Canadian Journal of General Internal Medicine
10 Volume 13, Special Issue 1, 2018
About the Authors
Jason Andrade and Laurent Macle are with the Electrophysiology Service at the Montreal Heart Institute and the Department of Medicine,
Université de Montal, Montreal, Canada. Jason Andrade and Marc Deyell are is with the Heart Rhythm Services, Department of
Medicine, The University of British Columbia, British Columbia, Canada.
Correspondence may be directed to: Jason.andrade@vch.ca
Atrial Fibrillation and Coronary Artery Disease:
Deciding on The Best Antithrombotic Regimen
Jason G. Andrade MD, Marc W. Deyell MD MSc, Laurent Macle MD
DOI: 10.22374/cjgim.v13iSP1.309
ABSTRACT
Atrial fibrillation (AF) is a chronic progressive disease characterized by exacerbations and
remissions. Up to 20–30% of patients with AF also have coronary artery disease (CAD).
In patients with concomitant AF and CAD, the management of antithrombotic therapy is
challenging. Oral anticoagulation (OAC) is indicated for the prevention of AF-related stroke
and systemic embolism, whereas antiplatelet therapy is indicated for the prevention of coronary
events. Each of these therapeutic avenues offers a relative efficacy benefit (e.g., dual antiplatelet
therapy [DAPT] is more effective than OAC alone in reducing cardiovascular death, myocardial
infarction, stent thrombosis, and ischemic coronary events in an ACS population), but with a
relative compromise (e.g., DAPT is significantly inferior to OAC for the prevention of stroke/
systemic embolism in an AF population at increased risk of AF-related stroke). The purpose
of this review is to explore the current evidence and rationale for antithrombotic treatment
strategies in patients with both AF and CAD.
Atrial Fibrillation Special Issue
Atrial fibrillation (AF) is the most common sustained arrhythmia,
and represents a major burden to our healthcare system. Current
evidence indicates that the prevalence of AF is in the range of
2% of the general population.
1,2
Of those with AF, up to 20–30%
have concomitant coronary artery disease (CAD), and 5–15%
will require percutaneous coronary intervention (PCI).
3,4
In patients with both AF and CAD the management of
antithrombotic therapy can be challenging. Oral anticoagulation
(OAC) is indicated for the prevention of AF-related stroke and
systemic embolism, whereas antiplatelet therapy is indicated for
the prevention of coronary events. Each offers a relative efficacy
benefit with either a relative efficacy compromise or a relative
safety compromise (e.g., dual antiplatelet therapy [DAPT] is
more effective than OAC alone in reducing ischemic coronary
events in an ACS population but is significantly inferior to OAC
alone for the prevention of stroke/systemic embolism in an AF
population).
5
As such clinicians have perceived an obligation
to treat patients with concomitant AF and CAD using both
OAC with and antiplatelet therapy in spite of the potential for
increased risk of fatal and nonfatal bleeding events, including
intracranial hemorrhage.
6–8
The purpose of this review is to explore the current evidence
and rationale for antithrombotic treatment strategies in AF
patients at risk for AF-associated stroke (i.e., those aged ≥ 65
years or CHADS2 score ≥ 1) with concomitant CAD. Specifically,
with a focus on the key clinical questions of: (1) What is the
Canadian Journal of General Internal Medicine
Volume 13, Special Issue 1, 2018 11
preferred antithrombotic therapeutic regimen for AF patients
with ACS or undergoing PCI? (2) Should we use NOACs as part
of the dual or triple therapy regimen? (3) What is the preferred
P2Y12 inhibitor as part of the combination therapy regimen?
(4)What is the optimal duration of triple antithrombotic therapy?
(5)What is the optimal antithrombotic therapy for AF patients
with stable CAD?
Question 1 – What Is the Preferred Antithrombotic
Therapeutic Regimen for af Patients With Acs or
Undergoing Pci?
The most complicated scenario for management of AF and CAD
is the patient with a strong indication for OAC therapy for stroke
prevention (aged ≥ 65 years or CHADS2 score ≥ 1), in whom
an acute coronary event has occurred. In this circumstance the
patient is at risk for both AF-related stroke/systemic embolism as
well as adverse ischemic coronary events (e.g., stent thrombosis
and recurrent myocardial infarction). There are three key
clinical trials that have been performed in an effort to address
the therapeutic dilemma associated with patients requiring oral
anticoagulation and dual antiplatelet therapy (Table 1).
The “What Is the Optimal Antiplatelet and Anticoagulation
Therapy in Patients With Oral Anticoagulation and Coronary
Stenting” (WOEST) study randomized 573 patients with a need
for anticoagulation undergoing PCI to dual pathway therapy
(OAC and clopidogrel 75mg/day) or to triple antithrombotic
therapy (OAC, clopidogrel, and aspirin 80 mg/day).
19,20
Treatment was continued for 1 month after BMS placement
(35% of patients) and for 1 year after DES placement (65% of
patients). The primary outcome of this open-label trial was any
Woest Pioneer AF-PCI Re-Dual PCI
Design Multicenter RCT Multicenter RCT Multicenter RCT
Population 573 2124 2725
Groups W+A+C (284)
W+C (279)
W+A+C (697)
R15+C (696)
R2.5+A+C (706)
W+A+C (981)
D110+C (981)
D150+C (763)
Follow-up 12 months 12 months 14 months
Age in years 68.7 70.1 70.8
Male 74.4% 74.4% 80.0%
% AF 69% 100% 100%
Outcomes
Any Bleeding HR 0.36
95%CI 0.26–0.50
R15+C - HR 0.59
95%CI 0.47–0.76
R2.5+A+C - HR 0.63
95%CI 0.50-0.80
D110 HR 0.52**
95%CI 0.42-0.63
D150 HR 0.72**
95%CI 0.58-0.88
Major TMI bleeding HR 0.56
95%CI 0.25-1.27
R15+C - HR 0.66
95% CI 0.33-1.31
R2.5+A+C - HR 0.57
95%CI 0.28-1.16
D110 HR 0.37*
95%CI 0.20-0.68
D150 HR 0.51
95%CI 0.28-0.93
MACE HR 0.6
1
95%CI 0.38-0.94
R15+C - HR 1.08
2
95%CI 0.69-1.68
R2.5+A+C - HR 0.93
2
95%CI 0.59-1.48
D110 HR 1.13
3
95%CI 0.90-1.43
D150 HR 0.89
3
95%CI 0.67-1.19
W = warfarin; A = ASA 81 mg daily; C = clopidogrel 75 mg daily; R15 = rivaroxaban 15 mg daily; R2.5 = rivaroxaban 2.5 mg bid; D110 = dabigatran 110 mg bid; D150 = dabigatran 150 mg bid.
**ISTH and clinically relevant non-major bleeding.
1
WOEST = death, myocardial infarction, stroke, target vessel revascularization, stent thrombosis.
2
PIONEER AF-PCI = cardiovascular death, myocardial infarction, stroke.
3
RE-DUAL PCI = Death, revascularization, myocardial infarction, stroke, systemic thromboembolism.
Table 1. Relative Comparison of the WOEST, PIONEER AF-PCI, RE-DUAL Trials
Andrade et al.
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
Canadian Journal of General Internal Medicine
Volume 13, Special Issue 1, 2018 13
Question 2 – Should We Use Noacs As Part of the
Dual or Triple Therapy Regimen?
It has been postulated that the use of NOACs may be beneficial
given the increased risk of fatal and nonfatal bleeding events
(including intracranial hemorrhage) observed with dual pathway
or triple antithrombotic therapy. Collectively the phase 3 clinical
trials studies comparing NOAC therapy to warfarin demonstrated
a non-significant 14% reduction in major bleeding with NOAC
therapy when compared to warfarin (95%CI 0.73-1.00).
9
The
majority of this benefit was achieved through a significant
reduction in hemorrhagic stroke, and subdural, epidural, and
subarachnoid bleeding (RR 0.48; 95%CI 0.39-0.59), which was
counterbalanced by an increase in gastrointestinal bleeding (RR
1.25; 95%CI 1.01–1.55).
For the subset of subjects (24–38%; total 21,722 patients)
who received combination OAC and antiplatelet therapy the use
of a standard-dose NOAC was not associated with any significant
difference in outcomes, however non-significant trends were
observed in terms of reduction in major bleeding (OR 0.94; 95%CI
0.80-1.10), all-cause mortality (OR 0.91; 95%CI 0.79-1.04), and
stroke (OR 0.89; 95%CI 0.62-1.30); with a non-significant increase
in the rates of myocardial infarction with NOAC therapy (OR
1.24; 95%CI 0.98-1.57) when compared to warfarin.
Question 3 – What Is the Preferred P2Y12 Inhibitor
As Part of the Combination Therapy Regimen?
In patients without a need for OAC, the antiplatelet guidelines
recommend the use of prasugrel or ticagrelor in preference to
clopidogrel for the management of non-ST-segment elevation
ACS and ST-elevation myocardial infarction. This is because of
their greater efficacy at reducing recurrent MI (11% reduction
with prasugrel; 15% reduction with ticagrelor), and stent
thrombosis (52% reduction with prasugrel; 26% reduction for
ticagrelor).
10,11
However, these agents are not recommended as a
part of a combination therapy owing to their greater propensity of
bleeding.
12
As such, clopidogrel is the preferred P2Y12 inhibitor
when used in combination therapies with an OAC.
Questions 4 – What Is the Optimal Duration
ofTriple Antithrombotic Therapy?
The benefit of triple antithrombotic therapy in reducing ischemic
outcomes is established in selected subgroups (i.e., those undergoing
high-risk PCI), however this benefit must be balanced against the
increased bleeding risk with this therapeutic regimen (Figure 2).
The “Intracoronary Stenting and Antithrombotic Regimen-
Testing of a 6-Week Versus a 6-Month Clopidogrel Treatment
Regimen in Patients with Concomitant Aspirin and Oral
Anticoagulant Therapy Following Drug-Eluting Stenting
(ISAR-TRIPLE) study randomized patients receiving OAC
to 6 weeks or 6 months of triple antithrombotic therapy (307
patients in each group).
13
All patients underwent PCI (33.2%
with ACS). The primary composite endpoint included death,
MI, stent thrombosis, stroke, or TIMI major bleeding. Although
underpowered, there was not difference in composite outcome
(cardiac death, MI, stent thrombosis, or ischemic stroke - 4.0%
vs. 4.3%; HR 0.93, 95%CI 0.43-2.05), TIMI major bleeding
Figure 1. Relative risk and benefits of antithrombotic therapies for each treatment phase.
Andrade et al.
Canadian Journal of General Internal Medicine
14 Volume 13, Special Issue 1, 2018
(5.3% vs. 4.0%; HR 1.35, 95%CI 0.64-2.84), or death (4.0% vs.
5.2%; HR 0.75, 95%CI 0.35-1.59). A post-hoc landmark analysis
from 6 weeks to 9 months (i.e. excluding the period where both
groups were on TT) demonstrated a significant reduction in
any bleeding in the 6 weeks group (20.5% vs. 27.9%; HR 0.68,
95%CI 0.47-0.98). In addition, the ischemic outcomes did not
differ between the 51% of patients in PIONEER AF-PCI used TT
durations shorter than 12 months, compared to those who were
on TT for a year. On balance, these findings suggest shortening
the triple antithrombotic therapy course to ≤ 6 months, and
thereafter continuing with OAC and clopidogrel, is reasonable
in patients at elevated bleeding risk.
Question 5 – What Is the Optimal Antithrombotic
Therapy for AF Patients With Stable CAD?
For patients with both AF and CAD the question that dominates
is whether OAC therapy alone is an adequate substitute for
ASA, or whether ASA should be added to OAC therapy on the
rationale that the anticoagulant effect of a VKA combined with the
antiplatelet effect of ASA may enhance antithrombotic efficacy.
Historically several studies have evaluated this question.
These studies randomized post myocardial infarction patients
to ASA alone vs. combined warfarin and aspirin therapy,
14–17
or ASA alone versus warfarin alone versus combined warfarin
and aspirin therapy.
18,19
Collectively these studies demonstrated
that combination therapy was associated with a reduction in the
combined endpoint of death/non-fatal MI/non-fatal stroke (OR
0.73; 95%CI 0.63-0.84) with a reduction in the rate of myocardial
infarction (OR 0.70; 95%CI 0.52-0.95) and stroke (RR 0.43;
95%CI 0.27-0.70), but an increase in the risk of bleeding (OR
2.32; 95%CI 1.63-3.29), when compared to ASA monotherapy.
20
Interestingly, OAC monotherapy was associated with similar
rates of death, MI, and stroke (e.g. 16.7% in warfarin group vs.
15.0% in Warfarin plus ASA group; P = 0.18) but lower rates of
bleeding compared to combined OAC and aspirin therapy (e.g.,
overall bleeding 2.82% vs. 3.27%).
18,19
When these studies are put together in a network meta-analysis
(132,657 CAD patients in 13 randomized and 7 non-randomized
studies) OAC monotherapy was associated with significantly
less major bleeding (OR 0.76; 95%CI 0.65-0.90), and a lower
all-cause mortality (OR 0.82; 95%CI 0.72-0.94), with a trend
towards reduced MI (OR 0.84; 95%CI 0.70-1.00) vs. combination
therapy. Therefore, for patients at risk of AF-associated stroke/
systemic embolism the cumulative evidence base supports the
use of OAC alone as it provides protection against both stroke
and coronary events. The addition of antiplatelet therapy to
OAC confers an increased risk of adverse bleeding outcomes
while providing only limited benefit on coronary outcomes.
Summary
General recommendations for antithrombotic therapy include
the following (see Figure 1):
1. For patients at low risk of AF-associated stroke
(age<65years and CHADS2 Score = 0) OAC therapy
ofthe coronary generally not recommended. The disease
should follow the recommendations found in the 2018
CCS/CAIC Focused Update of the Guidelines for the Use
of Antiplatelet Therapy.
2. For patients at high risk of AF-associated stroke
(age≥65years or CHADS
2
Score ≥ 1) and stable CAD we
recommend OAC alone.
Figure 2. Risk factors for bleeding, stroke, and coronary ischemic events.
Atrial Fibrillation and Coronary Artery Disease
Canadian Journal of General Internal Medicine
Volume 13, Special Issue 1, 2018 15
3. For patients at high risk of AF-associated stroke
(age ≥ 65 years or CHADS
2
Score ≥ 1) undergoing elective
or low-risk PCI, OAC combined with clopidogrel (dual
therapy) for one year should be employed.
4. For patients at high risk of AF-associated stroke
(age ≥ 65 years or CHADS
2
Score ≥ 1) undergoing high-
risk PCI, OAC combined with ASA and clopidogrel (triple
therapy) should be employed for up to 6 months post PCI,
followed by dual therapy with OAC plus clopidogrel until
one-year post PCI.
5. When OAC is used a NOAC is preferred.
6.
Clopidogrel is the preferred antiplatelet agent in dual
pathway or triple therapy.
Conclusion
The management of patients with concomitant AF and CAD
is challenging and requires a comprehensive assessment of the
competing risks of the therapeutic options. For most patients
OAC alone can be used for stable CAD, with triple therapy
used for a short period (<6 months) after ACS or high-risk PCI,
followed by dual therapy until 12 months post event.
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