldstein

et al. 2015

Annals of Neurology

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ObjectiveThere is little evidence to guide treatment strategies for intracerebral hemorrhage on vitamin K antagonists (VKA‐ICH). Treatments utilized in clinical practice include fresh frozen plasma (FFP) and prothrombin complex concentrate (PCC). Our aim was to compare case fatality with different reversal strategies.MethodsWe pooled individual ICH patient data from 16 stroke registries in 9 countries (n = 10 282), of whom 1,797 (17%) were on VKA. After excluding 250 patients with international normalized ratio < 1.3 and/or missing data required for analysis, we compared all‐cause 30‐day case fatality using Cox regression.ResultsWe included 1,547 patients treated with FFP (n = 377, 24%), PCC (n = 585, 38%), both (n = 131, 9%), or neither (n = 454, 29%). The crude case fatality and adjusted hazard ratio (HR) were highest with no reversal (61.7%, HR = 2.540, 95% confidence interval [CI] = 1.784–3.616, p < 0.001), followed by FFP alone (45.6%, HR = 1.344, 95% CI = 0.934–1.934, p = 0.112), then PCC alone (37.3%, HR = 1.445, 95% CI = 1.014–2.058, p = 0.041), compared to reversal with both FFP and PCC (27.8%, reference). Outcomes with PCC versus FFP were similar (HR = 1.075, 95% CI = 0.874–1.323, p = 0.492); 4‐factor PCC (n = 441) was associated with higher case fatality compared to 3‐factor PCC (n = 144, HR = 1.441, 95% CI = 1.041–1.995, p = 0.027).InterpretationThe combination of FFP and PCC might be associated with the lowest case fatality in reversal of VKA‐ICH, and FFP may be equivalent to PCC. Randomized controlled trials with functional outcomes are needed to establish the most effective treatment. Ann Neurol 2015;78:54–62

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Section: Discussionmentioning

confidence: 92%

Reversal strategies for vitamin K antagonists in acute intracerebral hemorrhage

Parry‐Jones

Napoli²,

Goldstein

et al. 2015

Annals of Neurology

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“…Although PCC has been associated with better reversal of coagulopathy induced by warfarin, the impact of PCC on real clinical outcomes is not clearly demonstrated [8] [9] [13]. In 2014, Fong et al [9] in a historical cohort study compared patients with intracranial haemorrhage related to warfarin who received either PCC or FFP.…”

Section: Discussionmentioning

confidence: 99%

“…The data from 88 patients with median INR value 2.9 were analysed, and a higher reduction in mortality rate was observed with PCC than with FFP administration (HR = 0.25, p = 0.01). When PCC was administered sooner, the benefits trended to be higher [8].…”

Section: Discussionmentioning

confidence: 99%

Superiority of Prothrombin Complex Concentrate versus Frozen Fresh Plasma in Cardiology Patients with Warfarin Intoxication–Observational Study

Soeiro¹,

César²,

Biselli³

et al. 2017

OJEM

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Objective: The objective of this study was to analyse the reversibility of the anticoagulant effect of warfarin by comparing prothrombin complex concentrate (PCC) versus frozen fresh plasma (FFP) in cardiology patients with serious warfarin intoxication. Methods: This was an observational and retrospective study comprising 67 patients (18 in group I [PCC] and 49 in group II [FFP]). The primary endpoint was the reversal of anticoagulant effect of warfarin after 2 and 24 hours of PCC or FFP administration. Comparisons between the groups were made using T-test and Q-square. Multivariate analyses were conducted using logistic regression, and the results were considered significant when p < 0.05. Complementary analysis was performed using the ROC curve, calculating the area under the curve (AUC), and calculating the cut-off score for the relation between PCC (UI/kg) or FFP (ml/kg) and INR reversibility. Results: The medium dose used was 27.6 UI/kg of PCC and 14.5 ml/kg of FFP. Significant differences were observed between groups I and II in the INR reversibility measurements after 2 hours (33.3% vs. 6.1%, p = 0.001) and 24 hours (38.9% vs. 12.2%, p = 0.009) as well as in the occurrence of pulmonary edema (5.6% vs. 42.9%, OR = 11.10, p = 0.04). The AUC for PCC was 0.891 (CI 95% [0.72 -1.0]), and for FFP, it was 0.291 (CI 95% [0.09 -0.49]). Conclusions: PCC is better than FFP treatment in reversing the warfarin intoxication after 2 and 24 hours of administration. Furthermore, PCC showed lower pulmonary edema in cardiology patients.

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“…22,23,29 One study showed an improvement in functional gains in patients receiving PCC versus plasma after warfarin-associated ICH as measured by the functional independence measure. 30 Of 3 studies evaluating red blood cell (RBC) transfusion, only the study by Hickey et al showed a reduction in the mean units of RBCs transfused. 19,22,29 Adverse events were included infrequently as study outcomes (n ϭ 4 studies), but there were fewer total events with PCC and no difference in thrombotic rates in 3 studies.…”

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confidence: 99%

“…27,29,[31][32][33][34] The proportion of patients achieving INR correction (as defined in individual studies) was significantly greater in patients receiving PCC compared with plasma in all 5 studies reporting this outcome. 26,27,29,30,35 Reversal of warfarin anticoagulation for major bleeding requires administration of vitamin K to reestablish the activity of vitamin K-dependent coagulation factors, an effect seen at least 6 hours after intravenous administration. Adjunctive replacement of coagulation factors with PCC or plasma contribute to the rapid normalization of hemostasis desired in the setting of major bleeding.…”

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confidence: 99%

Plasma versus prothrombin complex concentrate for warfarin-associated major bleeding: a systematic review

Siegal

Savage

2015

Hematology

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Learning Objective• To compare the efficacy and adverse effects of prothrombin complex concentrate and plasma for rapid correction of vitamin K antagonist-associated hemorrhagic emergency Clinical vignetteA 78-year-old female presents to the emergency department with brisk hematochezia, fatigue, and tachycardia. She is receiving chronic oral anticoagulant therapy with warfarin as thromboprophylaxis for a mechanical mitral valve. International normalized ratio (INR) is 4.2. Red blood cell transfusion is ordered, and 10 mg of intravenous vitamin K is given. You are asked whether plasma or prothrombin complex concentrate is more effective for emergent reversal of her warfarin-associated coagulopathy.Warfarin is a vitamin K antagonist (VKA) that has been the mainstay of oral anticoagulant therapy for the prevention and treatment of thromboembolism. Bleeding is the major complication of anticoagulant therapy with rates of major warfarin-related bleeding up to 7% reported depending on the indication for anticoagulation and study design. [1][2][3][4][5] Warfarin use increases the risk of major bleeding by 0.3%-0.5%/year and intracranial hemorrhage (ICH) by 0.2%/year compared to controls in clinical trials. 1 Despite the availability of warfarin-reversal agents, warfarin-associated bleeding leads to significant morbidity and mortality, with case fatality rates of 8%-13%. 5-8 Death in hospital or within 7 days of discharge has been reported in 18% of warfarin-treated atrial fibrillation patients presenting with major bleeding. 9 In patients presenting with warfarin-associated ICH, high mortality rates of 54% and 64% have been reported at 30 days and 6 months, respectively. 10Although direct oral anticoagulants (DOACs) are now approved for several indications, warfarin use is expected to continue for patients who are stably managed on long-term warfarin therapy, conditions in which DOACs are not proven (eg, antiphospholipid antibody syndrome, mechanical heart valves), patients with severe renal failure (creatinine clearance Ͻ30 mL/min), and patients for whom DOACs are cost prohibitive.Warfarin-associated major bleeding complications require urgent reversal of coagulopathy. When given intravenously, the effect of vitamin K on warfarin coagulopathy is evident within 6 hours. Plasma contains all coagulation factors and will correct coagulation factor deficiency attributable to inadequate synthesis. Time to thaw frozen plasma (FP) may in some circumstances be a limitation, but large blood banks typically have a continuous stock of thawed plasma. The infusion time depends on vascular access and volume status of the patient. Fluid overload and mild allergic reactions are the most common adverse reactions to plasma (ϳ1 in 100 transfusions). Serious allergic and transfusion-related acute lung injury reactions are rare (ϳ1 in 10 000 transfusions). [11][12][13][14][15][16] Prothrombin complex concentrates (PCCs) are plasma-derived products containing vitamin K-dependent factors II, VII, IX, and X (4-factor PCC) or II, IX, and X (3-...

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Warfarin‐related intracerebral haemorrhage: better outcomes when reversal includes prothrombin complex concentrates

Abstract: Background: Warfarin-related intracerebral haemorrhage (WRICH) has high mortal-

Cited by 47 publications

References 34 publications

Reversal strategies for vitamin K antagonists in acute intracerebral hemorrhage

Reversal strategies for vitamin K antagonists in acute intracerebral hemorrhage

Superiority of Prothrombin Complex Concentrate versus Frozen Fresh Plasma in Cardiology Patients with Warfarin Intoxication–Observational Study

Plasma versus prothrombin complex concentrate for warfarin-associated major bleeding: a systematic review

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