UNASSIGNED: Current guidelines recommend that patients with cerebral venous thrombosis (CVT) should be treated with vitamin K antagonists (VKAs) for 3-12 months. Direct oral anticoagulants (DOACs), however, are increasingly used in clinical practice. An exploratory randomized controlled trial including 120 patients with CVT suggested that the efficacy and safety profile of dabigatran (a DOAC) is similar to VKAs for the treatment of CVT, but large-scale prospective studies from a real-world setting are lacking.
UNASSIGNED: DOAC-CVT is an international, prospective, observational cohort study comparing DOACs to VKAs for the prevention of recurrent venous thrombotic events after acute CVT. Patients are eligible if they are 18 years or older, have a radiologically confirmed CVT, and have started oral anticoagulant treatment (DOAC or VKA) within 30 days of CVT diagnosis. Patients with an absolute contra-indication for DOACs, such as pregnancy or severe renal insufficiency, are excluded from the study. We aim to recruit at least 500 patients within a three-year recruitment period. The primary endpoint is a composite of recurrent venous thrombosis and major bleeding at 6 months of follow-up. We will calculate an adjusted odds ratio for the primary endpoint using propensity score inverse probability treatment weighting.
UNASSIGNED: DOAC-CVT will provide real-world data on the comparative efficacy and safety of DOACs versus VKAs for the treatment of CVT.
UNASSIGNED: ClinicalTrials.gov, NCT04660747.

Background: Sequential low molecular weight heparin (LMWH) plus warfarin, LMWH plus edoxaban, and LMWH plus dabigatran regimens have already shown efficacy and safety in the treatment of acute pulmonary embolism (PE). The efficacy and safety of sequential LMWH plus rivaroxaban regimen in the treatment of acute PE have been understudied. Methods: A retrospective study was performed to explore the efficacy and safety of sequential therapy regimens of subcutaneous LMWH (nadroparin 86 IU/kg every 12 h for a week) followed by oral rivaroxaban (20 mg once daily for 3 months) for the management of patients with established acute PE without hemodynamic instability, compared with those of nadroparin plus dabigatran and nadroparin plus warfarin. Results: The number of patients with total resolution of PE were 238 (80.1%), 220 (78.0%), and 166 (62.6%), in the nadroparin + rivaroxaban, nadroparin + dabigatra, and nadroparin + warfarin groups, respectively. (p = 0.001) The prevalence of DVT at the 3-month follow-up visit was 18 (6.1%), 14 (5.0%), and 11 (4.2%), in the aforementioned three groups, respectively. (p = 0.559) The NT-proBNP level (pg/ml) at the 3-month follow-up visit was 122.5 (97.4-158.9), 131.7 (102.2-166.3), and 357.8 (275.4-433.2) in the three groups, respectively. (p = 0.001) The D-dimer level (ng/ml) at the 3-month follow-up visit was 387.3 (310.9-465.2), 432.5 (382.4-489.6), and 854.0 (721.5-993.7) in the three groups, respectively (p < 0.001). The number of patients with major bleeding events was 3(0.9%), 6(1.8%), and 18 (5.5%) in the three groups, respectively (p < 0.001). Conclusion: The regimen of sequential subcutaneous nadroparin at body-weight adjusted dose for a week followed by oral rivaroxaban at a dose of 20 mg once daily for 3 months is effective and safe in the initial treatment of patients with acute pulmonary embolism.

BACKGROUND: Extended antithrombotic treatment is recommended for secondary prevention of unprovoked venous thromboembolism (VTE), however, there is no consensus on which antithrombotic strategy is preferable.
OBJECTIVE: To compare the efficacy and safety of different antithrombotic strategies for secondary prevention unprovoked VTE.
METHODS: Cochrane Central Register of Controlled Trials, Embase, and MEDLINE were systematically searched from inception to 22 July 2020 for randomized controlled trials (RCTs) that compared the efficacy and/or safety of extended antithrombotic strategies including aspirin, warfarin and direct oral anticoagulants (DOACs) for secondary prevention of unprovoked VTE. The primary outcome was risk of major bleeding and the secondary outcomes were risks of recurrent VTE and all-cause death. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using pairwise and network meta-analysis with random effect. Possible ranking of extended antithrombotic strategies was plotted using the surface under the cumulative ranking curve and mean ranks.
RESULTS: Seventeen RCTs met the inclusion criteria, and meta-analysis results showed that warfarin was associated with significantly higher risk of major bleeding than placebo/observation (OR 2.71, 95% CI 1.32-5.55) or apixaban (OR 10.65, 95% CI 1.06-107.13). Apixaban and low-apixaban were the top two strategies according to the ranking of major bleeding. Warfarin (OR 0.25, 95%CI 0.13-0.49), rivaroxaban (OR 0.18, 95%CI 0.03-0.90), apixaban (OR 0.18, 95%CI 0.04-0.85) and low-apixaban (OR 0.18, 95%CI 0.04-0.82) were related to significantly lower risk than placebo/observation; edoxaban was non-inferior to warfarin on the risk of recurrent VTE. Furthermore, apixaban was linked with significantly lower risk of all-cause death than placebo/observation (OR 0.29, 95% CI 0.09-0.88).
CONCLUSIONS: Apixaban showed superiority to other antithrombotic strategies on major bleeding and all-cause death for secondary prevention of unprovoked VTE. Further studies are warranted owing to the limited number of studies and positive cases.Key messagesAll antithrombotic strategies including warfarin, DOACs and aspirin were superior to placebo/observation on recurrent VTE for secondary prevention of unprovoked VTE.Apixaban demonstrated lower risk of major bleeding than warfarin, and lower risk of all-cause death than placebo/observation.Further research about the efficacy and safety of antithrombotic treatments for secondary prevention of unprovoked VTE is warranted.

Background: The drug therapy of venous thromboembolism (VTE) presents a significant economic burden to the health-care system in low- and middle-income countries. To understand which anticoagulation therapy is most cost-effective for clinical decision-making , the cost-effectiveness of apixaban (API) versus rivaroxaban (RIV), dabigatran (DAB), and low molecular weight heparin (LMWH), followed by vitamin K antagonist (VKA), in the treatment of VTE in China was assessed. Methods: To access the quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs), a long-term cost-effectiveness analysis was constructed using a Markov model with 5 health states. The Markov model was developed using patient data collected from the Xijing Hospital from January 1, 2016 to January 1, 2021. The time horizon was set at 30 years, and a 6-month cycle length was used in the model. Costs and ICERs were reported in 2020 U.S. dollars. One-way sensitivity analysis and probabilistic sensitivity analysis (PSA) were used to test the uncertainties. A Chinese health-care system perspective was used. Results: In the base case, the data of 231 VTE patients were calculated in the base case analysis retrospectively. The RIV group resulted in a mean VTE attributable to 95% effective treatment. API, DAB, and VKA have a negative ICER (-187017.543, -284,674.922, and -9,283.339, respectively) and were absolutely dominated. The Markov model results confirmed this observation. The ICER of the API and RIV was negative (-216176.977), which belongs to the absolute inferiority scheme, and the ICER value of the DAB and VKA versus RIV was positive (110,577.872 and 836,846.343). Since the ICER of DAB and VKA exceeds the threshold, RIV therapy was likely to be the best choice for the treatment of VTE within the acceptable threshold range. The results of the sensitivity analysis revealed that the model output varied mostly with the cost in the DAB on-treatment therapy. In a probabilistic sensitivity analysis of 1,000 patients for 30 years, RIV has 100% probability of being cost-effective compared with other regimens when the WTP is $10973 per QALY. When WTP exceeded $148,000, DAB was more cost-effective than RIV. Conclusions: Compared with LMWH + VKA and API, the results proved that RIV may be the most cost-effective treatment for VTE patients in China. Our findings could be helpful for physicians in clinical decision-making to select the appropriate treatment option for VTE.

Direct oral anticoagulants are widely used to treat and prevent thromboembolic disorders. With rising clinical application, monitoring concentrations of direct oral anticoagulants are necessary in certain clinical conditions. A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry method was developed for the simultaneous determination of dabigatran etexilate, dabigatran, rivaroxaban, edoxaban, and apixaban, in human plasma. Protein precipitation with methanol was performed for sample preparation. The direct oral anticoagulants and internal standards were separated under gradient conditions using a C18 column, at an analytical run time of 8 min. The mobile phase was composed of 0.1% (v/v) formic acid in water (solvent A) and 0.1% (v/v) formic acid in acetonitrile (solvent B) at a flow rate of 0.3 mL/min. Mass detection was performed in multiple reaction monitoring using positive ionization mode. The method was validated over a range of 1.0-500 ng/mL for dabigatran etexilate, 0.1-500 ng/mL for dabigatran, and 0.5-500 ng/mL for edoxaban, rivaroxaban, and apixaban. The method detection limits of five analytes were in the range of 0.05-0.5 ng/mL. The lower limits of quantification of five analytes ranged from 0.1 to 1 ng/mL. The linearity (r2 values) was higher than 0.997. The accuracy of the low, medium, and high quality control samples were between 85.9 and 114%, and intra- and inter-day precision were below 9.47%. This validated method was successfully used to determine the plasma concentrations of rivaroxaban in 32 patients, and of dabigatran etexilate and dabigatran in 1 patient.

OBJECTIVE: To date, the optimal treatment for portal vein thrombosis (PVT) in cirrhotic patients has not been established in guidelines or consensus. We conducted a systematic review and meta-analysis to evaluate the effect of anticoagulation therapy in patients with cirrhosis and PVT.
METHODS: PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched (until 31st October 2020) for studies evaluating the effect of anticoagulation therapy on treating PVT in patients with cirrhosis. Odds ratios (ORs) and their 95% confidence intervals (CIs) were pooled using the Mantel-Haenszel method.
RESULTS: A total of 13 studies were included in the analysis, comprising 6005 patients. Of these, three were prospective cohort studies, nine were retrospective cohort studies and one was case-control study. Compared to no treatment, anticoagulation therapy was associated with higher rates of PVT recanalization (OR 4.29; 95% CI 3.01-6.13). Anticoagulation therapy demonstrated a significant 74% reduction in PVT extension compared to no treatment (OR 0.26; 95% CI 0.14-0.49). Anticoagulation therapy was associated with a nonsignificantly lower risk of death (OR 0.53; 95% CI 0.20-1.40). However, anticoagulation therapy was associated with slightly higher risk of bleeding compared to no treatment (OR 1.16; 95% CI 1.02-1.32).
CONCLUSIONS: In cirrhotic patients with PVT, anticoagulation therapy helps increase rate of PVT recanalization and improve survival, but may also carry higher risks of bleeding compared to no treatment. Our findings support the use of anticoagulation in cirrhotic patients with PVT.

Diabetes mellitus is a common comorbidity of atrial fibrillation (AF), which can complicate the management of AF. The pharmacology of oral anticoagulants (OACs) have been implicated in pathogenesis of diabetes, but the relationship between different OACs and risk of diabetes remains unexamined. This study aimed to evaluate the risk of diabetes with use of different OACs in AF patients.
Population-based retrospective cohort study using an electronic healthcare database managed by the Hong Kong Hospital Authority. Patients newly diagnosed with AF from 2014 through 2018 and prescribed OACs were included and followed till December 31, 2019. Inverse probability of treatment weighting based on the propensity score (PS) is used to address potential bias due to nonrandomized allocation of treatment. The risks ofdiabetes were compared between different new OAC users using propensity score-weighted cumulative incidence differences (CID).
There were 13,688 new users of OACs (warfarin: n = 3454; apixaban: n = 3335; dabigatran: n = 4210; rivaroxaban: n = 2689). The mean age was 75.0 (SD, 11.2), and 6,550 (47.9%) were women. After a median follow-up of 0.93 years (interquartile range, 0.21-1.92 years), 698 incident diabetes cases were observed. In Cox-regression analysis, dabigatran use was significantly associated with reduced risk of diabetes when compared with warfarin use [HR 0.69 (95% CI 0.56-0.86; P < 0.001)], with statistically insignificant associations observed for use of apixaban and rivaroxaban. The corresponding adjusted CIDs at 2 years after treatment with apixaban, dabigatran, and rivaroxaban users when compared with warfarin were - 2.06% (95% CI - 4.08 to 0.16%); - 3.06% (95% CI - 4.79 to - 1.15%); and - 1.8% (- 3.62 to 0.23%). In head-to-head comparisons between women DOAC users, dabigatran was also associated with a lower risk of diabetes when compared with apixaban and rivaroxaban.
Among adults with AF receiving OACs, the use of dabigatran had the lowest risk of diabetes when compared with warfarin use.

BACKGROUND: The study of pharmacogenomics presents the possibility of individualised optimisation of drug therapy tailored to each patients\' unique physiological traits. Both antiplatelet and anticoagulant drugs play a key role in the management of cardiovascular disease. Despite their importance, there is a substantial volume of literature to suggest marked person-to-person variability in their effect. Areas covered: This article reviews the data available for the genetic cause for this inter-patient variability of antiplatelet and anticoagulant drugs. The genetic basis for traditional antiplatelets (i.e. aspirin) is compared with the newly available antiplatelet medicines (clopidogrel, prasugrel and ticagrelor). Similarly, the pharmacogenetics of warfarin is compared with the newer direct oral anticoagulants (DOACs) in detail. Expert Opinion: We identify strengths and weaknesses in the research thus far; including shortcomings in trial design and a review of newer analytical techniques. The direction of this research and its real-world implications are discussed.