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Antithrombotic Treatment of Embolic Stroke of Undetermined Source: RE-SPECT ESUS Elderly and Renally Impaired Subgroups.

ABSTRACT: Background and Purpose- The RE-SPECT ESUS trial (Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate Versus Acetylsalicylic Acid in Patients With Embolic Stroke of Undetermined Source) tested the hypothesis that dabigatran would be superior to aspirin for the prevention of recurrent stroke in patients with embolic stroke of undetermined source. This exploratory subgroup analysis investigates the impact of age, renal function (both predefined), and dabigatran dose (post hoc) on the rates of recurrent stroke and major bleeding. Methods- RE-SPECT ESUS was a multicenter, randomized, double-blind trial of dabigatran 150 or 110 mg (for patients aged ?75 years and/or with creatinine clearance 30 to <50 mL/minute) twice daily compared with aspirin 100 mg once daily. The primary outcome was recurrent stroke. Results- The trial, which enrolled 5390 patients from December 2014 to January 2018, did not demonstrate superiority of dabigatran versus aspirin for prevention of recurrent stroke in patients with embolic stroke of undetermined source. However, among the population qualifying for the lower dabigatran dose, the rate of recurrent stroke was reduced with dabigatran versus aspirin (7.4% versus 13.0%; hazard ratio, 0.57 [95% CI, 0.39-0.82]; interaction P=0.01). This was driven mainly by the subgroup aged ?75 years (7.8% versus 12.4%; hazard ratio, 0.63 [95% CI, 0.43-0.94]; interaction P=0.10). Stroke rates tended to be lower with dabigatran versus aspirin with declining renal function. Risks for major bleeding were similar between treatments, irrespective of renal function, but with a trend for lower bleeding rates with dabigatran versus aspirin in older patients. Conclusions- In subgroup analyses of RE-SPECT ESUS, dabigatran reduced the rate of recurrent stroke compared with aspirin in patients qualifying for the lower dose of dabigatran. These results are hypothesis-generating. Aspirin remains the standard antithrombotic treatment for patients with embolic stroke of undetermined source. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02239120.

SUBMITTER: Diener HC

PROVIDER: S-EPMC7379165 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Antithrombotic Treatment of Embolic Stroke of Undetermined Source: RE-SPECT ESUS Elderly and Renally Impaired Subgroups.

Diener Hans-Christoph HC Sacco Ralph L RL Easton J Donald JD Granger Christopher B CB Bar Michal M Bernstein Richard A RA Brainin Michael M Brueckmann Martina M Cronin Lisa L Donnan Geoffrey G Gdovinová Zuzana Z Grauer Claudia C Kleine Eva E Kleinig Timothy J TJ Lyrer Philippe P Martins Sheila S Meyerhoff Juliane J Milling Truman T Pfeilschifter Waltraud W Poli Sven S Reif Michal M Rose David Z DZ Šaňák Daniel D Schäbitz Wolf-Rüdiger WR

Stroke 20200514 6

Background and Purpose- The RE-SPECT ESUS trial (Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate Versus Acetylsalicylic Acid in Patients With Embolic Stroke of Undetermined Source) tested the hypothesis that dabigatran would be superior to aspirin for the prevention of recurrent stroke in patients with embolic stroke of undetermined source. This exploratory subgroup analysis investigates the ...[more]

PMID: 32404035

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Project description:INTRODUCTION:So far there is no uniform, commonly accepted diagnostic and therapeutic algorithm for patients with embolic stroke of undetermined source (ESUS). Recent clinical trials on secondary stroke prevention in ESUS did not support the use of oral anticoagulation. As ESUS comprises heterogeneous subgroups including a wide age-range, concomitant patent foramen ovale (PFO), and variable probability for atrial fibrillation (AF), an individualised approach is urgently needed. This prospective registry study aims to provide initial data towards an individual, structured diagnostic and therapeutic approach in ESUS patients. METHODS AND ANALYSIS:The open-label, investigator-initiated, prospective, single-centre, observational registry study (Catch-up-ESUS) started in 01/2018. Consecutive ESUS patients ?18 years who give informed consent are included and will be followed up for 3?years. Stratified by age <60?or ?60 years, the patients are processed following a standardised diagnostic and treatment algorithm with an interdisciplinary design involving neurologists and cardiologists. Depending on the strata, patients receive a transesophageal echocardiogram; all patients receive an implantable cardiac monitor. Patients <60 years with PFO and without evidence of concomitant AF are planned for PFO closure within 6 months after stroke. The current diagnostic and therapeutic workup of ESUS patients requires improvement by both standardisation and a more individualised approach. Catch-up-ESUS will provide important data with respect to AF detection and PFO closure and will estimate stratified stroke recurrence rates after ESUS. ETHICS AND DISSEMINATION:The study has been approved by the responsible ethics committee at the Ludwig Maximilian University, Munich, Germany (project number 17-685). Catch-Up-ESUS is conducted in accordance with the Declaration of Helsinki. All patients will have to give written informed consent or, if unable to give consent themselves, their legal guardian will have to provide written informed consent for their participation. The first observation period of the registry study is 1?year, followed by the first publication of the results including follow-up of the patients. Further publications will be considered according the predefined individual follow-up dates of the stroke patients up to 36 months. TRIAL REGISTRATION NUMBER:Clinicaltrialsregister.gov registry (NCT03820375).

Project description:BACKGROUND:Patent foramen ovale (PFO) is a contributor to embolic stroke of undetermined source (ESUS). Subgroup analyses from previous studies suggest that anticoagulation could reduce recurrent stroke compared with antiplatelet therapy. We hypothesised that anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, would reduce the risk of recurrent ischaemic stroke compared with aspirin among patients with PFO enrolled in the NAVIGATE ESUS trial. METHODS:NAVIGATE ESUS was a double-blinded, randomised, phase 3 trial done at 459 centres in 31 countries that assessed the efficacy and safety of rivaroxaban versus aspirin for secondary stroke prevention in patients with ESUS. For this prespecified subgroup analysis, cohorts with and without PFO were defined on the basis of transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE). The primary efficacy outcome was time to recurrent ischaemic stroke between treatment groups. The primary safety outcome was major bleeding, according to the criteria of the International Society of Thrombosis and Haemostasis. The primary analyses were based on the intention-to-treat population. Additionally, we did a systematic review and random-effects meta-analysis of studies in which patients with cryptogenic stroke and PFO were randomly assigned to receive anticoagulant or antiplatelet therapy. FINDINGS:Between Dec 23, 2014, and Sept 20, 2017, 7213 participants were enrolled and assigned to receive rivaroxaban (n=3609) or aspirin (n=3604). Patients were followed up for a mean of 11 months because of early trial termination. PFO was reported as present in 534 (7·4%) patients on the basis of either TTE or TOE. Patients with PFO assigned to receive aspirin had a recurrent ischaemic stroke rate of 4·8 events per 100 person-years compared with 2·6 events per 100 person-years in those treated with rivaroxaban. Among patients with known PFO, there was insufficient evidence to support a difference in risk of recurrent ischaemic stroke between rivaroxaban and aspirin (hazard ratio [HR] 0·54; 95% CI 0·22-1·36), and the risk was similar for those without known PFO (1·06; 0·84-1·33; pinteraction=0·18). The risks of major bleeding with rivaroxaban versus aspirin were similar in patients with PFO detected (HR 2·05; 95% CI 0·51-8·18) and in those without PFO detected (HR 2·82; 95% CI 1·69-4·70; pinteraction=0·68). The random-effects meta-analysis combined data from NAVIGATE ESUS with data from two previous trials (PICSS and CLOSE) and yielded a summary odds ratio of 0·48 (95% CI 0·24-0·96; p=0·04) for ischaemic stroke in favour of anticoagulation, without evidence of heterogeneity. INTERPRETATION:Among patients with ESUS who have PFO, anticoagulation might reduce the risk of recurrent stroke by about half, although substantial imprecision remains. Dedicated trials of anticoagulation versus antiplatelet therapy or PFO closure, or both, are warranted. FUNDING:Bayer and Janssen.

Dataset Information

Antithrombotic Treatment of Embolic Stroke of Undetermined Source: RE-SPECT ESUS Elderly and Renally Impaired Subgroups.

Publications

Antithrombotic Treatment of Embolic Stroke of Undetermined Source: RE-SPECT ESUS Elderly and Renally Impaired Subgroups.

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