Dataset Information

Differential benefit risk assessment of DOACs in the treatment of venous thromboembolism: focus on dabigatran.

ABSTRACT: Venous thromboembolism includes deep vein thrombosis and pulmonary embolism and is a serious medical condition that requires anticoagulation as part of treatment. Currently, standard therapy consists of parenteral anticoagulation followed by a vitamin K antagonist (VKA). The pharmacokinetic and pharmacodynamic profiles of the direct oral anticoagulants (DOACs) differ from VKAs, which overcome some of the limitations of VKAs and have practical implications on their use in clinical situations. Dabigatran is a prodrug that undergoes primarily renal elimination and does not affect cytochrome P450 enzymes. Assays to quantify the degree of anticoagulation and the therapeutic level of DOAC are either unavailable for routine clinical use or require specific calibration. Routine monitoring of DOACs is not recommended at this time. Dabigatran, rivaroxaban, and apixaban are DOACs that have been studied for treatment of venous thromboembolism. Clinical trials comparing DOACs with standard therapy have shown them to be non-inferior for acute and extended therapy. Each DOAC has a unique benefit and harm profile that should be considered prior to use. The distinguishing characteristics of dabigatran include a requirement of parenteral anticoagulation prior to acute treatment, clinical trial results comparing it with a VKA for extended treatment, association with upper gastrointestinal adverse events, and increased risk of gastrointestinal bleed. Rivaroxaban is the only DOAC that has once-daily dosing while apixaban is the only DOAC that has lower risk of overall, major, and gastrointestinal bleeding compared with VKA. A common drawback of DOACs is the lack of an available reversal agent. Clinical trials of reversal agents are ongoing and one application for approval has been submitted to the US Food and Drug Administration. Selection of a DOAC for acute and extended therapy requires a shared decision-making approach that includes a comprehensive assessment of the benefits and harms of each individual DOAC.

SUBMITTER: Leung TS

PROVIDER: S-EPMC4501448 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Differential benefit risk assessment of DOACs in the treatment of venous thromboembolism: focus on dabigatran.

Leung Timothy S TS Law Ernest H EH

Drug design, development and therapy 20150709

Venous thromboembolism includes deep vein thrombosis and pulmonary embolism and is a serious medical condition that requires anticoagulation as part of treatment. Currently, standard therapy consists of parenteral anticoagulation followed by a vitamin K antagonist (VKA). The pharmacokinetic and pharmacodynamic profiles of the direct oral anticoagulants (DOACs) differ from VKAs, which overcome some of the limitations of VKAs and have practical implications on their use in clinical situations. Dab ...[more]

PMID: 26185422

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Project description:In the phase 2b/3 DIVERSITY trial, 3 months treatment with dabigatran was noninferior to standard of care (SOC) for acute venous thromboembolism (VTE) in children. In a single-arm, phase 3, secondary VTE prevention study, up to 12 months dabigatran use was associated with favorable safety. Dabigatran is approved by the European Medicines Agency and US Food and Drug Administration for pediatric indications. We assessed primary composite efficacy (complete thrombus resolution and freedom from VTE recurrence/VTE-related death) in subgroups with thrombophilia vs those with negative/unknown thrombophilia status in the DIVERSITY trial and safety in both studies. Thrombophilia types were similar between the DIVERSITY trial (total population) and secondary prevention studies: factor V Leiden, 42% vs 33%; prothrombin mutation (G20210A), 19% vs 17%; antithrombin deficiency, 15% vs 20%; protein C/S deficiency, 23% vs 25%; and antiphospholipid antibodies, 18% vs 20% of patients, respectively. In DIVERSITY, 36% and 22% of thrombophilia subgroup patients treated with dabigatran and SOC, respectively, met the primary end point (Mantel-Haenszel-weighted rate difference, -0.135; 95% confidence interval, -0.36 to 0.08; noninferiority P = .0014); comparable to the total DIVERSITY trial population (46% vs 42%) showing dabigatran noninferiority to SOC. Within this subgroup, numerically fewer patients experienced VTE recurrence or progression of index thrombus in the dabigatran treatment group vs SOC. In the secondary prevention study, VTE recurrence at 12 months occurred in 2.8% of patients with thrombophilia vs 0% with negative/unknown thrombophilia. Safety profiles were consistent with those reported previously. Although they should be interpreted with caution, these exploratory findings suggest dabigatran could be an appropriate long-term anticoagulant for children with thrombophilia. These trials were registered at www.clinicaltrials.gov as #NCT01895777 and #NCT02197416.

Project description:BackgroundDabigatran was proven to have similar effect on the prevention of recurrence of venous thromboembolism (VTE) and a lower risk of bleeding compared to vitamin K antagonists (VKA). The aim of this study is to assess the cost-effectiveness (CE) of dabigatran for the treatment and secondary prevention in patients with VTE compared to VKAs in the Dutch setting.MethodsPreviously published Markov model was modified and updated to assess the CE of dabigatran and VKAs for the treatment and secondary prevention in patients with VTE from a societal perspective in the base-case analysis. The model was populated with efficacy and safety data from major dabigatran trials (i.e. RE-COVER, RECOVER II, RE-MEDY and RE-SONATE), Dutch specific costs, and utilities derived from dabigatran trials or other published literature. Univariate, probabilistic sensitivity and a number of scenario analyses evaluating various decision-analytic settings (e.g. the perspective of analysis, use of anticoagulants only for treatment or only for secondary prevention, or comparison to no treatment) were tested on the incremental cost-effectiveness ratio (ICER).ResultsIn the base-case scenario, patients on dabigatran gained an additional 0.034 quality adjusted life year (QALY) while saving €1,598. Results of univariate sensitivity analysis were quite robust. The probability that dabigatran is cost-effective at a willingness-to-pay threshold of €20,000/QALY was 98.1%. From the perspective of healthcare provider, extended anticoagulation with dabigatran compared to VKAs was estimated at €2,158 per QALY gained. The ICER for anticoagulation versus no treatment in patients with equipoise risk of recurrent VTE was estimated at €33,379 per QALY gained. Other scenarios showed dabigatran was cost-saving.ConclusionFrom a societal perspective, dabigatran is likely to be a cost-effective or even cost-saving strategy for treatment and secondary prevention of VTE compared to VKAs in the Netherlands.

Project description:AimTo characterise venous thromboembolism (VTE) in gastrointestinal cancer and assess the clinical utility of risk stratification scoring.MethodsWe performed a retrospective analysis using electronic patient records of 910 gastro-oesophageal (GO) cancer and 1299 colorectal cancer (CRC) patients referred to a tertiary cancer centre to identify the incidence of VTE, its relationship to chemotherapy and impact on survival. VTE risk scores were calculated using the Khorana index. Patients were classified as low risk (0 points), intermediate risk (1 to 2 points) or high risk (3 points). Data was analysed to determine the sensitivity of the Khorana score to predict VTE.ResultsThe incidence of VTE was 8.9% for CRC patients and 9.7% for GO cancer patients. Pulmonary emboli (PE) were more common in advanced than in localised CRC (50% vs 21% of events respectively) and lower limb deep vein thrombosis (DVT) were more common in localised than in advanced CRC (62% vs 39% of events respectively). The median time to VTE from cancer diagnosis was 8.3 mo for CRC patients compared to 6.7 mo in GO cancer. In localised CRC median time to VTE was 7.1 mo compared with 10.1 mo in advanced CRC. In contrast in GO cancer, the median time to VTE was 12.5 mo in localised disease and 6.8 mo in advanced disease. No survival difference was seen between patients with and without VTE in this cohort. The majority of patients with CRC in whom VTE was diagnosed had low or intermediate Khorana risk score (94% for localised and 97% in advanced CRC). In GO cancer, all patients scored either intermediate or high risk due to the primary site demonstrating a limitation of the risk assessment score in discriminating high and low risk patients with GO cancers. Additional risk factors were identified in this cohort including surgery, chemotherapy or hospital admission. Overall, 81% of patients with CRC and 77% of patients with GO cancer had one or more of these factors within 4 wk prior to diagnosis VTE. These should be factored into clinical risk assessment scores.ConclusionThe Khorana score has low sensitivity for thrombotic events in CRC and cannot discriminate low risk patients in high risk cancer sites such as GO cancer.

Dataset Information

Differential benefit risk assessment of DOACs in the treatment of venous thromboembolism: focus on dabigatran.

Publications

Differential benefit risk assessment of DOACs in the treatment of venous thromboembolism: focus on dabigatran.

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