Sixty-one RCTs (203,355 participants) were included in the review.
Low-dose aspirin-alone (35 trials, 87,581 participants, 338,735 person years of follow-up): Twenty-one studies reported adequate sequence generation, allocation concealment was reported in 18 RCTs and all RCTs used intention-to-treat analyses. Blinding was not described in 13 RCTs and there were inadequately reported losses to follow-up in two trials.
A protective effect for all-cause mortality was observed with low-dose aspirin treatment (RR 0.93, 95%CI 0.87 to 0.99; Ι²=11%; 32 RCTs) largely because of effects in secondary prevention populations. Treatment with low-dose aspirin was associated with increased incidence of: major gastrointestinal bleeding, (OR 1.55, 95% CI 1.27 to 1.90; Ι²=14%; 28 RCTs), numbers-needed-to-harm 500 (95% CI 334 to 1,000), IRD 1.1 (95% CI 0.4 to 1.7 per 1,000 person-years); any gastrointestinal bleeding (OR 1.31, 95% CI 1.21 to 1.42; Ι²=48%), numbers-needed-to-harm 166 (95% CI 125 to 250), IRD 2.1,(95% CI 0 to 4.7 per 1,000 person years); any bleeding (OR 1.54, 95% CI 1.36 to 1.74; Ι²=62%), numbers-needed-to-harm 71 (95% CI 63 to 90), IRD 8.1 (95% CI 4.0 to 12.2 per 1,000 person years).
There were no differences between low-dose aspirin groups and no low-dose aspirin/placebo groups for fatal bleeding or dyspepsia. Meta-regression analyses showed that the risks of major gastrointestinal bleeding and any gastrointestinal bleeding were higher for patients with histories of gastrointestinal bleeds and in studies of longer duration of follow-up.
Low-dose aspirin and clopidogrel (five trials, 81,765 participants): The reviewers stated that all studies reported methodologic issues. There were significant increases in major gastrointestinal bleeding (OR 1.86, 95% CI 1.49 to 2.31, IRD 8 95% CI 0 to 10 per 1,000 person-years) associated with dual therapy and in any bleeding (OR 1.46, 95% CI 1.15 to 1.86; Ι²=95%), IRD 22 (95% CI 2 to 43 per 1,000 person-years) compared to low-dose aspirin. There were no differences between groups for fatal bleeding, mortality, and fatal haemorrhagic strokes.
Low-dose aspirin and anticoagulants (18 RCTs, 9,875 participants, 64,481.5 person years of follow-up): Randomisation was reported in nine RCTs, allocation concealment was described in seven RCTs, and five trials reported blinding measures. Seventeen RCTs reported losses to follow-up and all trials used intention-to-treat analyses. There were significantly increased risks in: major gastrointestinal bleeding observed (OR 1.93, 95% CI 1.42 to 2.61; Ι²= 24%), approximate numbers-needed-to-harm 125 (95% CI 91 to 250), IRD 2.1 (95% CI 0 to 5 per 1,000 person-years); any gastrointestinal bleeding (OR 1.81, 95% CI 1.32 to 2.49; Ι²=76%) IRD 2.8(95% CI 0 to 9.3 per 1,000 person-years); any bleeding (OR2.28, 95% CI 1.81 to 2.87, Ι²=80% IRD 44 (95% CI 30 to 59 per 1,000 person-years); and haemorrhagic stroke (OR 1.86, 95% CI 1.08 to 3.22; Ι²=0%). There were no significant differences in all-cause mortality and fatal bleeding, and no data were available for dyspepsia.
Low-dose aspirin and proton pump inhibitors (three RCTs, 4,134 participants, 2,090 person years of follow-up): One RCT reported all quality items adequately, but the other RCT only reported losses to follow-up and the use of intention-to-treat analyses. The combination of adverse event rates from all the trials showed the use of proton pump inhibitors reduced the risk of adverse gastrointestinal events in patients given low doses of aspirin (OR 0.34, 95% CI 0.21 to 0.57).
The indirect comparisons found that the risk of major bleeding was increased with clopidogrel plus low-dose aspirin compared to no treatment (OR 2.75, 95% CI 1.83 to 4.12) and anti-coagulant therapy plus low-dose aspirin, but there were no differences between clopidogrel and anticoagulants plus aspirin. For the outcome of any bleeding clopidogrel plus aspirin, and anticoagulant therapy plus low-dose aspirin, were both associated with higher risks of any bleeds compared to no treatment.