Introduction

Coronary artery disease (CAD) including acute coronary syndromes (ACS) frequently complicates a diagnosis of atrial fibrillation (AF). Depending on the age of the studied cohort and the sensitivity of the qualifying definition, between 1 in 5 and 1 in 2 individuals with AF have concomitant CAD.¹ Both conditions are inexorably linked with advancing age and metabolic disease; in the context of an ageing population and increasing burden of both diabetes and obesity,² the rates of comorbid AF and CAD are likely to increase. Although therapies directed at diabetes, hypertension, sleep apnea, cigarette smoking, and obesity have indisputable mutual benefit, decisions regarding antithrombotic therapy are challenging and, at times, competing.

Anticoagulation has proven stroke prevention and mortality benefit in patients with AF; however, its role in the secondary prevention of CAD remains unclear.³ Dual antiplatelet therapy (DAPT) (i.e., the addition of a P2Y₁₂ receptor antagonist to aspirin background therapy) has an established role in CAD secondary prevention following either percutaneous coronary intervention (PCI) or recent ACS but is inferior to oral anticoagulation for stroke prevention.⁴ The use of triple therapy (i.e., a combination of an oral anticoagulant with DAPT) provides minimal incremental protection from ischemic events and is associated with a multiplicative risk of bleeding.^5,6 Attenuation of either or both of the antithrombotic classes is attractive; however, finding the optimal regimen has proven challenging.⁷ Increasing numbers of compounds in multiple classes, varying doses and durations, iterative risk scoring, and evolving stent technology have all added complexity.

Existing Evidence

The WOEST trial (What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulation and Coronary Stenting) evaluated patients on oral anticoagulants undergoing PCI to a regimen of vitamin K antagonist (VKA) with aspirin and clopidogrel or VKA with clopidogrel.⁸ The VKA/clopidogrel arm was associated with both reduced bleeding (hazard ratio [HR] 0.36; 95% confidence interval [CI], 0.26-0.50; p < 0.0001) and ischemic events (HR 0.60; 95% CI, 0.38-0.94; p = 0.025). The caveats are the size of the trial (n = 573), heterogenous oral anticoagulant indication (AF = 69%), low proportion of ACS, and only modest drug-eluted stent use.

PIONEER-AF PCI (An 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) randomized patients 1:1:1 with rivaroxaban 15 mg plus P2Y₁₂ receptor antagonist versus rivaroxaban 2.5 mg daily plus DAPT versus triple therapy with VKA.⁹ Although both rivaroxaban arms were associated with reduced bleeding compared with the triple therapy VKA cohort, neither of the rivaroxaban arms used a dose that has been formally shown to reduce stroke or systemic embolism. Put in context, rivaroxaban at a higher dose of 20 mg met its non-inferiority endpoint but was not superior to VKA for ischemic events (HR 0.88; 95% CI, 0.74-1.03; p < 0.001 for noninferiority; p = 0.12 for superiority).¹⁰

The REDUAL PCI trial (Randomized Evaluation of Dual Antithrombotic Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) randomized patients to either DAPT with a P2Y₁₂ receptor antagonist and dabigatran at either 110 mg or 150 mg or to triple therapy with VKA.¹¹ Although both dabigatran arms were associated with a graded reduction in bleeding events, higher rates of myocardial infarction (MI) (4.5% vs. 3.4%) and stent thrombosis (1.5% vs. 0.9%) were observed in the lower compared with higher dabigatran dose arms.

Recently presented at the European Society of Cardiology 2019 Congress, the open-label ENTRUST-AF PCI (Edoxaban-Based Antithrombotic Regimen in Patients With Atrial Fibrillation) trial compared edoxaban 60 mg plus a P2Y₁₂ receptor antagonist against triple therapy with VKA in 1,506 patients with AF undergoing PCI.¹² Numerically fewer bleeding events occurred in the edoxaban arm (HR 0.83; 95% CI, 0.65-1.05), which met the non-inferiority endpoint (p = 0.001) but did not reach statistical significance for superiority (p = 0.12).

These trials established the safety profile of direct acting oral anticoagulants (DOACs); however, their design did not assess whether the observed benefit was due to the use of standard- or reduced-dose DOAC or due to the omission of aspirin (Table 1).

Table 1: Key Characteristics of Randomized Trials Comparing Various Regimens of Double and Triple Therapy

Name [Year]	Study Arms	Sample	Duration	Antiplatelet Population			Anticoagulant Population
				Clopidogrel	ACS	Drug-eluting stent	CHA2DS2VASc	HAS-BLED
WOEST [2013]	• VKA + aspirin/clopidogrel • VKA + clopidogrel	573	12	100%	27.5%	64.7%	CHA2DS2 = 3 (median)	N/A
PIONEER-AF PCI [2016]	• VKA + aspirin/P2Y12 • Rivaroxaban 15 mg • Rivaroxaban 2.5 mg BD	2,124	12	94.7%	51.0%	65.9%	4 (median)	3 (median)
RE-DUAL PCI [2017]	• VKA + DAPT • Dabigatran (150) + P2Y12 • Dabigatran (110) + P2Y12	2,725	14	88%	50.5%	82.6%	3.6	2.7
AUGUSTUS [2019]	• Apixaban + P2Y12 + aspirin • Apixaban + P2Y12 + placebo • VKA + P2Y12 + aspirin • VKA + P2Y12 + placebo	4,614	6	92.6%	61.2%	?	3.9	2.9
ENTRUST-AF PCI [2019]	• Edoxaban + P2Y12 • VKA + P2Y12 + aspirin	1,506	12	93%	52%	?	4	3

AUGUSTUS

AUGUSTUS (Antithrombotic Therapy After Acute Coronary Syndrome or PCI in Atrial Fibrillation) was a prospective, multicenter two-by-two factorial randomized clinical trial.¹³ Participants with AF who had sustained an ACS or undergone PCI and were treated (or planned for treatment) with a P2Y₁₂ receptor antagonist were randomized to either apixaban or warfarin (anticoagulant factor, open label) and either aspirin or placebo (antiplatelet factor, placebo-controlled) (Figure 1). This trial design permitted two independent hypotheses with respect to bleeding:

1. Apixaban is non-inferior (and potentially superior) to VKA.
2. A P2Y₁₂ receptor as the sole antiplatelet is superior to DAPT.

Figure 1: AUGUSTUS Trial Design and Flow

The primary outcome for each study factor was International Society on Thrombosis and Haemostasis major or clinically relevant nonmajor bleeding. Two secondary outcomes included the composite of death or hospitalization or the composite of death or ischemic events (stroke, MI, stent thrombosis, or urgent revascularization). Each of the components in the secondary endpoint was considered an individual exploratory endpoint. The study follow-up duration was 6 months.

Between September 2015 and April 2018, 4,614 participants from 494 sites in 33 countries were enrolled. The median age was 70.7 years, and just under 1/3 were women. The overall mean CHA₂DS₂-VASc score was 3.9, and the HAS-BLED score was 2.9. Clopidogrel was the most commonly administered P2Y₁₂ inhibitor, and ACS was the qualifying indication in 61%.

The trial met its primary endpoint, with major or clinically relevant nonmajor bleeding occurring less frequently in patients receiving apixaban compared with VKA (10.5% vs. 14.7%; HR 0.69; 95% CI, 0.58-0.81; p < 0.001 for superiority) and more frequently in patients receiving aspirin compared with placebo (16.1% vs. 9.0%; HR 1.89; 95% CI, 1.59-2.24; p < 0.001). Fewer patients in the apixaban arm died or were hospitalized (23.5% vs. 27.4%; HR 0.83; 95% CI, 0.74-0.96; p = 0.002), driven mainly by hospitalization; however, no differences were observed between the aspirin and placebo arms (26.2% vs. 24.7%; HR 1.08; 95% CI, 0.96-1.21; p = NS). With respect to the other secondary outcome, there were no differences in the rates of death or ischemic events between apixaban- and VKA-treated patients, nor aspirin- and placebo-treated patients. There were numerical, non-significant increases in the rates of MI, stent thrombosis, and urgent revascularization associated with aspirin withdrawal.

Implications

AUGUSTUS is the largest study in the field and contributes almost half of all patients ever studied in trials evaluating a combined anticoagulation/antiplatelet strategy in patients with CAD and AF (Figure 2).¹⁴ The superior bleeding profile for full-dose apixaban significantly moves the needle toward a DOAC-based strategy; the magnitude of benefit is potentially even more impressive when one considers up to 23% of the VKA arm spent time below the therapeutic range. Whether these findings in their totality can be extended to other Xa or thrombin inhibitors remains unclear because prior trials were not designed to address this particular question and had varying efficacy when compared head-to-head with VKA.

Figure 2: Relative Contribution to the Evidence Evaluating Different Treatment Regimens

The trial definitively demonstrated that omission of aspirin from a triple therapy strategy produced a predictable, incremental reduction in bleeding (relative risk reduction 47%; absolute risk reduction 7.1%). However, it was not able to definitively exclude an increase in MI or stent thromboses; indeed, although rare, there were numerically more stent thromboses in the placebo arm (n = 21, 0.9%) compared with aspirin (n = 11, 0.5%). Applied at a population level, presuming a treatment effect of 0.4% absolute risk reduction, 250 patients would need to be treated with aspirin for 6 months to prevent 1 stent thrombosis, and it would come at a cost of 18 additional major or clinically relevant nonmajor bleeds. Although the relative weight and net clinical outcome of these events can be debated, there is a need to better understand (and potentially mitigate) the specific, patient-level factors that may influence early ischemic events in this highly select group of patients. In this regard, ongoing subgroup analysis may assist in identifying those individuals who are most likely to benefit from extended aspirin administration and, potentially, for how long.

Summary

In most patients with AF who sustain an ACS or require PCI and thus require treatment with a P2Y₁₂ receptor antagonist, an antithrombotic regimen that includes apixaban should be considered to reduce bleeding events when compared with VKA. Given that the majority of patients in AUGUSTUS were on aspirin for up to 6 days prior to randomization, it seems reasonable to continue aspirin for the hospitalization period and then withdraw to achieve further reduction in bleeding.

References

1. Michniewicz E, Mlodawska E, Lopatowska P, Tomaszuk-Kazberuk A, Malyszko J. Patients with atrial fibrillation and coronary artery disease - Double trouble. Adv Med Sci 2018;63:30-35.
2. GBD 2015 Obesity Collaborators, Afshin A, Forouzanfar MH, et al. Health Effects of Overweight and Obesity in 195 Countries over 25 Years. N Engl J Med 2017;377:13-27.
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4. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016;68:1082-115.
5. Lopes RD, Rao M, Simon DN, et al. Triple vs Dual Antithrombotic Therapy in Patients with Atrial Fibrillation and Coronary Artery Disease. Am J Med 2016;129:592-599.e1.
6. van Rein N, Heide-Jørgensen U, Lijfering WM, Dekkers OM, Sørensen HT, Cannegieter SC. Major Bleeding Rates in Atrial Fibrillation Patients on Single, Dual, or Triple Antithrombotic Therapy. Circulation 2019;139:775-86.
7. Capodanno D, Huber K, Mehran R, et al. Management of Antithrombotic Therapy in Atrial Fibrillation Patients Undergoing PCI: JACC State-of-the-Art Review. J Am Coll Cardiol 2019;74:83-99.
8. Dewilde WJ, Oirbans T, Verheugt FW, et al. 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;381:1107-15.
9. Gibson CM, Mehran R, Bode C, et al. Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. N Engl J Med 2016;375:2423-34.
10. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91.
11. Cannon CP, Bhatt DL, Oldgren J, et al. Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation. N Engl J Med 2017;377:1513-24.
12. 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;Sep 2:[Epub ahead of print].
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14. 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;Jun 19:[Epub ahead of print].

Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Arrhythmias and Clinical EP, Cardiovascular Care Team, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Prevention, Atherosclerotic Disease (CAD/PAD), Anticoagulation Management and ACS, Anticoagulation Management and Atrial Fibrillation, Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism, Novel Agents, Interventions and ACS, Interventions and Coronary Artery Disease, Hypertension, Smoking, Sleep Apnea

Keywords: Thrombin, Numbers Needed To Treat, Hemorrhage, Warfarin, Risk, Anticoagulants, Acute Coronary Syndrome, Atrial Fibrillation, Aspirin, Fibrinolytic Agents, Purinergic P2Y Receptor Antagonists, Coronary Artery Disease, Follow-Up Studies, Secondary Prevention, Confidence Intervals, Smoking, Aging, Prospective Studies, Pyridines, Pyridones, Thiazoles, Pyrazoles, Ticlopidine, Thrombosis, Embolism, Percutaneous Coronary Intervention, Stroke, Myocardial Infarction, Stents, Hemostasis, Diabetes Mellitus, Hypertension, Sleep Apnea Syndromes, Hospitalization, Obesity, Metabolic Diseases, Vitamin K

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