Safety and efficacy of double vs. triple antithrombotic therapy in patients with atrial fibrillation with or without acute coronary syndrome undergoing percutaneous coronary intervention: a collaborative meta-analysis of non-vitamin K antagonist oral anticoagulant-based randomized clinical trials

Abstract

Aims: Safety and efficacy of antithrombotic regimens in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) may differ based on clinical presentation. We sought to compare double vs. triple antithrombotic therapy (DAT vs. TAT) in AF patients with or without acute coronary syndrome (ACS) undergoing PCI.

Methods and results: A systematic review and meta-analysis was performed using PubMed to search for non-vitamin K antagonist oral anticoagulant (NOAC)-based randomized clinical trials. Data on subgroups of ACS or elective PCI were obtained by published reports or trial investigators. A total of 10 193 patients from four NOAC trials were analysed, of whom 5675 presenting with ACS (DAT = 3063 vs. TAT = 2612) and 4518 with stable coronary artery disease (SCAD; DAT = 2421 vs. TAT = 2097). The primary safety endpoint of ISTH major bleeding or clinically relevant non-major bleeding was reduced with DAT compared with TAT in both ACS (12.2% vs. 19.4%; RR 0.63, 95% CI 0.56-0.71; P < 0.0001; I2 = 0%) and SCAD (14.6% vs. 22.0%; RR 0.68, 95% CI 0.55-0.85; P = 0.0008; I2 = 66%), without interaction (P-int = 0.54). Findings were consistent for secondary bleeding endpoints, including intra-cranial haemorrhage. In both subgroups, there was no difference between DAT and TAT for all-cause death, major adverse cardiovascular events, or stroke. Myocardial infarction and stent thrombosis were numerically higher with DAT vs. TAT consistently in ACS and SCAD (P-int = 0.60 and 0.86, respectively). Findings were confirmed by multiple sensitivity analyses, including a separate analysis on dabigatran regimens and a restriction to PCI population.

Conclusions: DAT, compared with TAT, is associated with lower bleeding risks, including intra-cranial haemorrhage, and a small non-significant excess of cardiac ischaemic events in both patients with or without ACS.

Keywords: Acute coronary syndrome (ACS); Atrial fibrillation (AF); Double therapy (DAT); Non-vitamin K antagonist oral anticoagulant (NOAC); Percutaneous coronary intervention (PCI); Triple therapy (TAT).

Figure 1

Main bleeding endpoints in double antithrombotic therapy vs. triple antithrombotic therapy according to clinical presentation. Random-effects risk ratios and 95% confidence intervals for main bleeding endpoints. DAT, double antithrombotic therapy; ISTH, International Society on Thrombosis and Haemostasis; M–H, Mantel–Haenszel; TAT, triple antithrombotic therapy.

Figure 2

Clinically relevant non-major bleeding and intra-cranial haemorrhage in double antithrombotic therapy vs. triple antithrombotic therapy according to clinical presentation. Random-effects risk ratios and 95% confidence intervals clinically relevant non-major bleeding and intra-cranial haemorrhage.

Figure 3

Alternative bleeding definitions in double antithrombotic therapy vs. triple antithrombotic therapy according to clinical presentation. Random-effects risk ratios and 95% confidence intervals for primary bleeding endpoint trial-defined and thrombolysis in myocardial infarction major or minor bleeding.

Figure 4

Death, major adverse cardiovascular events, and stroke in double antithrombotic therapy vs. triple antithrombotic therapy according to clinical presentation. Random-effects risk ratios and 95% confidence intervals for all-cause death, major adverse cardiovascular events, and stroke.

Figure 5

Myocardial infarction and stent thrombosis in double antithrombotic therapy vs. triple antithrombotic therapy according to clinical presentation. Random-effects risk ratios and 95% confidence intervals for myocardial infarction and stent thrombosis. Note: stent thrombosis definition was definite ST for the RE-DUAL PCI, ENTRUST-AF PCI and PIONEER-AF PCI trials, and definite or probable ST for AUGUSTUS.

Figure 6

Number needed to treat for benefit or harm for double antithrombotic therapy vs. triple antithrombotic therapy according to risk of major bleeding and myocardial infarction in acute coronary syndrome and stable coronary artery disease subgroups. At each risk (%) ranging from 1% to 10% for both major bleeding and MI, the difference between NNTB and NNTH was calculated. Red indicates that the net benefit of double antithrombotic therapy vs. triple antithrombotic therapy is in favour of bleeding (NNTB < NNTH, thus reduction of bleeding is higher than the risk of MI) and its intensity refers to greater (dark red) or lower (light red/pink) benefit (with the cut-off range selected arbitrarily to be −100–100), while blue indicates a net ischaemic harm (NNTB > NNTH, thus the reduction of bleeding is lower than the risk of MI) and its intensity refers to greater (dark blue) or lower (light blue) harm (with the cut-off range selected arbitrarily to be −100–100). Orange indicates a neutral effect (NNTB = NNTH; we arbitrarily selected a range from −10 to 10 to consider the effect as neutral).

Figure 7

The summary of safety and efficacy endpoints in double antithrombotic therapy vs. triple antithrombotic therapy demonstrating there is a consistent effect across acute coronary syndrome and stable coronary artery disease subgroups. Pooled random-effects risk ratios with 95% confidence intervals and interaction P values for safety and efficacy endpoints. CRNM, clinically relevant non-major; DAT, double antithrombotic therapy; ISTH, International Society on Thrombosis and Haemostasis; MACE, major adverse cardiovascular events; TAT, triple antithrombotic therapy; TIMI, thrombolysis in myocardial infarction.