AUGUSTUS
Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation
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
PDF: 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.