Most vitamin K antagonists have a long half-life (acenocoumarol, 10 h; warfarin, 36-48 h; phenprocoumon, 120-150 h), Background-The aim of this study was to compare the management and prognosis of major bleeding in patients treated with dabigatran or warfarin. Methods and Results-Two independent investigators reviewed bleeding reports from 1034 individuals with 1121 major bleeds enrolled in 5 phase III trials comparing dabigatran with warfarin in 27 419 patients treated for 6 to 36 months. Patients with major bleeds on dabigatran (n=627 of 16 755) were older, had lower creatinine clearance, and more frequently used aspirin or non-steroid anti-inflammatory agents than those on warfarin (n=407 of 10 002). The 30-day mortality after the first major bleed tended to be lower in the dabigatran group (9.1%) than in the warfarin group (13.0%; pooled odds ratio, 0.68; 95% confidence interval, 0.46-1.01; P=0.057). After adjustment for sex, age, weight, renal function, and concomitant antithrombotic therapy, the pooled odds ratio for 30-day mortality with dabigatran versus warfarin was 0.66 (95% confidence interval, 0.44-1.00; P=0.051). Major bleeds in dabigatran patients were more frequently treated with blood transfusions (423/696, 61%) than bleeds in warfarin patients (175/425, 42%; P<0.001) but less frequently with plasma (dabigatran, 19.8%; warfarin, 30.2%; P<0.001). Patients who experienced a bleed had shorter stays in the intensive care unit if they had previously received dabigatran (mean 1.6 nights) compared with those who had received warfarin (mean 2.7 nights; P=0.01). Conclusions-Patients who experienced major bleeding on dabigatran required more red cell transfusions but received less plasma, required a shorter stay in intensive care, and had a trend to lower mortality compared with those who had major bleeding on warfarin. Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.113.002332Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz. Received February 28, 2013; accepted September 23, 2013. but their anticoagulant effects can be reversed within 10-20 minutes by prothrombin complex concentrates (PCCs) and within 6-12 h by vitamin K. 4 Dabigatran does not have an antidote but has a half-life of 12-14 h, 5 and withholding the drug for 1-2 days is sufficient to restore hemostasis in most cases of mild to moderate bleeding. In patients with life-threatening bleeding, more rapid restoration of hemostasis might be achieved by the use of hemodialysis to remove the drug, 6-8 activated charcoal to prevent gastrointestinal absorption of recently ingested drug, 9 and the administration of PCCs, 10 activated PCCs, 11 or recombinant activated factor VII (rFVIIa) 12 to enhance thrombin generation. Evidence concerning the efficacy of these approaches is, however, limited to experimental and animal studies and isolated case reports.10,13 Shortening of coagulation time is not always equivalent with restoration of hemostasi...
Objectives: Recent studies have shown that direct oral anticoagulants (DOACs) are effective for cancer-associated venous thromboembolism (CAT). This study investigated the treatment pattern and the rate of bleeding complications in real-world practice in CAT patients. Patients/Methods: We used the Korean Health Insurance Review and Assessment service database (2014-2018). Among patients with venous thromboembolism, patients with concomitant malignancy diagnostic codes were categorized as CAT, while all others were categorized as non-CAT. Treatments were categorized as DOAC, parenteral anticoagulant (PAC), warfarin, and mixed anticoagulant. Results: We identified 27,205 CAT and 57,711 non-CAT patients. DOACs were the most frequently used anticoagulants. The proportion of patients treated with PAC was significantly higher in CAT than non-CAT patients. (35.7% vs. 19.5%) (P<0.01). In CAT, the cumulative incidence of any/major bleeding was significantly higher with DOAC (8.1%/3.9%) than PAC (7.5%/3.2%; P=0.04 and 0.01, respectively). However, there was no difference in major bleeding when compared with warfarin (P=0.11) or mixed anticoagulant (P=0.94). Overall, gastrointestinal (GI) cancer patients showed higher risks of bleeding. The cumulative incidence of major GI bleeding was higher with DOAC than PAC (4.9% vs. 3.0%; P<0.01), while there was no difference compared with warfarin (P=0.59) or mixed anticoagulant (P=0.80). Major bleeding with each DOAC showed no difference among entire CAT (P=0.94), GI cancer (P=0.27), and GU cancer (P=0.88) patients. Conclusions: DOACs have become the most prescribed anticoagulant in CAT. Bleeding was more prevalent with DOAC than PAC. The bleeding complications should be carefully monitored to ensure optimal treatment, especially with DOAC.
19 Background. Although the use of dabigatran reduces bleeding compared to warfarin, these bleeds need to be managed when they occur. We describe the management of major bleeds and the prognosis in patients who bleed after treatment with dabigatran or warfarin. Methods. We analyzed the RE-LY trial for the use of resources and length of stay after major bleeds. Additionally, two independent investigators reviewed all reports on 1,121 major bleeds in 5 phase III long-term trials of dabigatran in atrial fibrillation, acute treatment and secondary prevention of venous thromboembolism involving 27,419 patients followed for 6 to 36 months. The effect of different blood products and factor concentrates to manage the bleeding was compared between patients on dabigatran and on warfarin. The effect was assessed as good, moderate or poor taking into account the totality of clinical data available. Results. Patients with major bleeds on dabigatran were older, had lower creatinine clearance and more frequent use of aspirin or non-steroid anti-inflammatory agents than those on warfarin. Factor concentrates were only used for 11 patients treated with dabigatran (prothrombin complex concentrate, 2; recombinant factor VIIa, 9), which was too few to determine the efficacy of these measures. Other results are shown in the table below. Patients on warfarin were transfused with red blood cells less frequently, but required more plasma transfusions and more vitamin K for bleeding management than patients on dabigatran. The difference in 30-day mortality in favor of dabigatran (univariate P=0.044) became stronger in logistic regression analysis (multivariate P=0.007). Conclusion. The prognosis after a major bleed on dabigatran was, despite lack of a specific antidote, better than with warfarin. There was also a shorter stay in intensive care with dabigatran compared to warfarin. Disclosures: Brueckmann: Boehringer Ingelheim Pharma GmbH &Co. KG: Employment. Connolly:Boehringer Ingelheim: Advisory Board Other, Consultancy, Research Funding, Speakers Bureau; Sanofi-Aventis: Advisory Board, Advisory Board Other, Consultancy, Research Funding, Speakers Bureau; Portola: Advisory Board, Advisory Board Other, Consultancy, Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding; Merck: Advisory Board Other, Consultancy. Eikelboom:Boehringer Ingelheim: Consultancy, Research Funding, Speakers Bureau; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Sanofi-Aventis: Consultancy, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Research Funding, Speakers Bureau; Eisai Pharmaceuticals: Consultancy, Speakers Bureau; Eli Lilly: Consultancy, Speakers Bureau; McNeil: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Corgenix Medical Corporation: Consultancy; Daiichi Sankyo: Consultancy. Ezekowitz:Boehringer Ingelheim: Advisory Board Other, Consultancy, Speakers Bureau; Astra Zeneca: Advisory Board, Advisory Board Other, Consultancy; Eisei: Advisory Board, Advisory Board Other, Consultancy; Pozen Inc: Advisory Board, Advisory Board Other, Consultancy; ARYx Therapeutics: Advisory Board Other, Consultancy; Pfizer: Advisory Board, Advisory Board Other, Consultancy; Sanofi: Advisory Board Other, Consultancy; Bristol Myers Squibb: Advisory Board, Advisory Board Other, Consultancy; Portola: Advisory Board, Advisory Board Other, Consultancy; Diachi Sanko: Advisory Board Other, Consultancy; Medtronics: Advisory Board, Advisory Board Other, Consultancy; Merck: Advisory Board, Advisory Board Other, Consultancy; Johnson & Johnson: Advisory Board, Advisory Board Other, Consultancy; Gilead: Advisory Board Other, Consultancy; Janssen Scientific Affairs: Advisory Board, Advisory Board Other, Consultancy. Wallentin:Boehringer Ingelheim: Advisory Board Other, Consultancy, Honoraria, Research Funding; Astra Zeneca: Advisory Board, Advisory Board Other, Consultancy, Honoraria, Research Funding; Glaxo Smith Kline: Advisory Board, Advisory Board Other, Consultancy, Honoraria, Research Funding; Eli Lilly: Advisory Board, Advisory Board Other, Consultancy, Honoraria; Schering-Plough: Advisory Board Other, Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Advisory Board, Advisory Board Other, Consultancy, Honoraria, Research Funding; Regardo Biosciences: Advisory Board Other, Consultancy; Athera Biosciences: Advisory Board, Advisory Board Other, Consultancy. Yusuf:Boehringer Ingelheim: Advisory Board Other, Consultancy, Honoraria, Research Funding; Astra Zeneca: Advisory Board, Advisory Board Other, Consultancy; Sanofi-Aventis: Advisory Board, Advisory Board Other, Consultancy; Bristol Myers Squibb: Advisory Board, Advisory Board Other, Consultancy. Schulman:Boehringer Ingelheim: Consultancy, Speakers Bureau; Bayer Healthcare: Consultancy, Research Funding; Sanofi-Aventis: Consultancy, Honoraria; Leo Pharma: Honoraria; GlaxoSmithKline: Consultancy; Astra Zeneca: Consultancy.
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