
Canadian Journal of General Internal Medicine
12 Volume 13, Special Issue 1, 2018
bleeding event within 1 year of follow-up (e.g., TIMI major plus
minor). Dual pathway therapy was associated with a significant
reduction in overall bleeding complications (19.4% with DT vs.
44.4% with TT), without significant differences in major bleeds
(3.2% vs. 5.6%). Though not powered to detect differences in
major thrombotic outcomes, the combined endpoint of major
adverse cardiac and cerebrovascular events (MACCE – death,
myocardial infarction, stroke, target vessel revascularization,
stent thrombosis) was significantly reduced with dual pathway
therapy (11.1% vs. 17.6) as was all-cause mortality (2.5% vs.
6.4%; P = 0.027).
The “Prevention of bleeding in patients with AF undergoing
PCI” (PIONEER AF-PCI) study randomized 2,124 patients
with non-valvular AF undergoing PCI for ACS (51%) or for
stable CAD to receive, in a 1:1:1 ratio: (1) P2Y12 inhibitor (94%
clopidogrel) plus rivaroxaban 15 mg daily (dual pathway) for 12
months (709 patients), (2) DAPT plus rivaroxaban 2.5 mg twice
daily (reduced dose triple antithrombotic therapy) for 1, 6 or 12
months (709 patients), or (3) traditional triple antithrombotic
therapy with warfarin (target INR 2-3) plus DAPT for 1, 6,
or 12 months (706 patients).
21
The primary safety endpoint,
consisting of clinically significant bleeding (e.g., TIMI major
plus minor), was lower in the dual pathway and reduced dose
triple antithrombotic therapy groups when compared to the
group receiving traditional triple antithrombotic therapy with
warfarin (16.8% in patients treated with dual pathway therapy,
18% in patients treated with reduced dose triple antithrombotic
therapy, and 26.7% in patients treated with traditional triple
antithrombotic therapy). Similar to WOEST there was a non-
significant reduction in major bleeding dual pathway and reduced
dose triple antithrombotic therapy groups when compared to
the group receiving traditional triple antithrombotic therapy
with warfarin.
The “Dual antithrombotic therapy with dabigatran after PCI
in atrial fibrillation” (RE-DUAL PCI) trial randomized 2,725
patients with non-valvular AF undergoing PCI for ACS (51%)
or stable CAD to: (1) dual pathway therapy with dabigatran
110mg bid plus P2Y12 inhibitor (D110 - 981 patients), (2) dual
pathway therapy with dabigatran 150mg bid plus P2Y12 inhibitor
(D150 - 763 patients), or (3) traditional triple antithrombotic
therapy with warfarin (target INR 2-3) plus a P2Y12 inhibitor
(clopidogrel or ticagrelor) plus ASA (981 patients).23 In the triple
antithrombotic therapy group aspirin was discontinued after 1
month (in patients with BMS) or after 3 months (in patients
with DES), however the P2Y12 inhibitor was continued for
12-months post-PCI. The primary outcome was ISTH major or
clinically relevant non-major bleeding, which was significantly
reduced in both dual pathway therapy groups when compared
to triple antithrombotic therapy (11.5% absolute reduction with
D110 and 5.5% absolute reduction with D150). In secondary
efficacy analyses both dual pathway therapy groups significant
reduced ISTH major bleeding (4.2% absolute reduction with
D110 and 2.8% absolute reduction with D150), and TIMI major
bleeding (2.4% absolute reduction with D110 and 1.8% absolute
reduction with D150). While the study was underpowered to
detect differences in thromboembolic events, the rates of death,
myocardial infarction, stroke, or stent thrombosis were similar
across the three groups, the use of dual pathway therapy was non-
inferior for the composite efficacy endpoint (thromboembolic
events).
There are several notable limitations to the above trials.
Firstly, a large proportion of patients were undergoing elective
PCI (72% in WOEST, 48% in PIONEER AF-PCI, and 44% in
RE-DUAL), meaning the rate relative risk of coronary outcomes
may be underestimated. Second, measures to decrease bleeding
risk were underutilized, suggesting that the observed bleeding
rate may be higher than contemporary practice. Third, it is
unknown whether the results of PIONEER AF-PCI and RE-
DUAL PCI would have been similar had the dual pathway
therapy groups utilized a VKA, or if the triple therapy group
utilized a standard-dose NOAC.
While each of the trials were individually underpowered
to detect meaningful differences in the incidence of ischemic
events a limited meta-analysis of these randomized trials
demonstrated that the use of dual pathway therapy was
associated with a significant reduction in major bleeding
events (2.22% vs 3.78%; OR 0.58, 95%CI 0.39-0.86), without
an excess in the occurrence of MI (3.58% vs. 3.21%; OR 0.96),
stent thrombosis (1.02% vs. 0.77%; OR 0.95), or stroke (1.35%
vs. 1.43%).
However, the meta-analysis focused only on the comparison
between dual pathway therapy and triple antithrombotic therapy.
We have performed a larger network meta-analysis of 114,887
ACS patients in 10 randomized and 38 non-randomized studies
to examine the relative risks/benefits of DAPT vs. dual pathway
therapy versus triple antithrombotic therapy. In comparison to
DAPT both dual pathway therapy and triple antithrombotic
therapy were associated with a significantly higher incidence
of major bleeding and with a significant reduction in stroke,
but no significant effect on myocardial infarction or all-cause
mortality (Figure 1). Compared to dual pathway therapy, triple
antithrombotic therapy demonstrated significantly more major
bleeding (OR 1.54; 95%CI 1.18-2.00), a trend towards less
myocardial infarction (OR 0.82; 95%CI 0.66-1.03) and stent
thrombosis (OR 0.66; 95%CI 0.42-1.03), with no differential
effect on stroke or all-cause mortality.
Atrial Fibrillation and Coronary Artery Disease