Among patients with cardiovascular disease (CVD) and compared with placebo, very low-dose (VLD) direct oral anticoagulants (DOACs) on a background of antiplatelet therapy reduced ischemic events without significantly increasing intracranial or fatal bleeds, at the expense of increased major and all bleeding, according to findings published in the European Heart Journal – Cardiovascular Pharmacotherapy. The reduction of stroke and total or cardiovascular mortality was not statistically significant.

Dual-pathway inhibition (DPI), which combines low dose (LD) DOACs with antiplatelet therapy, has been tested as a way to prevent ischemic events in patients with CVD. The study authors conducted a systematic review and meta-analysis to assess the overall efficacy and safety of LD DOACs compared with placebo on a background of antiplatelet therapy.

Using the Cochrane Collaboration and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines, two of the investigators independently searched Cochrane, EMBASE, MEDLINE/PubMed, and Web of Science, as well as abstracts and presentations from the annual meetings of the following societies: American College of Cardiology, American Heart Association, European Society of Cardiology, PCR, Society of Cardiovascular Angiography and Intervention, and Transcatheter Cardiovascular Therapeutics.

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Included studies compared LD DOAC regimens (defined as below the lowest dosage approved for stroke prevention) vs placebo among patients with CVD, with at least 50% of the population receiving single or dual antiplatelet therapy (DAPT), and all participants being followed for at least 6 months. To overcome different follow-up durations between trials, incidence rate ratios (IRRs) with 95% CIs were used. The primary safety endpoint was major bleeding, and the primary efficacy endpoint was major adverse cardiovascular events (MACE).

A total of 55,782 participants from 7 randomized controlled trials with a mean follow-up of 19 months was ultimately included.

Compared with placebo, LD DOACs were associated with significant reductions in myocardial infarction (IRR, 0.86; 95% CI, 0.78-0.95; P <.01; I2=0%) and MACE (IRR, 0.85; 95% CI, 0.78-0.91; P <.01; I2=32%) and significant increases of all bleeding (IRR, 1.82; 95% CI, 1.49-2.22; P <.01; I2=82%) or major bleeding (IRR, 2.05; 95% CI, 1.50-2.80; P <.01; I2=67%).

No significant differences were found between the groups for intracranial hemorrhage (IRR, 1.18; 95% CI, 0.71-1.96; P =.53, I2=45%), CV death (IRR, 0.90; 95% CI, 0.79-1.03; P =.13; I2=48%), and fatal bleeding (IRR, 1.13; 95% CI, 0.76-1.69; P =.54; I2=0%). A nonsignificant reduction was seen for stroke (IRR, 0.73; 95% CI, 0.53-1.01; P =.06; I2=72%) and all-cause death (IRR, 0.90; 95% CI, 0.80-1.01; P =.08; I2=52%).

In meta-regression analyses, a significant interaction was seen between the percentage of DAPT use and increased risk for major bleeding (P =.04), intracranial hemorrhage (P =.035), and stroke (P =.0003).

In the number needed to treat (NNT) and number needed to harm (NNH) analyses, the NNTs for DPI to prevent 1 MACE or cause 1 major bleeding in the overall population were 86 and 89, respectively. The NNHs for fatal bleeding and intracranial hemorrhage were high in the overall population and even higher in the VLD DOAC subgroup (1810 vs 7186 and 3170 vs 5660, respectively), suggesting that VLD DOAC (defined as one-third or less of the lowest dose approved for stroke prevention) is safe with respect to these complications, without a tradeoff in efficacy outcomes.

Study investigators concluded, “DPI with a [VLD] DOAC regimen compared [with] antiplatelet therapy alone is effective in reducing ischemic events among patients with CVD but at the cost of increased major and all bleeding. Since NNT and NNH were found to be similar among primary efficacy and safety endpoints, a careful evaluation of the ischemic and bleeding risk [for] the individual patient is required before starting a DPI strategy in clinical practice.

This analysis provides reassurance on the incidence of intracranial hemorrhage and fatal bleeding when a [VLD] DOAC regimen is used. Conversely, it emphasizes the significantly increased risk for major bleeding and intracranial events associated with a DPI strategy involving DAPT.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Galli M, Capodanno D, Benenati S, et al. Efficacy and safety of dual pathway inhibition in patients with cardiovascular disease: a systematic review and meta-analysis. Eur Heart J Cardiovasc Pharmacother. Published online June 19, 2021. doi:10.1093/ehjcvp/pvab043