Fixed Versus Variable Dosing of Prothrombin Complex Concentrate for Bleeding Complications of Vitamin K Antagonists-The PROPER3 Randomized Clinical Trial.

STUDY OBJECTIVE: To determine if a fixed dose of 1000 IU of 4-factor prothrombin complex concentrate (4F-PCC) is as effective as traditional variable dosing based on body weight and international normalized ratio (INR) for reversal of vitamin K antagonist (VKA) anticoagulation. METHODS: In this open-label, multicenter, randomized clinical trial, patients with nonintracranial bleeds requiring VKA reversal with 4F-PCC were allocated to either a 1,000-IU fixed dose of 4F-PCC or the variable dose. The primary outcome was the proportion of patients with effective hemostasis according to the International Society of Thrombosis and Haemostasis definition. The design was noninferiority with a lower 95% confidence interval of no more than -6%. When estimating sample size, we assumed that fixed dosing would be 4% superior. RESULTS: From October 2015 until January 2020, 199 of 310 intended patients were included before study termination due to decreasing enrollment rates. Of the 199 patients, 159 were allowed in the per-protocol analysis. Effective hemostasis was achieved in 87.3% (n=69 of 79) in fixed compared to 89.9% (n=71 of 79) in the variable dosing cohort (risk difference 2.5%, 95% confidence interval -13.3 to 7.9%, P=.27). Median door-to-needle times were 109 minutes (range 16 to 796) in fixed and 142 (17 to 1076) for the variable dose (P=.027). INR less than 2.0 at 60 minutes after 4F-PCC infusion was reached in 91.2% versus 91.7% (P=1.0). CONCLUSION: The large majority of patients had good clinical outcome after 4F-PCC use; however, noninferiority of the fixed dose could not be demonstrated because the design assumed the fixed dose would be 4% superior. Door-to-needle time was shortened with the fixed dose, and INR reduction was similar in both dosing regimens.

Method agreement analysis and interobserver reliability of the ISTH proposed definitions for effective hemostasis in management of major bleeding.

Essentials In 2016 the SSC proposed definitions for effective hemostasis in management of major bleeding. To validate these definitions, we studied the use in three large anticoagulant-reversal studies. Method agreement analysis and interobserver reliability showed at least acceptable agreement. Recommendations were made, advising use of the definition in hemostatic effectiveness studies. SUMMARY: Introduction In 2016 the Scientific and Standardization Subcommittee (SSC) on Control of Anticoagulation of the International Society on Thrombosis and Haemostasis (ISTH) proposed criteria to evaluate the effectiveness of anticoagulant reversal in major bleeding management. Testing and validation of these criteria are required. Objective To investigate the method agreement, interobserver reliability and applicability of the ISTH proposed definitions for hemostatic effectiveness. Methods Patient data from three anticoagulant-antidote studies were used for hemostatic effectiveness assessment using the ISTH-proposed definitions and clinical opinion. For every patient a case document was produced. For each cohort, four adjudicators were asked to assess the hemostatic effectiveness independently on a case-by-case basis. Agreement between the two methods of hemostatic effectiveness assessment was calculated using Cohen's kappa (κ), with a calculated sample size of at least 73 cases. Results The full dataset consisted of 116 cases, resulting in 464 assessments. Method agreement in outcome was observed in 364 of 464 assessments (78.5%), resulting in κ of 0.634 (95% CI: 0.575-0.694), or "substantial agreement." Interobserver reliability analysis of the proposed definitions computed an overall agreement of 54.2% with κ of 0.312 ("fair agreement"). Discussion Method agreement analysis shows that the conclusions drawn using the ISTH definitions have "substantial agreement" with clinical opinion. Interobserver reliability analysis demonstrated acceptable agreement. In-depth analysis provided minor opportunities for further improvement and correct application of the definition. The definition is recommended to be used in all future studies evaluating hemostatic effectiveness, taking the suggested recommendations into account.

Clinical outcome of patients with a vitamin K antagonist-associated bleeding treated with prothrombin complex concentrate.

BACKGROUND: Vitamin K antagonists (VKA) are used for the treatment of thromboembolism. Patients with severe VKA-associated bleeding require immediate restoration of haemostasis. Clinical studies on the effect of prothrombin complex concentrate (PCC) are heterogeneous with respect to outcome of bleeding. OBJECTIVE: To evaluate the clinical outcome of patients treated with PCC for VKA-associated bleeding. METHODS: We performed a cohort study of consecutive patients who received PCC for VKA-related bleeding in five Dutch hospitals. Data were collected by chart review on the bleeding event, international normalized ratio (INR), haemostatic efficacy, thromboembolic (TE) complications, and mortality. The primary outcome was effective haemostasis, assessed by an adaptation of the Sarode criteria with a surrogate outcome for patients with ICH without repeat CT. RESULTS: One hundred patients were included. Mean age was 74 years, 54% were male and 79% received VKA for atrial fibrillation. Most patients presented with ICH (41%) or GI bleeding (36%). Effective haemostasis was achieved in 67/98 (68%) patients using the adapted classification. Surrogate outcomes were applied for 32 patients and data for two patients was missing. Median pre-treatment INR was 3.9 (IQR 2.9-5.8). One hour after PCC infusion, the INR was available for 50 patients and of these, 35 (70%) had an INR ≤1.4. TE complications occurred in five patients and 22 died (60% bleeding-related) within 30 days. CONCLUSION: PCC achieved effective haemostasis in 68% of evaluable patients with VKA-associated bleeding. TE complication rates were low, but mortality rates were high, due to the large number of patients with ICH.

Randomised controlled trial protocol to evaluate a fixed dose prothrombin complex concentrate against the variable dose in vitamin K antagonist related bleeding (PROPER3).

INTRODUCTION: There 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 ANALYSIS: The 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 DISSEMINATION: Study results will be published in an international journal, communicated to discipline-specific associations and presented at (inter)national meetings and congresses. TRIAL REGISTRATION NUMBER: EUCTR2014-000392-33; Pre-results.