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AUGUSTUS

Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation

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Year of Publication: 2019

Authors: Renato D. Lopes, Gretchen Heizer, Ronald Aronson, ..., John H. Alexander

Journal: New England Journal of Medicine

Citation: N Engl J Med 2019;380:1509-24

Link: https://doi.org/10.1056/NEJMoa1817083

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJMoa1817083

Clinical Question

What is the optimal antithrombotic regimen for patients with atrial fibrillation who have acute coronary syndrome or undergo PCI?

Bottom Line

In patients with atrial fibrillation and recent ACS/PCI, apixaban without aspirin resulted in less bleeding and fewer hospitalizations compared to vitamin K antagonist with or without aspirin, without increasing ischemic events.

        Major Points
        First 2x2 factorial trial to separately assess anticoagulant choice and aspirin use in AF patients post-ACS/PCI
Apixaban superior to vitamin K antagonist for primary bleeding endpoint (10.5% vs 14.7%, HR 0.69)
Aspirin significantly increased bleeding compared to placebo (16.1% vs 9.0%, HR 1.89)
Apixaban reduced death/hospitalization vs vitamin K antagonist (23.5% vs 27.4%, HR 0.83)
No significant difference in ischemic events between anticoagulant groups
Aspirin did not reduce ischemic events compared to placebo
Lowest bleeding rates with apixaban + placebo (7.3%)
Highest bleeding rates with vitamin K antagonist + aspirin (18.7%)
92.6% of patients used clopidogrel as P2Y12 inhibitor
Median time in therapeutic range for warfarin was 59%

      

Design

Study Type: Multicenter, international, 2x2 factorial randomized controlled trial

Randomization: 1

Blinding: Open-label for anticoagulant comparison, double-blind for aspirin vs placebo

Enrollment Period: September 2015 - April 2018

Follow-up Duration: 6 months with 7-month visit

Centers: 492

Countries: 33

Sample Size: 4614

Analysis: Cox proportional-hazards model, hierarchical testing procedure, intention-to-treat for secondary outcomes

Inclusion Criteria

Age ≥18 years
Previous, persistent, permanent, or paroxysmal atrial fibrillation requiring long-term anticoagulation
Recent acute coronary syndrome or PCI
Planned P2Y12 inhibitor use for ≥6 months

Exclusion Criteria

Anticoagulation for other conditions (prosthetic valves, VTE, mitral stenosis)
Severe renal insufficiency
History of intracranial hemorrhage
Recent/planned CABG surgery
Coagulopathy or ongoing bleeding
Contraindication to study drugs

Baseline Characteristics

Characteristic	Control	Active
Median Age	70.9 years	70.4 years
Female	28.9%	29.1%
Median CHA2DS2-VASc	4	4
Median HAS-BLED	3	3
Previous VKA use	46.4%	51.7%
ACS + PCI	36.6%	38.0%
Medically managed ACS	23.9%	23.8%
Elective PCI	39.5%	38.2%

Arms

Field	Apixaban Group	Control	Aspirin Group	Control
Intervention	Apixaban 5mg twice daily (or 2.5mg if dose reduction criteria met) plus P2Y12 inhibitor	Vitamin K antagonist (target INR 2.0-3.0) plus P2Y12 inhibitor	Aspirin 81mg daily plus anticoagulant and P2Y12 inhibitor	Matching placebo plus anticoagulant and P2Y12 inhibitor
Duration	6 months	6 months	6 months	6 months

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
ISTH major or clinically relevant nonmajor bleeding	Primary	14.7% (VKA) vs 9.0% (placebo)	10.5% (apixaban) vs 16.1% (aspirin)	0.69 (apixaban vs VKA), 1.89 (aspirin vs placebo)	<0.001 for both comparisons
Death or hospitalization	Secondary	27.4% (VKA), 24.7% (placebo)	23.5% (apixaban), 26.2% (aspirin)	0.83 (apixaban), 1.08 (aspirin)	0.002 (apixaban), NS (aspirin)
Death or ischemic events	Secondary	7.1% (VKA), 7.3% (placebo)	6.7% (apixaban), 6.5% (aspirin)	0.93 (apixaban), 0.89 (aspirin)	NS for both
Stroke	Secondary	1.1% (VKA)	0.6% (apixaban)	0.50	0.03
ISTH major bleeding	Adverse	4.6% (VKA), 2.9% (placebo)	3.0% (apixaban), 4.7% (aspirin)	0.64 (apixaban), 1.70 (aspirin)
Intracranial hemorrhage	Adverse	0.6% (VKA), 0.4% (placebo)	0.2% (apixaban), 0.4% (aspirin)	0.39 (apixaban), 0.82 (aspirin)
Death	Adverse	3.2% (VKA), 3.4% (placebo)	3.3% (apixaban), 3.1% (aspirin)	1.03 (apixaban), 0.91 (aspirin)

Subgroup Analysis

Effects consistent across prespecified subgroups including age, indication, P2Y12 inhibitor type, and risk scores

Criticisms

Modest time in therapeutic range (59%) for vitamin K antagonist group
Not powered to detect differences in individual ischemic outcomes
Only 6-month follow-up period
Open-label design for anticoagulant comparison
Predominant use of clopidogrel (92.6%) rather than more potent P2Y12 inhibitors
Numerically more coronary ischemic events without aspirin (though not statistically significant)

Funding

Bristol-Myers Squibb and Pfizer

Based on: AUGUSTUS (New England Journal of Medicine, 2019)

Authors: Renato D. Lopes, Gretchen Heizer, Ronald Aronson, ..., John H. Alexander

Citation: N Engl J Med 2019;380:1509-24

Content summarized and formatted by NeuroTrials.ai.

AUGUSTUS

(2019)

Objective

Compare apixaban vs vitamin K antagonist and aspirin vs placebo in patients with atrial fibrillation and recent acute coronary syndrome or PCI on P2Y12 inhibitor therapy.

Study Summary

• 2x2 factorial trial, showed that apixaban + clopidogrel was associated with less bleeding risks and same efficacy as DAPT + anticoagulation for patients with acute coronary syndrome or PCI with Afib.

Intervention

Apixaban 5mg twice daily (or 2.5mg if dose reduction criteria met) vs vitamin K antagonist (target INR 2.0-3.0), plus aspirin 81mg daily vs matching placebo, all on background P2Y12 inhibitor therapy for 6 months.

Inclusion Criteria

Age ≥18 years with atrial fibrillation requiring long-term anticoagulation, recent acute coronary syndrome or PCI, planned P2Y12 inhibitor use for ≥6 months, pre-stroke independence.

Study Design

Arms: Apixaban vs Vitamin K Antagonist AND Aspirin vs Placebo (2x2 factorial)

Patients per Arm: 2,306 apixaban vs 2,308 vitamin K antagonist; 2,307 aspirin vs 2,307 placebo

Outcome

• Major/clinically relevant bleeding: 10.5% apixaban vs 14.7% vitamin K antagonist (HR 0.69, P<0.001); 16.1% aspirin vs 9.0% placebo (HR 1.89, P<0.001). <br>• Death/hospitalization: 23.5% apixaban vs 27.4% vitamin K antagonist (HR 0.83, P=0.002). <br>• Similar ischemic event rates between groups. <br>• Best outcome: apixaban + placebo (7.3% bleeding); worst: vitamin K antagonist + aspirin (18.7% bleeding).

Bottom Line

Major Points

First 2x2 factorial trial to separately assess anticoagulant choice and aspirin use in AF patients post-ACS/PCI
Apixaban superior to vitamin K antagonist for primary bleeding endpoint (10.5% vs 14.7%, HR 0.69)
Aspirin significantly increased bleeding compared to placebo (16.1% vs 9.0%, HR 1.89)
Apixaban reduced death/hospitalization vs vitamin K antagonist (23.5% vs 27.4%, HR 0.83)
No significant difference in ischemic events between anticoagulant groups
Aspirin did not reduce ischemic events compared to placebo
Lowest bleeding rates with apixaban + placebo (7.3%)
Highest bleeding rates with vitamin K antagonist + aspirin (18.7%)
92.6% of patients used clopidogrel as P2Y12 inhibitor
Median time in therapeutic range for warfarin was 59%

Study Design

Study Type: Multicenter, international, 2x2 factorial randomized controlled trial
Randomization: Yes
Blinding: Open-label for anticoagulant comparison, double-blind for aspirin vs placebo
Sample Size: 4614
Follow-up: 6 months with 7-month visit
Centers: 492

Primary Outcome

Definition: ISTH major or clinically relevant nonmajor bleeding

Control	Intervention	HR/OR	P-value
14.7% (VKA) vs 9.0% (placebo)	10.5% (apixaban) vs 16.1% (aspirin)	0.69 (apixaban vs VKA), 1.89 (aspirin vs placebo) (0.58-0.81 (apixaban), 1.59-2.24 (aspirin))	<0.001 for both comparisons

Limitations & Criticisms

Modest time in therapeutic range (59%) for vitamin K antagonist group
Not powered to detect differences in individual ischemic outcomes
Only 6-month follow-up period
Open-label design for anticoagulant comparison
Predominant use of clopidogrel (92.6%) rather than more potent P2Y12 inhibitors
Numerically more coronary ischemic events without aspirin (though not statistically significant)

Citation

N Engl J Med 2019;380:1509-24

View Original Publication →

AUGUSTUS

Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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