Efficacy and safety of dual pathway inhibition in patients with cardiovascular disease: a systematic review and Meta-analysis.

BACKGROUND Low-dose direct oral anticoagulants (DOACs) in adjunct to antiplatelet therapy, known as dual pathway inhibition (DPI), have been tested to prevent ischaemic events in patients with cardiovascular disease (CVD). We conducted a systematic review and meta-analysis to determine the overall safety and efficacy of low-dose DOACs vs. placebo on a background of antiplatelet therapy. METHODS All randomized controlled trials (RCTs) comparing low-dose DOAC (defined as a dosage below the lowest approved for stroke prevention) vs. placebo among patients with CVD receiving single or dual antiplatelet therapy 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. RESULTS A total of 55,782 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) and myocardial infarction (IRR 0.86, 95% CI 0.78-0.95) and significant increases of major (IRR 2.05, 95% CI 1.50-2.80) or all bleeding (IRR 1.82, 95% CI 1.49-2.22). CV death (IRR 0.90, 95% CI 0.79-1.03), intracranial (IRR 1.18, 95% CI 0.71-1.96) and fatal bleeding (IRR 1.13, 95% CI 0.76-1.69) did not differ significantly between strategies. Non-significant reductions of all-cause death (IRR 0.90, 95% CI 0.80-1.01) and stroke (IRR 0.73, 95% CI 0.53-1.01) favoured low-dose 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 low-dose DOAC, defined as ≤ 1/3 of the lowest approved dose for stroke prevention (i.e., rivaroxaban 2.5 mg twice daily) seems to mitigate the risk of bleeding without any trade-off in efficacy compared to other low-dose DOAC regimens. CONCLUSIONS In patients with CVD, a low-dose DOAC regimen vs. placebo, on a background of antiplatelet therapy, is effective in reducing ischaemic events at the expense of increased major and all bleeding, but without significantly increasing intracranial or fatal bleeds, while the reduction of cardiovascular and total mortality is not statistically significant. A DPI with very low-dose DOAC (i.e. rivaroxaban 2.5 mg twice daily) appears 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).