Association of Oral Anticoagulation With Stroke in Atrial Fibrillation or Heart Failure

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Major bleeding defined as clinically overt bleeding accompanied by one or more of the following: a decrease in the haemoglobin level of 2g/dL or more over a 24 hour period, transfusion of 2 or more units of packed red cells, bleeding at a critical site (intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal), or fatal bleeding. WASPO (2007) Comparative frequency of combined endpoints comprising of death, thromboembolism, serious bleeding and withdrawal from the study.
Serious bleeding defined as intracranial haemorrhage, fall in haemoglobin by >2g/dL, need for blood transfusion.

BAFTA (2007)
First occurrence of fatal or nondisabling stroke (ischaemic or hemorrhagic), other intracranial hemorrhage, or clinically significant arterial embolism.
Major hemorrhage was defined as extracranial haemorrhage defined as a fatal haemorrhage, or one that resulted in the need for transfusion or surgery, or intracranial haemorrhage (including haemorrhagic stroke). Major bleeding was defined as any bleeding requiring transfusion of at least two units of red blood cells or equivalent of whole blood, or which was severe (severe bleeding was bleeding associated with any of the following: death, drop in haemoglobin of at least 50g/L, substantial hypotension with the need for inotropic agents, intraocular bleeding leading to substantial loss of vision, bleeding requiring surgical intervention (other than vascular site repair), symptomatic intracranial hemorrhage, or requirement for a transfusion of at least four units of blood Primary event(cerebral infarction) or death.
A major hemorrhage was defined as one that required a blood transfusion, an emergency procedure, or both to terminate bleeding or remove a hematoma or that led to admission to an intensive care unit. SPAF (1991) Primary event(ischaemic stroke or systemic emboli) or death.
Bleeding that involved the central nervous system, management requiring hospitalization with transfusion and/or surgery, or permanent residual impairment. CAFA (1991) First occurrence of any of the following: ischaemic stroke except lacunar, other systemic embolism or intracranial or fatal hemorrhage.
A major bleeding event was defined as any bleeding episode associated with 20g/L decrease or more in serum haemoglobin or requiring a blood transfusion or bleeding into a sensitive location such as the pericardium or retinal. AFASAK (1989) Stroke (ischaemic or hemorrhagic) or a systemic thromboembolic event.
Major bleeding was defined as requiring medical intervention.
All bleeding that led to presentation to an acute care facility or hospitalization was considered as major. This included fatal bleeding, symptomatic bleeding into a critical organ, bleeding into a surgical site requiring reoperation, and bleeding that led to hospitalization (including presentation to an acute care facility without an overnight stay). Commander HF (2018) Composite of death from any cause, myocardial infarction, or stroke.
Major bleeding is defined as overt bleeding associated with a decrease in haemoglobin level of at least 2g/dL, transfusion of two or more units of packed red cells or whole blood, a critical site (intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome or retroperitoneal), or a fatal outcome. WARCEF (2012) Composite end point of ischaemic stroke, intracerebral haemorrhage, or death from any cause.
Major hemorrhage was defined as intracerebral, epidural, subdural, subarachnoid, spinal intramedullary, or retinal haemorrhage; any other bleeding causing a decline in the haemoglobin level of more than 2 g per decilitre in 48 hours; or bleeding requiring transfusion of 2 or more units of whole blood, hospitalization, or surgical intervention. WATCH (2009) All-cause mortality, nonfatal MI and nonfatal stroke.
Major bleeding was defined as bleeding episodes leading to death or disability (including loss of neurological or special senses function), requiring surgical intervention, or associated with an acute decline of haemoglobin of greater of more than 2gm/dL or transfusion of more than 1 unit of packed red cells or whole blood. HELAS (2006) Non-fatal stroke, peripheral or pulmonary embolism, myocardial (re)infarction, re-hospitalisation, exacerbation of heart failure, or death from any cause. Not reported.
WASH (2004)  *Aspirin taken by 93.1% of all patients. †Only aspirin control arm was included in the analysis. ‡Only triflusal control arm was included in the analysis.
**Placebo group may take aspirin. † †Stratum 2 excluded from analysis as therapy evaluated was low dose anticoagulation versus aspirin. ‡ ‡ All values for follow-up are reported as mean with the exception of SPEAF, this follow-up value is reported as median as mean was not reported. 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.

INTRODUCTION
Rationale 3 Describe the rationale for the review in the context of what is already known.

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Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).

Protocol and registration
5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.
(PROSPERO identifier: CRD42020153013) Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.

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Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

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Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

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Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).

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Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

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Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. 8

Risk of bias in individual studies
12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

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Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means).

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Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I 2 ) for each meta-analysis.

European Society of Cardiology
Grade 1A recommendation for oral anticoagulation to prevent thromboembolism in those with a CHA2DS2-VASC ≥ 2 (2020) 1 .
Grade IIa recommendation for chronic cardiac syndrome in sinus rhythm at high stroke risk (IIb for moderate risk) to consider dual antiplatelet therapy or low dose rivaroxaban (2019) 45 .
Do not recommend anticoagulation in patients with heart failure with reduced ejection fraction in the absence of atrial fibrillation (level B) (2013) 8 .

The American College of Chest Physicians
Recommend anticoagulation for a three-month period following an anterior myocardial infarction and left ventricular thrombus or an ejection fraction of ≤40%. Grade 2C recommendation against anticoagulation for those with non-ischaemic LV dysfunction (2012)   eFigure II -Contour enhanced funnel plot for HFrEF trials, all stroke outcome eFigure II -Contour enhanced funnel plot for HFrEF trials, all stroke outcome. Different levels of statistical significance for studies are indicated by the shaded regions, detailed within the figure. The grey vertical line represents the summary estimate for oral anticoagulation and all stroke. eFigure III -Cross Tabulation Risk of Bias eFigure III was generated using the Cochrane Risk of Bias 2 tool. https://methods.cochrane.org/bias/resources/rob-2-revised-cochrane-risk-bias-tool-randomized-trials