Management and outcome of major bleeding in patients receiving vitamin K antagonists for venous thromboembolism.

BACKGROUND: The optimal management of major bleeding in patients receiving vitamin K antagonists (VKA) for venous thromboembolism (VTE) is unclear. METHODS: We used the RIETE (Registro Informatizado Enfermedad TromboEmbólica) registry to assess the management and 30-day outcomes after major bleeding in patients receiving VKA for VTE. RESULTS: From January 2013 to December 2017, 267 of 18,416 patients (1.4%) receiving long-term VKA for VTE had a major bleeding (in the gastrointestinal tract 78, intracranial 72, hematoma 50, genitourinary 20, other 47). Overall, 151 patients (57%) received blood transfusion; 110 (41%) vitamin K; 37 (14%) fresh frozen plasma; 29 (11%) pro-haemostatic agents and 20 (7.5%) a vena cava filter. During the first 30 days, 59 patients (22%) died (41 died of bleeding) and 13 (4.9%) had a thrombosis. On multivariable analysis, patients with intracranial bleeding (hazard ratio [HR]: 4.58; 95%CI: 2.40-8.72) and those with renal insufficiency at baseline (HR: 2.73; 95%CI: 1.45-5.15) had an increased mortality risk, whereas those receiving vitamin K had a lower risk (HR: 0.47; 0.24-0.92). On the other hand, patients receiving fresh frozen plasma were at increased risk for thrombotic events (HR: 4.22; 95%CI: 1.25-14.3). CONCLUSIONS: Major bleeding in VTE patients receiving VKA carries a high mortality rate. Intracranial bleeding and renal insufficiency increased the risk. Fresh frozen plasma seems to increase this risk for recurrent VTE.

Lack of consistency in the relationship between asymptomatic DVT detected by venography and symptomatic VTE in thromboprophylaxis trials.

Asymptomatic deep-vein thrombosis (DVT) detected by mandatory venography, a surrogate outcome, comprises most of the efficacy outcome events in recent thromboprophylaxis trials. The validity of this surrogate to estimate trade-off between thrombotic and bleeding events in these clinical trials requires a consistent relationship between asymptomatic DVT and symptomatic venous thromboembolism (VTE). In this systematic review of high quality VTE prevention trials, we examined the consistency of the ratios of asymptomatic DVT to symptomatic VTE across a broad range of indications. Studies were identified from citations listed in the chapters on VTE prevention in the antithrombotic guidelines by the American College of Chest Physicians, 2012. A study was eligible if it: 1) was a randomised trial comparing an anticoagulant with standard of care; 2) included at least 500 participants; 3) reported asymptomatic or all DVT rates; and 4) reported symptomatic VTE rates. Of the 26 eligible trials, 19 trials were conducted in orthopaedic patients, five in general surgery patients and two in general medical patients. The overall median rates (ranges) for asymptomatic DVT and symptomatic VTE were 9.11 % (0.75 to 54.87 %) and 0.49 % (0.00 to 3.10 %), respectively. The median ratio was 14.53, with a wide range (2.75 to 103.86). Wide variability in the ratios persisted despite indication- and anticoagulant-specific analyses. In VTE prevention trials of alternative anticoagulants, the wide variability in the ratios of asymptomatic DVT to symptomatic VTE precludes judging the trade-off between thrombotic and bleeding events on the basis of composite outcomes dominated by venographic DVT.

Cluster randomized controlled trial of a simple warfarin maintenance dosing algorithm versus usual care among primary care practices.

Many patients using warfarin are being managed in primary care and typically achieve a lower time in therapeutic range (TTR) for the international normalized ratio (INR) than patients in specialized care. A simple warfarin maintenance dosing tool could assist primary care physicians with improving TTR. We tested whether a simple warfarin maintenance dosing algorithm can improve TTR compared with usual care among Canadian primary care physicians. Primary care practices managing warfarin therapy without an anticoagulation clinic, computer decision support system or patient self-management tools enrolled 10-30 patients with target INR range 2-3. Practices were randomized to manage warfarin maintenance with the algorithm, or as usual in 2009-2010. Primary outcome was the mean individual patient TTR, and was compared between groups with adjustment for clustering within practices. There were 13 practices randomized to the Algorithm and 15 practices to Control, enrolling 240 and 297 patients respectively, with a mean follow-up of 280 days. Mean (standard deviation; SD) TTR before the study was comparable between groups [68 % (SD 26) for usual care vs. 70 % (SD 27) for the algorithm; p = 0.49]. Dosing decisions during the study in the algorithm group were more often in agreement with the algorithm's recommendations than with usual care (81 vs. 91 %; p < 0.0001). Mean study TTR of the algorithm group was not superior to usual care: [72.1 (SE 1.7) vs. 71.4 % (SE 1.5) respectively; p = 0.73]. The simple warfarin maintenance dosing algorithm did not improve TTR compared with usual care among Canadian primary care practices.

Randomised comparison of a simple warfarin dosing algorithm versus a computerised anticoagulation management system for control of warfarin maintenance therapy.

Excellent control of the international normalised ratio (INR) is associated with improved clinical outcomes in patients receiving warfarin, and can be achieved by anticoagulation clinics but is difficult in general practice. Anticoagulation clinics have often used validated commercial computer systems to manage the INR, but these are not usually available to general practitioners. It was the objective of this study to perform a randomised trial of a simple one-step warfarin dosing algorithm against a widely used computerised dosing system. During the period of introduction of a commercial computerised warfarin dosing system (DAWN AC) to an anticoagulation clinic, patients were randomised to have warfarin dose adjustment done according to recommendations of the existing warfarin dosing algorithm or to those of the computerised system. The study tested if the computerised system was non-inferior to the existing algorithm for the primary outcome of time in therapeutic INR range of 2.0-3.0 (TTR), with a one-sided non-inferiority margin of 4.5%. There were 541 patients randomised to commercial computerised system and 527 to the algorithm. Median follow-up was 159 days. A dose recommendation was provided and followed in 91% of occasions for the computerised system and in 90% for the algorithm (p=0.03). The mean TTR was 71.0% (standard deviation [SD] 23.2) for the computerised system and 71.9% (SD 22.9) for the algorithm (difference 0.9% [95% confidence interval: -1.4% to 4.1%]; p-value for non-inferiority=0.002; p-value for superiority=0.34). In conclusion, similar maintenance control of the INR was achieved with a simple one-step dosing algorithm and a commercial computerised management system.

Incidence of postpartum haemorrhage in women receiving therapeutic doses of low-molecular-weight heparin: results of a retrospective cohort study.

Background Low-molecular-weight heparin (LMWH) is the drug of choice to prevent venous thrombosis in pregnancy, but the optimal dose for prevention while avoiding bleeding is unclear. This study investigated whether therapeutic doses of LMWH increase the incidence of postpartum haemorrhage (PPH) in a retrospective controlled cohort. Methods All pregnant women who received therapeutic doses of LMWH between 1995 and 2008 were identified in the Academic Medical Center, Amsterdam, The Netherlands. The controls were women registered for antenatal care in the same hospital who did not use LMWH during pregnancy, matched by random electronic selection for age, parity and delivery date to LMWH users. The incidence of PPH (blood loss >500 ml), severe PPH (blood loss >1000 ml) and median blood loss were compared in two cohorts of LMWH users and non-users. Results The incidence of PPH was 18% in LMWH users (N=95) and 22% in non-users (N=524) (RR 0.8; 95% CI 0.5 to 1.4). The incidence of severe PPH was 6% in both groups (RR 1.2; 0.5 to 2.9). The median amount of blood loss differed only in normal vaginal deliveries. It was 200 ml in LMWH users and 300 ml in non-users (difference -100 ml; 95% CI -156 to -44). Conclusion Therapeutic doses of LMWH in pregnancy were observed not to be associated with a clinically meaningful increase in the incidence of PPH or severe PPH in women delivered in this hospital, although this observation may be confounded by the differential use of strategies to prevent bleeding. A randomised controlled trial is necessary to provide a definite answer about the optimal dose of LMWH in pregnancy.