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Managing Antithrombotic Therapies in Patients With Atrial

Fibrillation Who Have Undergone Percutaneous Coronary
Intervention CME
Renato D. Lopes, MD, MHS, PhD

Posted: 2/10/2020
This brief CME publication reviews the current evidence on antithrombotic therapy for patients with atrial fibrillation (AF) who
have undergone percutaneous coronary intervention (PCI) and explores the emerging standards of care in this setting. In
addition, this activity features a short video that provides expert commentary from Renato Lopes, MD, on the challenge of
managing antithrombotic therapy for these patients and how the evidence from recent clinical trials is informing practice.

INTRODUCTION
Atrial fibrillation (AF) currently affects 2.7 to 6.1 million individuals in the United States (US), and the prevalence is expected
to increase as the population ages.[1] Estimates suggest that 1 to 2 million patients with AF who are receiving chronic oral
anticoagulation (OAC) for stroke risk reduction are candidates for coronary revascularization, often in the form of
percutaneous coronary intervention (PCI).[2] Indeed, approximately 5% to 10% of patients undergoing PCI have AF.[2]

Determining the optimal approach to antithrombotic therapy for patients with AF with acute coronary syndrome (ACS) and/or
recent or upcoming PCI has been challenging.[3] Although OAC reduces the risk of stroke in patients with AF, it does not
seem to prevent stent thrombosis as well as antiplatelet therapy.[3,4] To prevent stent thrombosis in patients undergoing
PCI, dual antiplatelet therapy (DAPT) has been recommended ever since DAPT with aspirin plus clopidogrel was shown to
be superior to aspirin plus intensive anticoagulation with a vitamin K antagonist (VKA) in reducing stent thrombosis in the
early days of stent implantation.[5,6] However, this treatment approach has not been shown to effectively reduce stroke risk.
[4] Interestingly, triple antithrombotic therapy (TAT) with OAC, aspirin, and a P2Y inhibitor subsequently emerged as the
12
standard of care by expert consensus, without clear evidence from randomized clinical trials (RCTs) to support this
approach and despite the increased bleeding risk associated with combining OAC and DAPT.[3,6]

Recent RCTs have challenged the paradigm of triple therapy in patients with AF.[3,4,7] This brief activity reviews the state of
current evidence on antithrombotic therapy for patients with AF who have undergone PCI and explores emerging standards
of care in this setting.

LIMITATIONS OF EVIDENCE-BASED GUIDELINES

Despite a range of options for patients with AF who require stent replacement, including the emergence of novel
anticoagulant and antiplatelet therapies and advances in stent design, clinicians historically have had little data to guide
decision making.[8] Over the past 20 years, only 8.5% of American College of Cardiology (ACC)/American Heart Association
(AHA) guideline recommendations have been supported by multiple RCTs or a single large RCT, reflecting the highest level
of evidence (LOE A).[9] In fact, most guideline recommendations are based on weaker evidence, such as observational
studies or a single RCT (LOE B) or expert opinion only (LOE C).[9]

Even when based on RCT evidence, guideline recommendations quickly become outdated.[10] For instance, in 2019, the
AHA/ACC/Heart Rhythm Society (HRS) published a focused update on AF management.[10] Recommendations for post-
PCI anticoagulation in patients with AF were based on available evidence, which included data from the WOEST, PIONEER
AF-PCI, and RE-DUAL PCI trials.[10-13] In keeping with the anticoagulants evaluated in these trials, the 2019 guidelines

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address warfarin, rivaroxaban, and dabigatran use in this setting, but they do not capture findings from AUGUSTUS and
ENTRUST-AF PCI, which were published later the same year.[4,7,10-13]

EARLY TRIALS: WOEST, PIONEER AF-PCI, AND RE-DUAL PCI

The WOEST, PIONEER AF-PCI, and RE-DUAL PCI trials provided the first wave of evidence in support of double
antithrombotic therapy (DAT), yet limitations in the trial designs left some questions unanswered (Table 1).[11-13] The
WOEST trial showed a reduction in bleeding risk with clopidogrel-based DAT compared with TAT; however, the trial enrolled
patients with broad indications for OAC, including AF, mechanical valve, apical aneurysm, pulmonary embolus, peripheral
artery disease, or ejection fraction of less than 30%.[11] The PIONEER AF-PCI and RE-DUAL PCI trials demonstrated the
safety of non–vitamin K oral anticoagulant (NOAC)-based DAT relative to VKA-based TAT.[12,13] However, these trials were
not designed to determine whether the reductions in bleeding observed in the DAT arms were due to the NOAC itself, the
discontinuation of aspirin, or both.[11-13]

TABLE 1. Initial Trials of Double Versus Triple Antithrombotic Therapy [11-13]

Trial (Year) Comparison Groups No. of Key Findings Secondary Endpoints

Participants

WOEST 573
DAT: OAC Fewer patients with Stroke: DAT vs TAT
(2013)
plus bleeding episodes on DAT (1.2% vs 2.8%; HR,
clopidogrel vs TAT (19.4% vs 44.4%; 0.37; 95% CI, 0.1-
TAT: OAC HR, 0.36; 95% CI, 0.26- 1.4; P = .128)
plus 0.50; P < .0001) Target vessel
clopidogrel revascularization
and aspirin (PCI): DAT vs TAT
(6.1% vs 5.6%; HR,
1.06; 95% CI, 0.54-
2.1; P = .869)

PIONEER ~2,100
DAT: Lower rates of bleeding Stroke:
AF-PCI
rivaroxaban with either rivaroxaban- DAT vs VKA-
15 mg OD based regimen compared based TAT
(2016)
plus a with VKA-based TAT (1.3% vs
P2Y12 Rivaroxaban 15 mg 1.3%; HR,
inhibitor once daily plus a 1.07; 95%
TAT: P2Y12 inhibitor vs CI, 0.39-
rivaroxaban VKA plus DAPT 2.96; P =
2.5 mg (16.8% vs 26.7%; .89)
twice daily HR, 0.63; 95% CI, Rivaroxaban-
plus DAPT 0.50-0.80; P < .001) based TAT
TAT: VKA Rivaroxaban 2.5 mg vs VKA-
plus DAPT twice daily plus based TAT
DAPT vs VKA plus (1.5% vs
DAPT (18.0% vs 1.2%; HR,
26.7%; HR, 0.59; 1.36; 95%
95% CI, 0.47-0.76; P CI, 0.52-
< .001) 3.58; P =
.53)

RE-DUAL 2,725
DAT110: Lower rates of bleeding Stroke:
PCI
dabigatran with either dabigatran- DAT110 vs
110 mg based DAT regimen vs TAT TAT (1.7% vs
(2017)
twice daily 1.3%; HR,
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plus a DAT110 vs TAT 1.3; 95% CI,

P2Y12 (15.4% vs 26.9%; 0.63-2.67; P
inhibitor HR, 0.52; 95% CI, = 0.48)
DAT150: 0.42-0.63; P < .001) DAT150 vs
dabigatran DAT150 vs TAT TAT (1.2% vs
150 mg (20.2% vs 25.7%; 1.0%; HR,
twice daily HR, 0.72; 95% CI, 1.09; 95%
plus a 0.58-0.88; P < .001) CI, 0.42-
P2Y12 2.83; P =
inhibitor .85)
TAT: Composite efficacy
warfarin endpoint of
plus a thromboembolic
P2Y12 events, death, or
unplanned
inhibitor
revascularization:
and aspirin
DAT110 vs
TAT (15.2%
vs 13.4%;
HR, 1.13;
95% CI, 0.9-
1.43; P = .3)
DAT150 vs
TAT (11.8%
vs 12.8%;
HR, 0.89;
95% CI,
0.67-1.19; P
= .44)

AF = atrial fibrillation; CI = confidence interval; DAPT = dual antiplatelet therapy; DAT = double antithrombotic therapy; HR =
hazard ratio; OAC = oral anticoagulation; PCI = percutaneous coronary intervention; TAT = triple antithrombotic therapy;
VKA = vitamin K antagonist.

AUGUSTUS TRIAL

Several features of the AUGUSTUS trial design contributed unique insights to anticoagulant and antiplatelet therapy in
patients with AF and recent ACS and/or PCI.[4] Relative to the earlier trials, AUGUSTUS was the first to include patients
with ACS who were treated medically (ie, without PCI).[14] The trial enrolled 4,614 patients with AF who were undergoing
PCI (elective or not) or who experienced ACS (treated with PCI or medical management) and were planning to start
treatment with an approved P2Y12 inhibitor for at least 6 months.[4]

In addition, AUGUSTUS utilized a 2-by-2 factorial design to compare anticoagulation and antiplatelet strategies
independently.[4] First, patients were randomly assigned to receive apixaban (n = 2,306) or a VKA (n = 2,308), and, in a
second randomization, aspirin (n = 2,307) or placebo (n = 2,307) for 6 months. The primary endpoint was major or clinically
relevant non-major (CRNM) bleeding at 6 months.[4]

The median patient age was 70.7 years, and 29% of patients were women.[4] In total, 37.3% of patients underwent PCI for
ACS, 23.9% had medically managed ACS, and 38.8% underwent elective PCI. The median CHA2DS2-VASc score was 4.0,
and the median HAS-BLED score was 3.0. The median time to randomization was 6 days.[4]

Results of the anticoagulation comparison showed the superiority of apixaban relative to VKA (P < .001 for superiority)
(Table 2).[4] At 6 months, 10.5% of patients treated with apixaban and 14.7% of those treated with a VKA had a major or
CRNM bleeding event. Measured in terms of event rate per 100 patient-years, bleeding was 31% less likely with apixaban
compared with VKA (HR, 0.69; 95% CI, 0.58-0.81). Apixaban was also superior to VKA for the composite secondary
endpoint of death or hospitalization (P = .002).[4]

TABLE 2. AUGUSTUS Primary and Secondary Endpoints[4]

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Events per 100 Patient-Years Anticoagulation Comparison Antiplatelet Comparison

Apixaban VKA HR (95% CI) Aspirin Placebo HR (95% CI)

Primary endpoint

Major bleeding or CRNM 24.7a 35.8 0.69 (0.58- 40.5 21.0b 1.89 (1.59-
bleeding 0.81) 2.24)

Secondary endpoints

Death or hospitalization 57.2c 69.2 0.83 (0.74- 65.7 60.6 1.08 (0.96-
0.93) 1.21)

Death or ischemic event 14.3 15.3 0.93 (0.75- 13.9 15.7 0.89 (0.71-
1.16) 1.11)

a P < .001 for superiority vs VKA.

b P < .001 for superiority vs aspirin.

c P = .002 for superiority vs VKA.

CI = confidence interval; CRNM = clinically relevant non-major; HR = hazard ratio; VKA = vitamin K antagonist.

In the comparison of antiplatelet strategies, 16.1% of patients in the aspirin group reached the primary bleeding endpoint,
compared with 9.0% of those in the placebo group.[4] The event rate per 100 patient-years was significantly higher with
aspirin than placebo (HR, 1.89; 95% CI, 1.59-2.24); thus, placebo was superior to aspirin (P < .001 for superiority). Across
the 4 regimens, the percentage of patients with a major or CRNM bleeding event was[4]:

VKA plus aspirin: 18.7%

Apixaban plus aspirin: 13.8%
VKA plus placebo: 10.9%
Apixaban plus placebo: 7.3%

ENTRUST-AF PCI TRIAL

The multicenter, open-label, phase 3b ENTRUST-AF PCI trial was the first to compare an edoxaban-based DAT against
VKA-based TAT in patients with AF who underwent PCI.[7] The trial enrolled 1,506 patients with AF who had PCI for ACS or
stable coronary artery disease. Patients were randomly assigned to DAT with edoxaban plus a P2Y12 inhibitor for 12 months
(n = 751) or TAT with a VKA in combination with a P2Y12 inhibitor for 12 months and aspirin for 1 to 12 months (n = 755).
The primary endpoint was major or CRNM bleeding within 12 months.[7]

The median patient age was 70 years, and 26% of patients were women.[7] The median CHA2DS2-VASc score was 4.0,
and the median HAS-BLED score was 3.0. The median time from PCI to randomization was 45.1 hours. Among those
assigned to the VKA-based regimen, the median duration of TAT was 66 days.[7]

Results support edoxaban-based DAT as a reasonable alternative to VKA-based TAT (Table 3).[7] At 12 months, 17.0% of
patients in the edoxaban group and 20.0% of those in the VKA group had a major or CRNM bleeding event. The annualized
bleeding rates were 20.7% and 25.6%, respectively (HR, 0.83; 2-sided 95% CI, 0.65-1.05). DAT with edoxaban plus a
P2Y12 inhibitor was noninferior to VKA-based TAT (P = .0010 for noninferiority) but did not meet statistical significance for
superiority (P = .1154 for superiority).[7]

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The annualized event rate for the main efficacy composite endpoint of cardiovascular death, stroke, systemic embolic event,
myocardial infarction (MI), or definite stent thrombosis was 7.3% with DAT and 6.9% with TAT, indicating no difference in
ischemic events between groups.[7] Thus, edoxaban-based DAT was noninferior to VKA-based TAT for bleeding in patients
with AF who had undergone PCI, with no increase in ischemic events.[7]

TABLE 3. ENTRUST-AF Primary, Secondary, and Efficacy Endpoints[7]

Event Rate per Year Edoxaban VKA Two-Sided HR

Regimen Regimen (95% CI)

Primary endpoint

Major bleeding or CRNM bleeding 20.7%a 25.6% 0.83 (0.65-1.05)

Secondary endpoint

Major bleeding 6.7% 7.2% 0.95 (0.63-1.42)

Efficacy endpoint

Cardiovascular death, stroke, systemic embolism, MI, or definite 7.3% 6.9% 1.06 (0.71-1.69)
stent thrombosis

a P = .0010 for noninferiority versus VKA regimen.

CI = confidence interval; CRNM = clinically relevant non-major; HR = hazard ratio; MI = myocardial infarction; VKA = vitamin
K antagonist.

META-ANALYSIS OF THE RCTs

In 2019, Lopes and colleagues published a network meta-analysis that evaluated the safety and efficacy of antithrombotic
strategies in patients with AF undergoing PCI.[3] This study included more than 10,000 participants from the WOEST,
PIONEER AF-PCI, RE-DUAL PCI, and AUGUSTUS trials. The analysis showed the following odds ratios (ORs) for TIMI
major bleeding compared with VKA plus DAPT (P2Y12 inhibitor plus aspirin)[3] :

0.58 (95% CI, 0.31-1.08) for VKA plus P2Y12 inhibitor

0.49 (95% CI, 0.30-0.82) for NOAC plus P2Y12 inhibitor
0.70 (95% CI, 0.38-1.23) for NOAC plus DAPT

Regarding intracranial bleeding, the NOAC plus P2Y12 inhibitor had the lowest OR among the regimens (VKA plus DAPT,
reference; VKA plus P2Y12 inhibitor, 1.44 [95% CI, 0.40-5.22]; NOAC plus DAPT, 0.54 [95% CI, 0.15-1.92]; NOAC plus
P2Y12 inhibitor, 0.26 [95% CI, 0.08-0.79]).[3] In addition, the analysis showed that there was no significant difference in
major adverse cardiovascular events when aspirin was omitted. The results from this analysis support the use of NOAC plus
P2Y12 inhibitor (without aspirin) as the preferred post-PCI regimen for high-risk patients with AF.[3]

CONCLUSION
Effective anticoagulation that balances the risks of stroke, bleeding, MI, and stent thrombosis is critical for the growing
population of patients with AF undergoing PCI. Evidence to date supports the use of DAT with a NOAC plus a P2Y12
inhibitor as the preferred post-PCI regimen for patients with AF. Classic TAT in the form of a VKA plus DAPT (ie, a P2Y12
inhibitor plus aspirin) should generally be avoided in these patients.
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References

1. Centers for Disease Control and Prevention. Atrial fibrillation. December 9, 2019.
www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_atrial_fibrillation.htm. Accessed January 6, 2020.
2. Capodanno D, Angiolillo DJ. Management of antiplatelet and anticoagulant therapy in patients with atrial fibrillation in
the setting of acute coronary syndromes or percutaneous coronary interventions. Circ Cardiovasc Interv.
2014;7(1):113-124.
3. Lopes RD, Hong H, Harskamp RE, et al. Safety and efficacy of antithrombotic strategies in patients with atrial
fibrillation undergoing percutaneous coronary intervention: a network meta-analysis of randomized controlled trials.
JAMA Cardiol. 2019;4(8):747-755.
4. Lopes RD, Heizer G, Aronson R, et al; AUGUSTUS Investigators. Antithrombotic therapy after acute coronary
syndrome or PCI in atrial fibrillation. N Engl J Med. 2019;380(16):1509-1524.
5. Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-
artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med. 1998;339(23):1665-1671.
6. Duerschmied D, Brachmann J, Darius H, et al. Antithrombotic therapy in patients with non-valvular atrial fibrillation
undergoing percutaneous coronary intervention: should we change our practice after the PIONEER AF-PCI and RE-
DUAL PCI trials? Clin Res Cardiol. 2018;107(7):533-538.
7. Vranckx P, Valgimigli M, Eckardt L, et al. Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen
after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label,
phase 3b trial. Lancet. 2019;394(10206):1335-1343.
8. Gibson CM. Going polymer free and dual antiplatelet free earlier: the coevolution of stent and pharmacotherapy. J
Am Coll Cardiol. 2017;69(2):172-175.
9. Fanaroff AC, Califf RM, Windecker S, et al. Levels of evidence supporting American College of Cardiology/American
Heart Association and European Society of Cardiology Guidelines, 2008-2018. JAMA. 2019;321(11):1069-1080.
10. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline
for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American
Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol.
2019;74(1):104-132.
11. DeWilde WJ, Oirbans T, Verheugt FW, et al; WOEST study investigators. Use of clopidogrel with or without aspirin in
patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label,
randomised, controlled trial. Lancet. 2013;381(9872):1107-1115.
12. Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl
J Med. 2016;375(25):2423-2434.
13. Cannon CP, Bhatt DL, Oldgren J, et al; RE-DUAL PCI Steering Committee and Investigators. Dual antithrombotic
therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med. 2017;377(16):1513-1524.
14. Jones DW, Minhas S, Fierro JJ, et al. From WOEST to AUGUSTUS: a review of safety and efficacy of triple versus
dual antithrombotic regimens in patients with atrial fibrillation requiring percutaneous coronary intervention for acute
coronary syndrome. Ann Transl Med. 2019;7(17):405.

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