Prothrombin complex concentrate for reversal of vitamin K antagonist treatment in bleeding and non-bleeding patients.
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ABSTRACT:
SUBMITTER: Johansen M
PROVIDER: S-EPMC6516823 | biostudies-literature | 2015 Jul
REPOSITORIES: biostudies-literature
Publications
Prothrombin complex concentrate for reversal of vitamin K antagonist treatment in bleeding and non-bleeding patients.
Johansen Mathias M Wikkelsø Anne A Lunde Jens J Wetterslev Jørn J Afshari Arash A
The Cochrane database of systematic reviews 20150707 7
<h4>Background</h4>Treatment with vitamin K antagonists is associated with increased morbidity and mortality. Reversal therapy with prothrombin complex concentrate (PCC) is used increasingly and is recommended in the treatment of patients with bleeding complications undertaking surgical interventions, as well as patients at high risk of bleeding. Evidence is lacking regarding indication, dosing, efficacy and safety.<h4>Objectives</h4>We assessed the benefits and harms of PCC compared with fresh ...[more]
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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.
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Project description:IntroductionThere is currently little evidence for the optimal dosing strategy of four-factor prothrombin complex concentrates (PCC) in vitamin K antagonist (VKA)-related bleeds. The generally accepted dosing strategy is the use of a variable dose calculated using patient-specific characteristics as per manufacturer's instruction. However, evidence exists that the use of a fixed low dose of 1000 international units of factor IX (IU fIX) might also suffice. Recent studies indicate that in terms of haemostatic effectiveness, the fixed dosing strategy might be even superior to the variable dosing strategy. The PROPER3 (PROthrombin complex concentrate: Prospective Evaluation and Rationalisation, number 3) study aims to confirm the non-inferiority, and explore superiority, in haemostatic effectiveness of the fixed PCC dosing strategy compared with the variable dosing strategy in VKA-related extracranial bleeding emergencies.Methods and analysisThe study is designed as a randomised controlled multicentre non-inferiority trial. Eligibility criteria are an indication for PCC due to VKA-related extracranial bleeding in subjects 18 years of age or older. The control group will receive a variable dose, determined by patient-specific bodyweight and international normalised ratio. The intervention group is dosed a fixed 1000 IU fIX PCC. Primary outcome is the haemostatic effectiveness of both treatments, as defined by the 2016 International Society on Thrombosis and Haemostasis (ISTH) criteria. The sample size is set at 155 patients per treatment arm, requiring 310 patients in total. Non-inferiority on the proportion (risk) difference of the primary outcome will be evaluated using the asymptotic Wald test for non-inferiority. The non-inferiority margin is set at 6%. The primary analysis will be based on the per-protocol population.Ethics and disseminationStudy results will be published in an international journal, communicated to discipline-specific associations and presented at (inter)national meetings and congresses.Trial registration numberEUCTR2014-000392-33; Pre-results.
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