ARTESIA
PubMed • Full text • PDF • ClinicalTrials.gov
Clinical Question
Is apixaban more effective and safer than aspirin in some patients with subclinical atrial fibrillation?
Bottom Line
In certain patients with subclinical atrial fibrillation, apixaban reduced the risk of stroke and systemic embolism compared to aspirin, but increased rate of bleeding.
Major Points
Antithrombotic therapy reduces the rate of stroke and systemic embolism in many patients with persistent atrial fibrillation, but whether this holds true for certain patients with subclinical atrial fibrillation has been unclear. ARTESIA enrolled patients with a prior history of pacemaker or implanted defibrillator who experienced subclinical, device-detected atrial fibrillation, and who were at a higher risk of stroke or systemic thromboembolism based on clinical factors. Over 4,000 patients were randomized to apixaban or aspirin and followed for the primary outcomes of stroke or systemic embolism and for the primary safety outcome of major bleeding. Stroke or systemic embolism was reduced in patients receiving apixaban (HR 0.63), while major bleeding was more common in apixaban-treated patients (HR 1.80).
The ARTESIA trial highlights the efficacy of apixaban in reducing the risk of stroke or systemic embolism by 37% compared to aspirin in patients with subclinical atrial fibrillation and risk factors for stroke. Additionally, apixaban significantly lowers the risk of disabling or fatal stroke by 49%. However, this benefit comes with an increased risk of major bleeding, although the authors highlight that most bleeding incidents were manageable with supportive care. The trial's findings emphasize the importance of a balanced approach in considering the benefits and risks of anticoagulation therapy with apixaban in this patient population. The high discontinuation rate also warrants careful consideration and shared decision making.
Guidelines
ACC/AHA/ACCP/HRS Atrial Fibrillation Management (2023, adapted)[1]
- For patients with a device-detected atrial high-rate episode (AHRE) lasting ≥24 hours and with a CHA2DS2-VASc score ≥2 or equivalent stroke risk, it is reasonable to initiate oral anticoagulation within a shared decision making (SDM) framework that considers episode duration and individual patient risk.
- For patients with a device-detected AHRE lasting between 5 minutes and 24 hours and with a CHA2DS2-VASc score ≥3 or equivalent stroke risk, it may be reasonable to initiate anticoagulation within a SDM framework that considers episode duration and individual patient risk.
- Patients with a device-detected AHRE lasting <5 minutes and without another indication for oral anticoagulation should not receive oral anticoagulation.
Design
- Multicenter, double-blind, double-dummy, randomized, controlled trial
- N=4,012 patients with subclinical atrial fibrillation at higher risk of complications
- Apixaban (n=2,015)
- Aspirin (n=1,997)
- Setting: 263 sites in Europe and North America
- Enrollment: 2015-2021
- Mean follow-up: 3.5 years for ITT, 2.5 years for on-treatment analysis
- Analysis: Intention-to-treat for primary efficacy outcome, on-treatment for primary safety outcome
- Primary outcomes: (1) Stroke or systemic embolism (efficacy), (2) major bleeding (safety)
Population
Inclusion Criteria
- Age ≥55 years
- Permanent pacemaker or defibrillator (with or without resynchronization) or insertable cardiac monitor capable of detecting SCAF
- ≥1 episode of device-detected subclinical atrial fibrillation (SCAF) lasting ≥6 minutes but no single episode >24 hours at any time prior to enrollment. No distinction will be made between atrial fibrillation and atrial flutter. SCAF requires electrocardiogram confirmation unless ≥6 hours in duration
- At least one additional risk factor for stroke:
- Previous stroke, TIA or systemic arterial embolism
- Age ≥75 years
- Age 65-74 with ≥2 other risk factors
- Age 55-64 with ≥3 other risk factors
Exclusion Criteria
- Clinical atrial fibrillation documented by surface ECG lasting ≥6 minutes
- Indication for anticoagulation (mechanical valve, DVT, etc.)
- Indication for combination antiplatelet therapy
- Allergy to aspirin or apixaban, or drug interaction preventing use
- Severe renal insufficiency (Cr >2.5 mg/dL, CrCl <25 ml/min)
- Serious bleeding in prior 6 months or known bleeding disorder
- Moderate to severe hepatic impairment
- Life expectancy <2 years
Baseline Characteristics
| Characteristic | Value |
|---|---|
| Mean age | 76.8 ± 7.6 years |
| Gender | 36.1% women |
| Race or ethnicity | 94.2% white |
| Mean CHA2DS2-VASc Score | 3.9 ± 1.1 |
| Hypertension history | 81.5% |
| Coronary Artery Disease history | 37% |
| Diabetes Mellitus | 29.1% |
| Heart Failure history | 28.3% |
| Stroke, Systemic Embolism, or TIA history | 9% |
- Baseline antiplatelet use:
- Aspirin: 57.4%
- Other single antiplatelet Agent: 3.9%
- Dual antiplatelet therapy: 3.4%
- History of major bleeding (>6 months before enrollment): 2.4%
- Device type:
- Pacemaker: 69.4%
- ICD: 13.8%
- CRT-ICD or CRT Pacemaker: 11.6%
- ICM: 5.2%
- Number of SCAF episodes ≥6 months in prior 6 months
- 0 episodes: 17.7%
- 1-5 episodes: 63.7%
- 6-50 episodes: 16.5%
- >50 episodes: 4.1%
Interventions
- Randomized to:
- Apixaban 5 mg BID (dose reduced as indicated per package insert)
- Aspirin 81 mg/d
Outcomes
Comparisons are apixaban vs. aspirin.
Primary Outcomes
- Stroke or systemic embolism
- 0.78% vs. 1.24% per patient-year (HR 0.63; 95% CI 0.45-0.88; P=0.007)
- Major bleeding
- 1.71% vs. 0.94% per patient-year (HR 1.80; 95% CI 1.26-2.57; P=0.001)
Adverse Events
- Fatal bleeding
- 5 vs. 8 patients (HR 0.63; 95% CI 0.20-1.91)
- Symptomatic intracranial hemorrhage
- 12 vs. 15 (HR 0.77; 95% CI 0.36-1.64)
- Gastrointestinal Bleeding
- 0.89% vs. 0.40% per patient-year (HR 2.23; 95% CI 1.32-3.78)
- Transfusion performed
- 0.51% vs. 0.36% per patient-year (HR 1.43; 95% CI 0.78-2.61)
Criticisms
- Study population consisted of older adults at higher risk for stroke who also had an implanted pacemaker, defibrillator, or cardiac monitor. Results of this study do not apply to a younger, healthier, general population affected by SCAF.
Funding
- Canadian Institutes of Health Research: A national peer-reviewed granting agency that was a primary funder of the trial
- Bristol-Myers Squibb–Pfizer Alliance: Provided the apixaban, aspirin, and matching placebos, as well as funding for the trial