All randomized controlled trials (RCTs) comparing LD DOAC (defined as a dosage below the lowest approved for
stroke prevention) vs placebo among patients with CVD receiving single or dual antiplatelet
therapy (
DAPT) in at least 50% of the population and followed for at least 6 months, were included. Incidence rate ratios (IRRs) with 95% confidence intervals (CIs) were used to overcome different follow-up durations across trials. The primary efficacy endpoint was major adverse cardiovascular events (
MACE) and the primary safety endpoint major
bleeding. A pre-specified subgroup analysis was performed for different DOAC-dose regimens. A total of 49 802 patients from 7 RCTs were included. Low-dose DOACs vs placebo were associated with significant reductions in
MACE (
IRR 0.85, 95% CI 0.78-0.91, number needed to treat, NNT, 86) and
myocardial infarction (
IRR 0.86, 95% CI 0.78-0.95, NNT 355) and significant increases of major (
IRR 2.05, 95% CI 1.50-2.80, number needed to harm, NNH, 89) or all
bleeding (
IRR 1.82, 95% CI 1.49-2.22, NNH 23). Cardiovascular death (
IRR 0.90, 95% CI 0.79-1.03, NNT 784), intracranial (
IRR 1.18, 95% CI 0.71-1.96, NNH 1810), and fatal
bleeding (
IRR 1.13, 95% CI 0.76-1.69, NNH 3170) did not differ significantly between strategies. Non-significant reductions of all-cause death (
IRR 0.90, 95% CI 0.80-1.01, NNT 821) and
stroke (
IRR 0.73, 95% CI 0.53-1.01, NNT 315) favoured LD DOACs. Meta-regression analyses showed a significant interaction between percentage of
DAPT use and increased risk of major
bleeding (P = 0.04), intracranial haemorrhage (P = 0.035), and
stroke (P = 0.0003). Subgroup analysis of very LD DOAC, defined as ≤1/3 of the lowest approved dose for
stroke prevention (i.e.
rivaroxaban 2.5 mg twice daily) seemed to mitigate the risk of
bleeding without any trade-off in efficacy compared to other LD DOAC regimens.
CONCLUSIONS: In patients with CVD, LD DOAC vs placebo on a background of antiplatelet
therapy, reduced ischaemic events at the expense of increased major and all
bleeding, but without significantly increasing intracranial or fatal bleeds, while the reduction of cardiovascular or total mortality and
stroke was not statistically significant. A DPI with very LD DOAC (i.e.
rivaroxaban 2.5 mg twice daily) appeared particularly advantageous, especially when combined with a single
antiplatelet agent and used among patients at high ischaemic and low
bleeding risk.
STUDY REGISTRATION: This study is registered in PROSPERO (CRD42021232744).