Table 2 Characteristics of included SR/MA

Aguilar 2005 [49]

SR

To assess the efficacy and safety of long-term APT for primary prevention in stroke of patients with chronic non-valvular AF.

Studies n = 5, 1965 participants, mean age 70 years

Warfarin INR 2.8–4.2 vs ASA 75 mg/d vs placebo, ASA 125 mg/d vs placebo, warfarin INR 2–4.5 vs control and ASA 325 mg/d vs placebo

All strokes, ischaemic strokes, all disabling or fatal stroke, myocardial infarction, systemic emboli, all intracranial haemorrhage, major extracranial haemorrhage, vascular death and the composite of all stroke, myocardial infarction, vascular death and all-cause mortality

Aguilar 2007 [30]

SR

To characterize the relative effect of long-term oral anticoagulant treatment compared with antiplatelet therapy on major vascular events in patients with non-valvular AF and no history of stroke or TIA.

Studies n = 7, 9598 participants, mean age 64–75 years

Clopidogrel 75 mg/d + ASA 75-100 mg/d vs warfarin INR 2–3, ASA 75 mg/d vs warfarin INR 2.8–4.2 vs placebo, ASA 300 mg/d vs fixed-dose warfarin vs fixed-dose warfarin + ASA 300 mg/d vs adjusted-dose warfarin INR 2–3, ASA 100 mg/d vs fixed-dose VKA vs adjusted-dose VKA INR 2.6–3.5, triflusal 600 mg/d vs adjusted-dose VKA INR 2–3, ASA 150 mg/d vs warfarin INR 2.5–3.5 vs low-dose warfarin INR 1.1–1.6, ASA 325 mg/d vs warfarin INR 2–4.5, ASA 325 mg/d vs adjusted-dose warfarin INR 2–4.5

Primary outcome: all strokes; Secondary outcomes: ischaemic strokes, all disabling or fatal strokes, myocardial infarction, systemic emboli, all intracranial haemorrhages, major extracranial haemorrhages, vascular death, all-cause mortality

Andersen 2008 [43]

MA

To evaluate the efficacy of warfarin in preventing systemic embolism (embolism to limbs or viscera) in patients with AF

Studies n = 15, 16,058 participants, mean age 63.3–81.5 years

Warfarin vs placebo vs ASA 75 mg/d, warfarin vs placebo, warfarin vs ASA 325 mg/d, warfarin vs low-dose warfarin (INR 1.2–1.5) + ASA 325 mg/d, warfarin vs indobufen 200 mg/d, warfarin vs low-dose warfarin 1.25 mg/d, warfarin vs low-dose warfarin 1.25 mg/d vs low-dose warfarin + ASA 300 mg/d vs ASA 300 mg/d, warfarin vs ASA 150 mg/d vs low-dose warfarin (INR 1.1–1.6), warfarin vs low-dose warfarin (INR 1.5–2.1), warfarin vs ASA 150-160 mg/d, warfarin vs clopidogrel 75 mg/d + ASA 75-100 mg/d, warfarin vs ASA 300 mg/d, warfarin vs ASA 75 mg/d

Systemic embolism and major bleeding

Assiri 2013 [44]

MA

A mixed treatment comparison meta-analysis to evaluate direct and indirect treatment data including ASA, warfarin apixaban, dabigatran, edoxaban and rivaroxaban for the prevention of primary or secondary stroke in patients with AF

Studies n = 21, 80,906 participants, mean age 71 years

ASA vs warfarin vs placebo, ASA vs warfarin, warfarin vs placebo, ASA vs placebo, ASA + warfarin vs placebo, ASA + clopidogrel vs warfarin, dabigatran vs warfarin, ASA vs ASA + clopidogrel, edoxaban vs warfarin, apixaban vs warfarin, rivaroxaban vs warfarin

Any stroke or embolism, all-stroke, ischemic stroke, systemic embolism, vascular death, all-cause mortality, major and non-major bleeding, and intra-cranial haemorrhage

Baigent 2009 [28]

MA

To assess the benefits and risks in primary prevention; Identify risk factors for various outcomes in people in the primary prevention trials

Studies n = 6 primary prevention, 16 secondary prevention, 112,000 participants, subgroup ≥ 65 years

ASA 500 mg/d, ASA 325 mg/d vs placebo, ASA 75 mg/d vs warfarin vs placebo, ASA 75 mg/d vs placebo, ASA 100 mg/d vs control, ASA 100 mg/d vs placebo

Vascular events (myocardial infarction, stroke, death from vascular cause), major coronary event, any stroke, death from any cause, major extracranial bleeding

Cameron 2014 [46]

NMA

To examine the comparative efficacy and safety of antithrombotic treatments (apixaban, dabigatran, edoxaban, rivaroxaban and VKA at a standard adjusted dose (target international normalised ratio 2.0–3.0), ASA, ASA and clopidogrel) for non-valvular atrial fibrillation and among subpopulations

Studies n = 16, 82,314 participants, mean age 62–83, subgroup-analysis age ≥ 75 years

Dabigatran 150 mg twice daily vs dabigatran 110 mg twice daily vs adjusted-dose VKA, edoxaban 60 mg/d vs edoxaban 30 mg/d vs adjusted-dose VKA, ASA 100 mg/d + clopidogrel 75 mg/d vs adjusted-dose VKA, ASA 100 mg/d vs placebo, ASA 100 mg/d vs adjusted-dose VKA, adjusted-dose VKA vs placebo, ASA 100-300 mg/d vs placebo, ASA 100-300 mg/d vs adjusted-dose VKA, rivaroxaban 20 mg/d vs adjusted-dose VKA, apixaban 5 mg twice daily vs adjusted-dose VKA, dabigatran 150 mg twice daily 100-300 mg ASA vs adjusted-dose VKA, apixaban 2.5 mg twice daily vs apixaban 5 mg twice daily vs adjusted-dose VKA

Primary outcomes: all-cause stroke, systemic embolism, major bleeding

Cooper 2006 [42]

NMA

To identify different stroke prevention treatments for atrial fibrillation assessed in randomized controlled trials and to compare them within a single evidence synthesis framework

Studies n = 19, 17,833 participants, mean age 64–80.5 years

Warfarin INR 2–3 vs ximelegatran 72 mg/d, warfarin 1.25 mg/d + ASA 75 mg/d vs control, warfarin INR 2.2–3.5 vs warfarin INR 1.5–2.1, warfarin INR 1.2–1.5 vs control, warfarin prothrombin-time 1.2–1.5 vs placebo, warfarin INR 2–3 vs placebo, warfarin vs ASA 300 mg/d vs placebo, ASA 325 mg/d vs warfarin vs placebo, warfarin 1.25 mg/d vs warfarin 1.25 mg/d + ASA 300 mg/d vs ASA 300 mg/d vs warfarin INR 2.3, coumarin INR 2.5–3.5 vs coumarin INR 1.1–1.6 vs ASA 150 mg/d, indobufen 100 or 200 mg/d vs warfarin INR 2–3.5, warfarin INR 1.25 mg/d vs warfarin INR 2–3, warfarin INR 1.2–1.5 + ASA 325 mg/d vs warfarin INR 2–3, ASA 125 mg/d vs ASA 125 mg/d on alternate days vs control

Primary outcome: ischaemic stroke, major or fatal bleeding

Coleman 2012 [56]

MA

To identify the propensity difference between various AP and anticoagulation for stroke prevention in patients with AF to cause MGIB

Studies n = 16, 42,983 participants, mean age 65–75 years

Clopidogrel 75 mg/d + ASA 75-100 mg/d, ASA 75-100 mg/d vs dabigatran 110 mg BID vs dabigatran 150 mg BID vs adjusted-dose warfarin, ASA 150-200 mg/d vs control, adjusted-dose warfarin vs ximelagatran 36 mg BID, triflusal 600 mg/d vs adjusted-dose VKA vs adjusted-dose VKA + ASA 100 mg/d, adjusted-dose VKA + placebo vs adjusted-dose VKA + ASA 100 mg/d, adjusted-dose warfarin vs low-dose warfarin, adjusted-dose VKA vs low-dose VKA vs ASA 150 mg/d, adjusted-dose warfarin vs low-dose warfarin vs ASA 300 mg/d vs low-dose warfarin + ASA 300 mg/d, indobufen 200 mg BID vs adjusted-dose warfarin, low-dose warfarin + ASA 325 mg/d, adjusted-dose warfarin (INR 2–3 or 2–4.5) vs ASA 325 mg/d, adjusted-dose VKA vs ASA 300 mg/d vs placebo, adjusted-dose warfarin vs placebo, warfarin vs no treatment, adjusted-dose warfarin vs ASA 75 mg/d vs placebo

Major gastrointestinal bleeding

Connolly 2013 [61]

MA

To characterize the risk of subdural hematoma associated with antiplatelet therapy

Studies n = 9, 97,254 participants, mean age 57 years, subgroup ≥ 70 years

ASA 325 mg/d vs placebo, ASA 75 mg/d vs placebo, ASA 150-200 mg/d vs control, ASA 81-100 mg/d vs control, ASA 325 mg every other day vs placebo, ASA 50 mg/d + dipyridamol 400 mg/d vs placebo, ASA 75 mg/d vs placebo, ASA 100 mg every other day vs placebo, ASA 100 mg/d vs placebo

Subdural hematomas, intracerebral haemorrhage

Dogliotti 2014 [41]

NMA

To synthesise the evidence from trials using a multiple treatment comparison methods thereby permitting a broader comparison across multiple therapies

Studies n = 20, 79,808 participants, mean age 64–83

Adjusted-dose warfarin vs ASA vs placebo, adjusted-dose warfarin vs placebo, adjusted-dose VKA vs ASA vs placebo, adjusted-dose warfarin vs ASA, adjusted-dose coumarin vs ASA, ASA vs no treatment, adjusted-dose warfarin vs ASA + clopidogrel, ASA vs no treatment, clopidogrel + ASA vs ASA, adjusted-dose warfarin vs ASA, dabigatran 110 mg twice daily vs dabigatran 150 mg twice daily vs adjusted-dose warfarin, apixaban vs adjusted-dose warfarin, apixaban vs ASA, adjusted-dose warfarin vs rivaroxaban

Primary outcomes: stroke, composite of ischaemic stroke or systemic embolism, death from any cause, major bleeding

Gandhi 2015 [54]

MA

To compare Dual-antiplatelet Therapy to Mono-antiplatelet Therapy after Transcatheter Aortic Valve Implantation

Studies n = 4, 640 participants, mean age 82.2 years

ASA 80 mg/d + clopidogrel 75 mg/d or ticlopidin 500 mg BID vs ASA 75-160 mg/d, ASA 75 mg/d + clopidogrel 75 mg/d (300 mg loading-dose) vs ASA 75 mg/d or clopidogrel 75 mg/d, ASA 75 mg/d + clopidogrel 75 mg/d (300 mg loading-dose) vs ASA 75 mg/d (300 mg loading-dose), ASA 100 mg/d + clopidogrel 75 mg/d (300 mg loading-dose) vs ASA 100 mg/d

Primary outcome: combined end point of 30-day stroke, spontaneous myocardial infarction, all-cause-mortality, combined lethal and major bleeding. Secondary outcomes: 30-day major stroke, 30-day spontaneous myocardial infarction, 30-day all-cause mortality, 30-day combined lethal and major bleeding, 6-months major stroke, 6-months myocardial infarction, 6-months all-cause mortality, 6-months combined lethal and major bleeding

Halkes 2008 [56]

MA

To study the effect of combination therapy with ASA and dipyridamole (A + D) over ASAalone in secondary prevention after transient ischemic attack or minor stroke of presumed arterial origin and to perform subgroup analyses to identify patients that might benefit most from secondary prevention with A + D

Studies n = 5, 7612 participants, mean age 65 years

ASA + dipyridamol vs ASA, ASA + dipyridamol vs ASA vs dipyridamol vs placebo. ASA ranged from 50 mg/d-990 mg/d. Dipyridamol ranged from 150 mg/d-400 mg/d.

Death from all vascular causes, nonfatal stroke, nonfatal myocardial infarction

Hart 2007 [40]

MA

To characterize the efficacy and safety of antithrombotic agents for stroke prevention in patients who have atrial fibrillation, adding 13 recent randomized trials to a previous meta-analysis

Studies n = 29, 28,044 participants, mean age 71 years

Warfarin vs ASA vs placebo, warfarin vs control, warfarin vs placebo, LMWH vs control, warfarin vs ASA, warfarin vs low-dose warfarin + ASA, warfarin vs indobufen, ASA vs dipyridamol vs ASA + dipyridamol vs placebo, warfarin vs low-dose warfarin vs ASA vs low-dose warfarin + ASA, warfarin vs low-dose warfarin, warfarin vs low-dose warfarin vs ASA, ASA daily vs ASA every other day vs control, ASA vs placebo, warfarin vs warfarin, fluindione vs fluindione + ASA, ximelagatran vs warfarin, low-dose warfarin + ASA vs control, triflusal vs VKA vs triflusal + VKA, ximelagatran vs warfarin, ASA vs control, warfarin vs clopidogrel + ASA, dabigatran vs dabigatran +ASA vs warfarin

All strokes, ischaemic stroke, intracranial haemorrhage, all-cause mortality, major extracranial haemorrhage

Hart 1999 [39]

MA

To analyse the increased risk of intracranial haemorrhage when ASA is combined with Warfarin

Studies n = 16, 9874 participants, mean age 69–71 years

Warfarin INR 2.8–4.2 vs ASA 75 mg/d, ASA 300 mg/d vs warfarin INR 2–3, warfarin vs placebo + ASA 325 mg/d vs Placebo, ASA 325 mg/d vs warfarin 2–4.5, warfarin INR 1.2–1.5 + ASA 325 mg/d vs warfarin INR 2–3, warfarin INR 1.2–1.5 vs Control, warfarin vs placebo, warfarin 1.2–1.5 vs placebo, OAC INR 3–4.5 vs ASA 300 mg/d vs placebo, indobufen 100-200 mg vs warfarin INR 2–3.5, warfarin fixed-dose 1.25 mg/d vs warfarin INR 2–3, ASA 150 mg/d vs warfarin INR 2.5–3.5, LMWH vs control, ASA 125 mg/d vs ASA 125 mg/d on alternate days vs control, ASA 600 mg/d vs ASA 300 mg/d vs placebo

All strokes, ischaemic stroke, intracranial haemorrhage, all-cause mortality, major extracranial bleeding

He 1998 (JAMA) [29]

MA

To estimate the risk of haemorrhagic stroke associated with ASA treatment

Studies n = 16, 55,462 participants, mean age 63.7 years, subgroup ≥64 years

ASA 1200 mg/d vs placebo, ASA 1300 mg/d vs placebo, ASA 900 mg/d vs placebo, ASA 1000 mg vs ASA 1000 mg + 325 mg dipyridamol, ASA 1000 mg/d vs placebo, ASA 1500 mg/d vs placebo, ASA 160 mg/d vs streptokinase vs both vs placebo, ASA 500 mg/d vs placebo, ASA 325 mg/d vs placebo, ASA 75 mg/d vs warfarin vs placebo, ASA 325 mg/d vs warfarin vs placebo, ASA 75 mg/d vs placebo, ASA 300 mg/d vs placebo

Primary outcome: stroke. Secondary outcomes: myocardial infarction, cardiovascular disease mortality, all-cause mortality

Leonardi-Bee 2005 [55]

MA

To assess whether dipyridamole, given with or without ASA, reduced stroke in patients with previous ischemic cerebrovascular disease

Studies n = 7, 11,459 participants, mean age 65.4, subgroup age ≥ 65 years

Dipyridamol 100-200 mg/d vs control, dipyirdamol 20 mg/d + ASA 300 mg/d vs ASA 300 mg/d vs control, dipyridamol 75 mg/d + ASA 330 mg/d vs ASA 330 mg/d vs control, dipyridamol 75 mg/d + ASA 325 mg/d vs ASA 325 mg/d, dipyridamol 75 mg/d vs dipyridamol 75 mg/d + ASA 300 mg/d vs ASA 300 mg/d, dipyridamol 100 mg/d + ASA 50 mg/d vs dipyridamol 100 mg/d, dipyridamol 75 mg/d + ASA 330 mg/d vs control, dipyridamol 200 mg/d + ASA 25 mg/d vs ASA 25 mg/d vs dipyridamol 200 mg/d vs control

Primary outcome: composite of death from all vascular causes, fatal stroke, non-fatal myocardial infarction. Secondary outcomes: composite of death from all vascular causes or non-fatal stroke, all death, death from vascular causes, fatal and non-fatal stroke, fatal and non-fatal myocardial infarction

Lin 2015 [63]

NMA

To summarize and compare clinical and safety outcomes of oral antithrombotics for stroke prevention in AF in younger (65–74 years) and older (≥ 75 years) elderly

Studies n = 49, 897,748 participants, mean age 71 years, subgroup age ≥ 75 years

Dabigatran 150 mg vs dabigatran 110 mg vs warfarin, dabigatran 150 mg vs warfarin, rivaroxaban vs warfarin, apixaban vs warfarin, edoxaban vs warfarin, ASA vs warfarin, warfarin vs ASA + clopidogrel, warfarin vs ASA vs control, warfarin vs control, ASA vs control, apixaban vs ASA, ASA + clopidogrel vs ASA, warfarin vs ASA, warfarin vs ASA vs control, dabigatran 150 mg vs warfarin vs rivaroxaban, dabigatran vs rivaroxaban, dabigatran 150 mg vs dabigatran 110 mg vs rivaroxaban vs warfarin, dabigatran vs rivaroxaban vs warfarin, dabigatran vs warfarin, rivaroxaban vs warfarin, warfarin vs ASA vs ASA + clopidogrel

Primary outcomes: stroke, systemic embolism, major bleeding. Secondary outcomes: ischaemic stroke, all-cause mortality, intracranial bleeding, gastrointestinal bleeding

Lip 2006 [45]

MA

To compare the effectiveness of ASA, warfarin, and ximelagatran as thromboprophylaxis in patients with non-valvular atrial fibrillation

Studies n = 13, 14,423 participants, mean age 64–80 years

Warfarin INR 2.8–4.2 vs ASA 75 mg/d vs placebo, warfarin INR 1.5–2.7 vs placebo, warfarin INR 2–3 vs placebo, warfarin prothrombin time 1.3–1.8 vs placebo, warfarin INR 1.4–2.8 vs placebo, warfarin 2.5–4.0 vs placebo, warfarin INR 2.7 vs ASA 325 mg/d, warfarin INR 2.6 vs ASA 325 mg/d, warfarin INR 2–3 vs fixed low-dose warfarin + ASA 325 mg/d, warfarin INR 2–3 vs ASA 300 mg/d vs fixed low-dose warfarin vs fixed low-dose warfarin + ASA 300 mg/d, warfarin INR 2.5–3.5 vs ASA 150 mg/d vs fixed low-dose warfarin, warfarin INR 2–3 vs ASA 75-300 mg/d, warfarin INR 2–3 vs ximelagatran 72 mg/d, warfarin INR 2–3 vs ximelagatran 72 mg/d

Ischaemic stroke, systemic embolism, mortality, haemorrhage

Segal 2000 [38]

MA

To appropriate use of drugs to prevent thromboembolism in patients with AF involves comparing the patient’s risk of stroke and risk of haemorrhage. Summarize the evidence regarding the efficacy of the medicaments

Studies n = 11, 8690 participants, mean age 66–80 years

Warfarin vs placebo, ASA 325 mg/d vs warfarin, warfarin vs ASA 325 mg/d + low-dose warfarin, ASA 75 mg/d vs warfarin vs placebo, warfarin vs ASA 300 mg/d vs ASA 300 mg/d + low-dose warfarin, warfarin vs ASA 300 mg/d vs placebo, warfarin vs indobufen 200 mg, anti-factor Xa vs placebo

Stroke, major haemorrhage, minor haemorrhage, total mortality

Taylor 2001 [37]

MA

To examine the benefits and risks of long term anticoagulation (warfarin) compared with antiplatelet treatment (ASA/indoprofen) in patients with non­rheumatic atrial fibrillation

Studies n = 6, 3298 participants, mean age 64–80 years

ASA 75 mg/d vs warfarin INR 2.8–4.2, ASA 325 mg/d vs warfarin INR 2–4.5, ASA 300 mg/d vs warfarin INR 2–3, indoprofen 400 mg/d vs warfarin INR 2–3.5, ASA 150 mg/d vs warfarin INR 2.5–3.5

Fatal and non-fatal cardiovascular events, fatal and major non-fatal bleeding events

Warkentin 2012 [57]

MA

To provide a pooled estimate of the bleeding risk from randomized controlled trials RCTs comparing warfarin and ASA at the dose ranges recommended in evidencebased guidelines

Studies n = 8, 2948 participants, mean age 62–83 years, subgroup age ≥ 70 years

ASA 80 mg/d vs warfarin INR 2–2.5, ASA 100 mg/d vs warfarin INR 2–3, ASA 300 mg/d vs warfarin INR 2–3, ASA 75 mg/d vs warfarin INR 2–3, ASA 325 mg/d vs warfarin INR 2–3, ASA 162 mg/d vs warfarin INR 2–3.5

Major bleeding

Zhou 2012 [52]

MA

To evaluate the benefits and harms of combined ASA and clopidogrel therapy on major cardiovascular outcomes

Studies n = 7, 48,248 participants, mean age 61.7–71 years

Clopidogrel 75 mg/d + ASA 75-325 mg/d vs ASA 75-325 mg/d, clopidogrel 75 mg/d + ASA 100-200 mg/d vs ASA 100-200 mg/d, clopidogrel 75 mg/d + ASA 75-100 mg/d vs ASA 75-100 mg/d, clopidogrel 75 mg/d + ASA 162 mg/d vs ASA 162 mg/d, clopidogrel 75 mg/d + ASA 75-162 mg/d vs ASA 75-162 mg/d, clopidogrel 75 mg/d + ASA 81-325 mg/d vs ASA 81-325 mg/d, clopidogrel 75 mg/d + ASA 75 mg/d vs clopidogrel 75 mg/d

Major cardiovascular events, myocardial infarction, stroke, mortality, major bleeding events, other adverse reaction