Effectiveness and Safety of Antithrombotic Medication in Patients With Atrial Fibrillation and Intracranial Hemorrhage: Systematic Review and Meta-Analysis

Background: For patients with atrial fibrillation who survive an intracranial hemorrhage (ICrH), the decision to offer oral anticoagulation (OAC) is challenging and necessitates balancing risk of thromboembolic events with risk of recurrent ICrH. Methods: This systematic review assesses the effectiveness and safety of OAC and/or antiplatelets in patients with atrial fibrillation with nontraumatic ICrH. Bibliographic databases CENTRAL, MEDLINE, EMBASE, and CINAHL were searched. Articles on adults with atrial fibrillation with spontaneous ICrH (intracerebral, subdural, and subarachnoid), receiving antithrombotic therapy for stroke prevention were eligible for inclusion. Results: Twenty articles (50 470 participants) included 2 randomized controlled trials (n=304)‚ 8 observational studies, 8 cohort studies, and 2 studies that meta-analyzed individual-level data from observational studies. OAC therapy was associated with a significant reduction in thromboembolic events (summary relative risk [sRR], 0.51 [95% CI, 0.30–0.86], heterogeneity I2=2%; P=0.39, n=5 studies) and all-cause mortality (sRR, 0.52 [95% CI, 0.38–0.71], heterogeneity I2=0; P=0.44, n=3 studies). OAC therapy was not associated with an increased risk of recurrent ICrH (sRR, 1.44 [95% CI, 0.38–5.46], heterogeneity I2=70%, P=0.02, n=5 studies). Nonvitamin K antagonist OACs were more effective at reducing the risk of thromboembolic events (sRR, 0.65 [95% CI, 0.44–0.97], heterogeneity I2=72%, P=0.03, n=3 studies) and were associated with a lower risk of recurrent ICrH (sRR, 0.52 [95% CI, 0.40–0.67], heterogeneity I2=0%, P=0.43, n=3 studies) than warfarin. Conclusions: In nontraumatic ICrH survivors with atrial fibrillation, OAC therapy is associated with a reduced risk of thromboembolic events and all-cause mortality without significantly increasing risk of recurrent ICrH. This finding is primarily based on observational data, and further larger randomized controlled trials are needed to corroborate or refute these findings.

A laboratory measurement used to determine the effects of oral anticoagulants on the body's blood clotting. Intracerebral haemorrhage Bleeding that occurs within the brain parenchyma.
Includes cerebellar, brain steam, and deep haemorrhages.

Intracranial haemorrhage
Bleeding that occurs within the skull. Includes intracerebral, subdural, subarachnoid, and epidural haemorrhages. Ischaemic stroke A stroke caused by blockage of blood supply in the brain.

Major vascular event
An injury that affects the vascular system, such as ischaemic stroke, myocardial infarction, sudden cardiac death. Modified Rankin scale A tool that assesses disability in an individual who has suffered a stroke.

Oral anticoagulation
Oral medication that prevents coagulation of the blood.

Systemic embolism
Presence of emboli (clots) in the arterial circulation. Thromboembolic event The formation of a blood clot that partially or fully obstructs venous or arterial blood flow. This includes conditions such as ischaemic stroke, systemic embolism, transient ischaemic attack).

Time in therapeutic range
The percentage of time in which a patient's international normalised ratio remains in the target range. Transient ischaemic attack Temporary disruption of blood supply in the brain. *Other definitions as used by the included papers were also accepted by the systematic review authors. 25. (rivaroxaban OR dabigatran OR edoxaban OR apixaban).ab 26. 1 OR 2 OR 3 27. 4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 28. 18 OR 19 OR 20 OR 21 OR 22 OR 23 OR 24 OR 25 29. 26 AND 27 AND 28 30. limit 29 to yr="2000-Current" 31. limit 30 to (adaptive clinical trial or clinical study or clinical trial, all or clinical trial or comparative study or controlled clinical trial or equivalence trial or evaluation study or multicenter study or observational study or pragmatic clinical trial or randomized controlled trial)    Table S2 27

INTRODUCTION
Rationale 3 Describe the rationale for the review in the context of existing knowledge. 5 Objectives 4 Provide an explicit statement of the objective(s) or question(s) the review addresses. 5

METHODS
Eligibility criteria 5 Specify the inclusion and exclusion criteria for the review and how studies were grouped for the syntheses. 5-6, 7 Information sources 6 Specify all databases, registers, websites, organisations, reference lists and other sources searched or consulted to identify studies. Specify the date when each source was last searched or consulted.
6 Search strategy 7 Present the full search strategies for all databases, registers and websites, including any filters and limits used. Supp. Table  S2 Selection process 8 Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.

6
Data collection process 9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.

6-7
Data items 10a List and define all outcomes for which data were sought. Specify whether all results that were compatible with each outcome domain in each study were sought (e.g. for all measures, time points, analyses), and if not, the methods used to decide which results to collect. 7, Table 1 10b List and define all other variables for which data were sought (e.g. participant and intervention characteristics, funding sources). Describe any assumptions made about any missing or unclear information. 7, Supp. Table S3 Study risk of bias assessment 11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.

7, 14
Effect measures 12 Specify for each outcome the effect measure(s) (e.g. risk ratio, mean difference) used in the synthesis or presentation of results. 7 Synthesis methods 13a Describe the processes used to decide which studies were eligible for each synthesis (e.g. tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).

Fig 1
13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions.

7
13c Describe any methods used to tabulate or visually display results of individual studies and syntheses. 13d Describe any methods used to synthesize results and provide a rationale for the choice(s). If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.

7
13e Describe any methods used to explore possible causes of heterogeneity among study results (e.g. subgroup analysis, meta-regression). 7, 13, Supp. Table S4 13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results. 13, Supp. Table S4 Reporting bias assessment 14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases). 7, 13 Certainty assessment 15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome. 7

Study selection
16a Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.
8, Fig 1   16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded.

OTHER INFORMATION
Registration and protocol 24a Provide registration information for the review, including register name and registration number, or state that the review was not registered. 5 24b Indicate where the review protocol can be accessed, or state that a protocol was not prepared. 5 24c Describe and explain any amendments to information provided at registration or in the protocol. N/A Support 25 Describe sources of financial or non-financial support for the review, and the role of the funders or sponsors in the review. 18 Competing interests 26 Declare any competing interests of review authors. 18 Availability of data, code and other materials 27 Report which of the following are publicly available and where they can be found: template data collection forms; data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review.