Dataset Information

Optimal delay time to initiate anticoagulation after ischemic stroke in atrial fibrillation (START): Methodology of a pragmatic, response-adaptive, prospective randomized clinical trial.

ABSTRACT: RATIONALE:An estimated 15% of all strokes are associated with untreated atrial fibrillation. Long-term secondary stroke prevention in atrial fibrillation is anticoagulation, increasingly with non-vitamin K oral anticoagulants. The optimal time to initiate anticoagulation following an atrial fibrillation-related stroke that balances hemorrhagic conversion with recurrent stroke is not yet known. AIMS:To determine if there is an optimal delay time to initiate anticoagulation after atrial fibrillation-related stroke that optimizes the composite outcome of hemorrhagic conversion and recurrent ischemic stroke. SAMPLE SIZE ESTIMATES:The study will enroll 1500 total subjects split between a mild to moderate stroke cohort (1000) and a severe stroke cohort (500). METHODS AND DESIGN:This study is a multi-center, prospective, randomized, pragmatic, adaptive trial that randomizes subjects to four arms of time to start of anticoagulation. The four arms for mild to moderate stroke are: Day 3, Day 6, Day 10, and Day 14. The time intervals for severe stroke are: Day 6, Day 10, Day 14, and Day 21. Allocation involves a response adaptive randomization via interim analyses to favor the arms that have a better risk-benefit profile. STUDY OUTCOMES:The primary outcome event is the composite occurrence of an ischemic or hemorrhagic event within 30 days of the index stroke. Secondary outcomes are also collected at 30 and 90 days. DISCUSSION:The optimal timing of direct oral anticoagulants post-ischemic stroke requires prospective randomized testing. A pragmatically designed trial with adaptive allocation and randomization to multiple time intervals such as the START trial is best suited to answer this question in order to directly inform current practice on this question.

SUBMITTER: King BT

PROVIDER: S-EPMC7401695 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Optimal delay time to initiate anticoagulation after ischemic stroke in atrial fibrillation (START): Methodology of a pragmatic, response-adaptive, prospective randomized clinical trial.

King Benjamin T BT Lawrence Patrick D PD Milling Truman J TJ Warach Steven J SJ

International journal of stroke : official journal of the International Stroke Society 20190818 9

<h4>Rationale</h4>An estimated 15% of all strokes are associated with untreated atrial fibrillation. Long-term secondary stroke prevention in atrial fibrillation is anticoagulation, increasingly with non-vitamin K oral anticoagulants. The optimal time to initiate anticoagulation following an atrial fibrillation-related stroke that balances hemorrhagic conversion with recurrent stroke is not yet known.<h4>Aims</h4>To determine if there is an optimal delay time to initiate anticoagulation after at ...[more]

PMID: 31423922

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Project description:It is uncertain whether bridging anticoagulation is necessary for patients with atrial fibrillation who need an interruption in warfarin treatment for an elective operation or other elective invasive procedure. We hypothesized that forgoing bridging anticoagulation would be noninferior to bridging with low-molecular-weight heparin for the prevention of perioperative arterial thromboembolism and would be superior to bridging with respect to major bleeding.We performed a randomized, double-blind, placebo-controlled trial in which, after perioperative interruption of warfarin therapy, patients were randomly assigned to receive bridging anticoagulation therapy with low-molecular-weight heparin (100 IU of dalteparin per kilogram of body weight) or matching placebo administered subcutaneously twice daily, from 3 days before the procedure until 24 hours before the procedure and then for 5 to 10 days after the procedure. Warfarin treatment was stopped 5 days before the procedure and was resumed within 24 hours after the procedure. Follow-up of patients continued for 30 days after the procedure. The primary outcomes were arterial thromboembolism (stroke, systemic embolism, or transient ischemic attack) and major bleeding.In total, 1884 patients were enrolled, with 950 assigned to receive no bridging therapy and 934 assigned to receive bridging therapy. The incidence of arterial thromboembolism was 0.4% in the no-bridging group and 0.3% in the bridging group (risk difference, 0.1 percentage points; 95% confidence interval [CI], -0.6 to 0.8; P=0.01 for noninferiority). The incidence of major bleeding was 1.3% in the no-bridging group and 3.2% in the bridging group (relative risk, 0.41; 95% CI, 0.20 to 0.78; P=0.005 for superiority).In patients with atrial fibrillation who had warfarin treatment interrupted for an elective operation or other elective invasive procedure, forgoing bridging anticoagulation was noninferior to perioperative bridging with low-molecular-weight heparin for the prevention of arterial thromboembolism and decreased the risk of major bleeding. (Funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health; BRIDGE ClinicalTrials.gov number, NCT00786474.).

Project description:Three target-specific oral anticoagulants (TSOACs)-dabigatran, rivaroxaban, and apixaban-have been approved by the FDA to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; however, no agents are currently approved to reverse the anticoagulant effects of these TSOACs in cases of active bleeding. This review discusses the benefits and risks of these TSOACs from a clinician's perspective, with a focus on the interruption of treatment for either elective or emergent surgery, monitoring, and reversal of anticoagulation. Available coagulation assays are not ideal for monitoring the effects of TSOACs and do not provide reliable quantitative measurement of their anticoagulant effects. When necessary, activated partial thromboplastin time (aPTT) may provide qualitative information on dabigatran, and prothrombin time (PT) may provide qualitative assessment of the presence of the factor Xa inhibitors, rivaroxaban and apixaban. Current recommendations for reversal of TSOACs are based largely on limited and sometimes conflicting data from in vitro or in vivo animal models, and clinical experience with these recommendations is also limited. Methods that have been investigated for effectiveness for reversal of the pharmacodynamic effects of the TSOACs include dialysis, activated charcoal, prothrombin complex concentrate (PCC), and recombinant activated factor VII. It is important to note that even within a class of anticoagulant drugs, compounds respond differently to reversal agents; therefore, recommendations for one agent should not be extrapolated to another, even if they are from the same therapeutic class. New antidotes are being explored, including a mouse monoclonal antibody to dabigatran; andexanet alfa, a potential universal factor Xa inhibitor reversal agent; and a synthetic small molecule (PER977) that may be effective for the reversal of factor Xa inhibitors and direct thrombin inhibitors. Given the short half-lives of TSOACs, watchful waiting, rather than reversal, may be the best approach in some circumstances.

Dataset Information

Optimal delay time to initiate anticoagulation after ischemic stroke in atrial fibrillation (START): Methodology of a pragmatic, response-adaptive, prospective randomized clinical trial.

Publications

Optimal delay time to initiate anticoagulation after ischemic stroke in atrial fibrillation (START): Methodology of a pragmatic, response-adaptive, prospective randomized clinical trial.

Similar Datasets

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