Safety and Efficacy of Antithrombotic Strategies in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention: A Network Meta-analysis of Randomized Controlled Trials

Abstract

Importance: The antithrombotic treatment of patients with atrial fibrillation (AF) and coronary artery disease, in particular with acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI), poses a significant treatment dilemma in clinical practice.

Objective: To study the safety and efficacy of different antithrombotic regimens using a network meta-analysis of randomized controlled trials in this population.

Data sources: PubMed, EMBASE, EBSCO, and Cochrane databases were searched to identify randomized controlled trials comparing antithrombotic regimens.

Study selection: Four randomized studies were included (n = 10 026; WOEST, PIONEER AF-PCI, RE-DUAL PCI, and AUGUSTUS).

Data extraction and synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used in this systematic review and network meta-analysis between 4 regimens using a Bayesian random-effects model. A pre hoc statistical analysis plan was written, and the review protocol was registered at PROSPERO. Data were analyzed between November 2018 and February 2019.

Main outcomes and measures: The primary safety outcome was Thrombolysis in Myocardial Infarction (TIMI) major bleeding; secondary safety outcomes were combined TIMI major and minor bleeding, trial-defined primary bleeding events, intracranial hemorrhage, and hospitalization. The primary efficacy outcome was trial-defined major adverse cardiovascular events (MACE); secondary efficacy outcomes were individual components of MACE.

Results: The overall prevalence of ACS varied from 28% to 61%. The mean age ranged from 70 to 72 years; 20% to 29% of the trial population were women; and most patients were at high risk for thromboembolic and bleeding events. Compared with a regimen of vitamin K antagonist (VKA) plus dual antiplatelet therapy (DAPT; P2Y12 inhibitor plus aspirin), the odds ratios (ORs) for TIMI major bleeding were 0.58 (95% CI, 0.31-1.08) for VKA plus P2Y12 inhibitor, 0.49 (95% CI, 0.30-0.82) for non-VKA oral anticoagulant (NOAC) plus P2Y12 inhibitor, and 0.70 (95% CI, 0.38-1.23) for NOAC plus DAPT. Compared with VKA plus DAPT, the ORs for MACE were 0.96 (95% CI, 0.60-1.46) for VKA plus P2Y12 inhibitor, 1.02 (95% CI, 0.71-1.47) for NOAC plus P2Y12 inhibitor, and 0.94 (95% CI, 0.60-1.45) for NOAC plus DAPT.

Conclusions and relevance: A regimen of NOACs plus P2Y12 inhibitor was associated with less bleeding compared with VKAs plus DAPT. Strategies omitting aspirin caused less bleeding, including intracranial bleeding, without significant difference in MACE, compared with strategies including aspirin. Our results support the use of NOAC plus P2Y12 inhibitor as the preferred regimen post-percutaneous coronary intervention for these high-risk patients with AF. A regimen of VKA plus DAPT should generally be avoided.

Figure 1.. Network of 4 Antithrombotic Treatment Regimens

The nodes represent antithrombotic treatment regimens to be compared and the edges represent the observed direct comparisons in the included trials. The size of nodes is proportional to the number of patients assigned to the treatment regimen and the thickness of edges is proportional to the sample size of each study. AUGUSTUS indicates Open-label, 2 × 2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of Apixaban vs Vitamin K Antagonist and Aspirin vs Aspirin Placebo in Patients With Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention; DAPT, dual antiplatelet therapy; NOAC, non–vitamin K antagonist oral anticoagulant; PIONEER AF-PCI, Open-label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention; RE-DUAL PCI, Randomized Evaluation of Dual Antithrombotic Therapy With Dabigatran vs Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention; VKA, vitamin K antagonist; WOEST, What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients With Oral Anticoagulation and Coronary Stenting.

Figure 2.. Forest Plots for Safety Outcomes

Odds ratios and 95% credible intervals (CIs) comparted with vitamin K antagonist (VKA) plus dual antiplatelet therapy (DAPT) (reference) are plotted. A total of 9924 patients were contributed to network meta-analyses for all safety outcomes. The estimated between-trial effect heterogeneity and its 95% CI (in standard deviation of the log odds ratio scale) from NMA for each outcome is 0.24 (95% CI, 0.01-0.71), 0.35 (95% CI, 0.03, 0.88), 0.46 (95% CI, 0.16, 1.03), and 0.52 (95% CI, 0.02, 1.52). A, TIMI major bleeding. B, TIMI major or minor bleeding. C, Trial-defined primary safety outcome. D, Intracranial hemorrhage. NOAC indicates non–vitamin K antagonist oral anticoagulant.

Figure 3.. Forest Plots for Efficacy Outcomes

Odds ratios and 95% credible intervals (CIs) compared with vitamin K antagonist (VKA) plus dual antiplatelet therapy (DAPT) (reference) are plotted. A total of 9995 patients were contributed to network meta-analyses for all efficacy outcomes except the hospitalization outcome. The network meta-analysis for the hospitalization outcome included 10 001 patients. The estimated between-trial effect heterogeneity and its 95% credible interval (in standard deviation of the log odds ratio scale) from the NMA for each outcome is 0.23 (0.01-0.50), 0.31 (0.01, 0.83), 0.22 (0.01, 0.66), 0.17 (0.01, 0.37), 0.47 (0.03, 0.94), 0.34 (0.01, 0.72), and 0.22 (0.05, 0.43). MACE indicates major adverse cardiac event; NOAC, non–vitamin K antagonist oral anticoagulant.

Figure 4.. Odds Ratios for TIMI Major Bleeding and MACE

Odds ratios compared with vitamin K antagonist (VKA) plus dual antiplatelet therapy (DAPT) (reference) and associated 95% credible intervals are plotted: TIMI major bleeding (orange) on the x-axis and major adverse cardiac event (MACE) (blue) on the y-axis. Network meta-analyses for the TIMI major bleeding and MACE outcomes included 9924 and 9995 patients, respectively.