Meta-analysis of antithrombotic therapy with new oral anticoagulants in patients with atrial fibrillation after percutaneous coronary intervention

The 2018 expert recommendations suggest new oral anticoagulant (OAC) over vitamin K antagonist (VKA) and double therapy (OAC + P2Y12 inhibitor) over triple therapy (OAC+P2Y12 inhibitor and aspirin) after hospital discharge for most patients with atrial fibrillation (AF) after percutaneous coronary intervention (PCI).¹ While these recommendations were derived from two trials of new OACs,^2,3 previous meta-analyses advocated the strategy of using double therapy versus triple therapy but did not specify whether the use of any particular OAC was more beneficial.⁴ In the wake of new randomized data,⁵ we performed a meta-analysis to assess whether a new OAC-based double therapy strategy is comparable with VKA-based triple therapy in patients with AF after PCI.

Three randomized controlled trials^2,3,5 were selected using PubMed, Embase and CENTRAL to April 2019 (Table 1). The screening process is shown in Supplementary Figure 1. The co-primary endpoints were all-cause mortality and thrombolysis in myocardial infarction (TIMI) major bleeding. The secondary endpoints were cardiovascular mortality, myocardial infarction (MI), stent thrombosis, stroke, trial-defined major adverse cardiovascular endpoints (MACE), International Society on Thrombosis and Hemostasis (ISTH) major and minor bleeding, TIMI minor bleeding and intracranial hemorrhage. We selected rivaroxaban 15 mg once daily dose from PIONEER AF-PCI as2.5 mg is not approved for stroke prevention.² We performed separate analyses by pooling dabigatran 150 mg twice daily (BID) and 110 mg BID estimates reported in REDUAL-PCI.³ The AUGUSTUS trial used 5 mg BID or 2.5 mg BID as per apixaban’s label instruction.⁵ The Cochrane Collaboration tool was used for risk of bias assessment (Supplementary Table 1). Two independent reviewers (NY and AK) were involved in study selection, data adjudication and quality assessment. The meta-analysis was conducted in accordance with PRISMA guidelines.

Table 1.

Baseline demographics of included randomized controlled trials.

Trial name, year	Treatment regimen	Age, years	Men, %	CHA2DS2-VASc score	DES, %	ACS, %	Duration of therapy	Follow-up duration	MACE definition
AUGUSTUS, 20195
NOAC group	Apixaban 5 mg or 2.5 mg twice daily + aspirin 81 mg daily/matching placebo + P2Y12 inhibitor	70.4	70.9	3.9 ± 1.6	NA	61.8	6 months	6 months	NA
Control group	VKA (target INR 2.0–3.0) + aspirin 81 mg daily/matching placebo + P2YI2 inhibitor	70.9	71.1	4.0 ± 1.6	NA	60.5
PIONEER-AF PCI, 20I72
NOAC group	Rivaroxaban 15 mg once daily + clopidogrel/ticagrelor/prasugrel	70.4	74.5	3.7 ± 1.7	67.4	51.5	6 months	13 months	Cardiovascular death, myocardial infarction, or stroke
Control group	Warfarin (target INR2.0–3.0) + aspirin ≤ 100 mg daily+P2Y12 inhibitor	69.9	73.4	3.8 ± 1.5	68.2	52.2
RE-DUAL PCI, 20173
NOAC group	Dabigatran 150 mg or 110 mg twice daily + clopidogrel/ticagrelor	68.6, 7I.5†	77.6, 74.2†	3.3 ± 1.5, 3.7± l.6†	82.8, 84.0†	51.2, 5l.9†	12.3 months	14 months	Cardiovascular death, myocardial infarction, or stroke
Control group	Warfarin (target INR2.0–3.0) + aspirin (≤100 mg daily up to 3 months) + P2YI2 inhibitor	71.7	76.5	3.8 ± 1.5	85.9	48.4

Values are mean or median with corresponding variances.

^†Dabigatran 150 mg, dabigatran 110 mg.

ACS: acute coronary syndrome; DES: drug-eluting stent; MACE: major adverse cardiovascular event; NOAC: non-vitamin K oral anticoagulant; VKA: vitamin K antagonist; INR: international normalized ratio.

Estimates were reported as random effects hazard ratios (HRs) with 95% confidence intervals (CIs). Statistical heterogeneity was quantified using I² statistics. Statistical significance was set at 5%. Publication bias was not assessed due to the lesser number of studies (<10). We calculated the power of this meta-analysis as suggested by Valentine et al.⁶ and Quintana⁷ (Supplementary Table 2). All data were analyzed using CMA V-3.0 (Biostat, Englewood, NJ, USA) and the R project for statistical computing.

In meta-analysis using dabigatran 150 mg BID estimates, there were no significant differences between new OAC + P2Y12 inhibitor and VKA-based triple therapy, in terms of all-cause mortality (HR 0.92, 95% CI 0.72–1.18; P = 0.52) or TIMI major bleeding (HR 0.91, 95% CI 0.38–2.16; P = 0.83). Similarly, there were no statistical differences between two strategies with respect to the secondary endpoints (Figure 1). These results were consistent after regrouping dabigatran 110 mg BID estimates: all-cause mortality (HR 1.01, 95% CI 0.80–1.28; P = 0.91), TIMI major bleeding (HR 0.81, 95% CI 0.29–2.27;P = 0.69), cardiovascular mortality (HR 1.05, 95% CI 0.80–1.38;P = 0.75), MI (HR 1.01, 95% CI 0.67–1.51; P = 0.97), stent thrombosis (HR 1.01, 95% CI 0.43–2.38;P= 0.99), stroke (HR 1.14, 95% CI 0.74–1.76; P = 0.55), MACE (HR 1.12, 95% CI 0.91–1.37; P = 0.28),ISTH major bleeding (HR 0.85, 95% CI 0.36–2.01;P = 0.71), ISTH minor bleeding (HR 1.08, 95% CI 0.29–3.92;P = 0.91), TIMI minor bleeding (HR 1.32, 95% CI 0.65–2.71; P = 0.44) or intracranial hemorrhage (HR 0.55, 95% CI 0.27–1.11; P = 0.10). Power calculation analysis suggested that current meta-analysis was 91% powered to detect a 10% difference in all-cause mortality or TIMI major bleeding with moderate heterogeneity.

Figure 1.

Meta-Analysis of Clinical Outcomes.

While previous reports have demonstrated a significant reduction in bleeding events with double therapy compared with triple therapy without worsening cardiovascular outcomes,^8,9 and clinical trials have shown non-inferiority of new OACs versus VKA in preventing thromboembolism in AF without increasing bleeding risk,¹⁰ the current meta-analysis addresses the question of whether differences between dual versus triple therapy are due to a new OAC versus VKA-based approach. These analyses show that new OAC-based double therapy is equally effective and safe compared with VKA-based triple therapy after PCI in patients with AF.

None of the included trials was powered to assess differences in ischemic endpoints. To detect differences in rare events such as mortality, conducting a large clinical trial with adequate power might be burdensome, hence pooling results from available randomized data remains the best means of assessing the cardiovascular efficacy of the interventions at hand. Future clinical trials, such as ENTRUST AF-PCI, which is designed to evaluate edoxaban 60 mg plus P2Y12 inhibitor versus VKA-based triple therapy in AF after PCI, might shed further light on this issue. Another noteworthy aspect is that in PIONEER AF-PCI, rivaroxaban 15 mg once daily plus P2Y12 inhibitor had a lower incidence of clinically significant bleeding, a composite endpoint, but showed no significant reduction in the major bleeding endpoint.² In the AUGUSTUS trial, 50% of patients in both new OAC and VKA cohorts were randomly assigned to receive triple therapy and a higher rate of bleeding events was limited to patients receiving aspirin versus placebo.⁵ In REDUAL PCI, there was a significantly lower risk of TIMI major bleeding with the use of dabigatran.³ To avoid heterogeneity in bleeding estimates, we selected more robust endpoints with universal definitions; thus showing a comparable risk of bleeding among both strategies.

This report has limitations inherent to any meta-analysis. First, there was heterogeneity across patients in terms of the indication for PCI (elective vs. emergency), choice of P2Y12 inhibitor (clopidogrel vs. ticagrelor vs. prasugrel), mean duration of therapy (range 6–12 months) and follow-up duration across the trials. Due to limited trial-level data and lack of participant-level information, subgroup analyses could not be performed. Second, in the AUGUSTUS trial, 50% of patients in both new OAC and VKA groups received aspirin, which may bias the outcome.⁵ Third, we had a paucity of data in terms of certain endpoints. That said, data were contributed for all the key endpoints, such as major bleeding events, mortality and cardiovascular outcomes.

In conclusion, in patients with AF who received PCI, double therapy with new OACs has equivalent efficacy and safety as compared to VKA-based triple therapy. These results provide objective evidence to support expert guidelines preferring new OACs over VKA and double therapy over triple therapy in most patients with AF after PCI.¹¹