Optimal dosing strategy for prothrombin complex concentrate

Ongeveer 1% van alle 420.000 gebruikers van bloedverdunners in Nederland belandt jaarlijks in het ziekenhuis met een ernstige bloeding. Het loont voor deze groep om daar niet, zoals gebruikelijk, een ingewikkelde en tijdrovende berekening uit te voeren naar de juiste hoeveelheid stoleiwitten om de bloeding te stoppen. Dat stelt Nakisa Khorsand in haar promotieonderzoek. Een simpele, vaste doseerwijze is net zo effectief en goedkoper dan de variabele doseerwijze. Om afsluiting van de bloedvaten te voorkomen, krijgen mensen met trombose bloedverdunners voorgeschreven. Het is lastig om de juiste dosering te bepalen. Een te hoge dosering bloedverdunners kan leiden tot een ernstige bloeding. Ieder jaar belanden ruim vierduizend mensen met zo’n ernstige bloeding in het ziekenhuis. Daar krijgen ze stoleiwitten toegediend, bereid uit het bloed van gezonde donoren. De dosering stoleiwitten wordt berekend op basis van lichaamsgewicht, de mate van ontstolling op het moment van bloeden en de gewenste mate van stolling. Deze wijze van doseren kost tijd. Om geen tijd te verliezen in een spoedeisende en levensbedreigende situatie, onderzocht Khorsand samen met collega’s van Apotheek Haagse Ziekenhuizen en het UMCG of de stoleiwitten ook simpeler gedoseerd kunnen worden. Dat blijkt het geval te zijn. Een lage, vaste dosering voor iedere patiënt bleek in de klinische praktijk net zo goed te werken als de dosering die op basis van lichaamsgewicht en mate van ontstolling berekend moest worden. Dit komt waarschijnlijk door de snelheid waarmee de behandeling kan worden gestart. Ook zijn de behandelkosten van de vaste dosering gemiddeld per patiënt 1.634 tot 2.100 euro lager. De promovenda is nu betrokken bij vervolgonderzoek naar de toepasbaarheid van de vaste en variabele dosering in een grotere onderzoekspopulatie

A meta-analysis of andexanet alfa and prothrombin complex concentrate in the treatment of factor Xa inhibitor-related major bleeding

BACKGROUND: Andexanet alfa (andexanet) and prothrombin complex concentrate (PCC) are both reversal agents for major bleeding in patients using factor Xa inhibitors (FXaIs). Our aim was to evaluate the current evidence for the effectiveness and safety of andexanet and PCC in a systematic review and meta‐analysis. OBJECTIVES: Primary objective was hemostatic effectiveness. Secondary objectives were thromboembolic event rate and mortality. METHODS: A systematic review was performed in PubMed and Embase. Studies describing the effectiveness and/or safety of PCC or andexanet in patients with major bleeding using FXaIs were included. Meta‐analysis was performed using a random‐effects model. RESULTS: Seventeen PCC studies, 3 andexanet studies, and 1 study describing PCC and andexanet were included, comprising 1428 PCC‐treated and 396 andexanet‐treated patients. None of the included studies had control groups, hampering a pooled meta‐analysis to compare the two reversal agents. Separate analyses for andexanet and PCC were performed. In subgroup analysis, the pooled proportion of patients with effective hemostasis in studies that used Annexa‐4 criteria demonstrated a hemostatic effectiveness of 0.85 (95% confidence interval [CI], 0.80‐0.90) in PCC and 0.82 (95% CI, 0.78‐0.87) in andexanet studies. The pooled proportion of patients with thromboembolic events was 0.03 (95% CI, 0.02‐0.04) in PCC and 0.11 (95% CI, 0.04‐0.18) in andexanet studies. CONCLUSION: Based on the available evidence with low certainty from observational studies, PCC and andexanet demonstrated a similar, effective hemostasis in the treatment of major bleeding in patients using FXaIs. Compared to PCC, the thromboembolic event rate appeared higher in andexanet‐treated patients

Fixed Versus Variable Dosing of Prothrombin Complex Concentrate in Vitamin K Antagonist-Related Intracranial Hemorrhage:A Retrospective Analysis

Millions of patients receive vitamin K antagonist (VKA) therapy worldwide. Annually 0.2-1 % of all VKA users develops an intracranial hemorrhage (ICH). Prothrombin complex concentrate (PCC) is administered to restore the INR In a before and after design, we compared successful achievement of an INR A median dosage of 1750 IU was given per patient in the variable dose group (n = 25) versus 1000 IU in the fixed dose group (n = 28). In the intention-to-treat analysis, 96 % achieved an INR The fixed dose protocol necessitates additional PCC infusions more frequently to achieve a target IN

SIMULASI PENDISTRIBUSIAN AIR MINUM PADA SUMBER AIR GUA SEROPAN KABUPATEN GUNUNG KIDUL

Kabupaten Gunung Kidul adalah salah satu wilayah yang mempunyai potensi air berlimpah tapi penduduk kekurangan air. Karena sebagian besar kondisi alamnya merupakan pegunungan kapur, maka digunakan teknologi untuk memperoleh air. Tujuan dari penulisan ini adalah adalah membuat simulasi jam pendistribusian air yang efektif khusus untuk kecamatan Ngawen dengan bantuan program Epanet 2.0, sehingga diperoleh waktu pendistribusian sesuai dengan kebutuhan pelanggan dengan waktu distribusi dilihat dari kebiasaan masyarakat mengkonsumsi atau menggunakan air dalam aktifitas sehari-harinya. Metode yang digunakan pada penulisan ini yaitu deskripsi komperatif yaitu mejelaskan pengaturan pendistribusian air yang terdapat di Kecamatan Ngawen dibandingkan dengan pengaturan simulasi dengan bantuan program Epanet 2.0, sehingga diperoleh simulasi pendistribusian yang efektif. Berdasarkan hasil analisa jaringan air minum kecamatan Ngawen untuk waktu pelayanan kondisi eksisting 12 jam selalu terjadi kekurangan. Sedangkan hasil simulasi jam pendistribusian kecamatan Ngawen untuk waktu distribusi 24 jam masih terjadik kekurangan. Dari hal tersebut diatas perlu adanya penelitian lebih lanjut tentang masalah yang menyebabkan jaringan air minum di kecamatan Ngawen sering terjadi kekurangan

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

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 (), 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 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 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

A systematic review of prothrombin complex concentrate dosing strategies to reverse vitamin K antagonist therapy

Management of patients with a major bleed while on vitamin K antagonist (VKA) is a common clinical challenge. Prothrombin Complex Concentrates (PCC) provide a rapid reversal of VKA induced coagulopathy. However, a well-defined PCC dosing strategy, especially in emergency setting, is still lacking. We performed a systematic review to describe the currently used PCC dosing strategies and to present their efficacy in terms of target INR achievement and clinical outcome. We used outcome definitions as used in the individual studies. MEDLINE and EMBASE databases were searched for studies reporting the use of PCC for emergency VKA reversal. Twenty-eight studies, including 4 randomized trials, were found. In these, fifteen different PCC dosing protocols were identified in which the PCC dose ranged from 8 to 50 IU factor IX/kg. These strategies were based on: bodyweight; bodyweight and initial INR; bodyweight and initial INR and target INR; individual doctors decision; or a fixed dose. Study quality was moderate with large variation in outcome definitions. Relatively good clinical and INR outcomes were reported with the use of any treatment protocol while less good results were reported for INR outcome when a predefined protocol was missing (doctor strategy). Lowest PCC dosages were infused in the fixed dose strategy. In emergency VKA reversal, a predefined PCC dosing protocol seems essential. We found no evidence that one dosing strategy is superior. Future studies should be designed to investigate if body weight and INR are relevant for PCC dosing. In these, we need uniform outcome definitions. (C) 2014 Elsevier Ltd. All rights reserved