CardioNerds Journal Club is a monthly forum for CardioNerds to discuss and breakdown recent publications on twitter and are produced with a corresponding infographic and detailed blog post. For more information, check out the CardioNerds Journal Club Page. This Journal Club focuses on the ARTESIA trial

Table of contents for the The STEP-HFpEF Trial summary:

• Visual abstract
• Summary
• References
• Credits
• Twitter Archive

https://www.nejm.org/doi/full/10.1056/NEJMoa2310234

Relevant literature

Atrial fibrillation (AF) is a significant risk factor for embolic events (stroke and systemic). The thromboembolic event risk is proportional to the patient’s risk for stroke and also to the burden of AF, which is related to the total time in AF but more importantly to the continuous AF rhythm duration.¹ It is well known that anticoagulation in patients with AF is effective in reducing embolic events without significantly increasing the risk of major bleeding compared to placebo, aspirin, or aspirin plus clopidogrel, conferring a net clinical benefit for anticoagulation.² Studies have shown that direct oral anticoagulants (DOACs) are at least as effective as warfarin but with significantly fewer safety events.^2-4  Prior to the popularization of DOACs, in patients considered to be high risk for bleeding and warfarin use, aspirin demonstrated a questionable effectiveness in reducing embolic events compared to placebo but it caused fewer major bleeding than DAPT (aspirin plus clopidogrel).^5,6  The optimal management of subclinical AF with an episodic duration between 6 minutes and 24 hours, however, remains unclear.  

Relevant Guidelines

• 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines

• Device-detected subclinical atrial tachyarrhythmias: definition, implications and management—an European Heart Rhythm Association (EHRA) consensus document

Briefly, the decision of anticoagulation should be based on:

• The diagnosis of atrial fibrillation (AF) and risk for thromboembolic events (CHA2DS2VASc score or equivalent).

For patients without a diagnosis of AF but asymptomatic atrial high rate episodes (AHRE)* (subclinical AF) anticoagulation decision is based on the:

• The burden (duration) and thromboembolic risk (CHA2DS2VASc score or equivalent)

*AHRE: Typically detected by reliable monitor devices (telemetry, pacemaker, defibrillators, recorders)

Anticoagulation is recommended (high risk for thromboembolic events >2% annually):

• In patients with atrial fibrillation documented by ECG plus CHA2DS2VASc ≥ 2 for man and CHA2DS2VASc ≥ 3 without anticoagulation contraindication 

OR

• In patients without a previous diagnosis of atrial fibrillation but asymptomatic atrial high rate episodes (AHRE) (episode ≥ 24 hr, detected by a reliable monitor device) plus CHA2DS2VASc ≥ 2 for man and CHA2DS2VASc ≥ 3 without anticoagulation contraindication 

Anticoagulation is reasonable (intermediate risk 1-2 % annually):

• In patients with atrial fibrillation plus CHA2DS2VASc 2 for men and CHA2DS2VASc 2 for women without anticoagulation contraindication 
• Persistent afib in the setting of acute medical illness or postoperative – individual risk assessment of bleeding risk, thromboembolic risk, and close follow-up are factors when short-term anticoagulation is being considered

Anticoagulation is contraindicated:

• The risk for major bleeding outweighs the anticoagulation clinical benefits in patients with anticoagulation afib indication, or
• Afib in patients with low risk for thromboembolic events (CHA2DS2VASc 0 for men and CHA2DS2VASc ≤ 1 for women)
• In patients without a previous diagnosis of atrial fibrillation but AHRE (episode < 5 min) regardless of the CHA2DS2VASc score.  

Literature/Guideline gap (uncertainty)

• Patients without afib but asymptomatic AHRE between 5 min and 24 hr

Figure 1. 2023 ACC/AHA/ACCP/HRS Guidelines

Study Rationale:

Subclinical atrial fibrillation is associated with an increased risk of stroke, systemic embolism, and atrial fibrillation development. However, it is unknown if anticoagulation in patients with subclinical atrial fibrillation with a duration between 6 min and 24 hr has a clinical benefit.

Objectives:

Investigate the efficacy and safety of apixaban vs aspirin in patients with subclinical atrial fibrillation detected by implanted cardiac devices/monitors.

Trial – The ARTESIA Trial

• Phase IV, prospective, international multicenter (247 sites, 16 European and North American countries), parallel, double-blind, randomized trial

Intervention

• Patients were randomly assigned to:
• Aspirin 81 mg daily plus placebo-apixaban

OR

• Apixaban 5 mg twice daily (or 2.5 mg BID, if indicated) plus placebo-aspirin.

Enrollment Criteria

If subclinical atrial fibrillation ≥ 24 hr or clinical atrial fibrillation developed (symptoms) patient became ineligible, therefore the apixaban or aspirin was stopped, follow-up was continued, treatment with an open-label anticoagulant was initiated, and these patients were censored in the analysis.  

Enrollment

Patients were recruited at the time of pacemaker or defibrillator follow-up visit or after identification of eligible patients by review of local pacemaker databases.

Study follow-up/outcome assessment

Follow-up visits at 30 days from enrollment, then every 6 months, when patients were assessed for outcome events and with questions to verify stroke-free status. Follow-up endpoint expected (not achieved) until 248 primary events have occurred (expected ~36 months).

Primary Outcome

• Efficacy: Composite of stroke (including TIA with evidence of cerebral infarction on diffusion-weighted MRI) and systemic embolism
• Safety: Major bleeding as defined by the ISTH criteria

Secondary Outcome:

• Ischemic stroke
• Myocardial infarction (MI)
• Vascular death Total death (vascular and non-vascular) Composite of stroke, MI, systemic embolism, and total death
• Composite of stroke, MI, systemic embolism, total death and major bleeding

Outcome assessment

Stroke, systemic embolism, and major bleeding events were adjudicated by a committee of experts who were unaware of the trial-group assignments.

Statistical Analysis

Sample size was calculated from ASSERT data:

• A study population of 4000 patients has 80% power to detect a relative reduction of 35% in the risk of stroke or systemic embolism in the apixaban group, assuming a risk of 2.75% per patient-year in the control group, a crossover frequency of 8.5%, and the occurrence of 248 primary-outcome events in the two groups.

• Primary outcomes presented using the Kaplan-Meier curve and hazard ratio (HR with 95% CI) comparisons between the groups’ treatment effects were derived by the Cox proportional hazards model. Significance defined by 2-sided p ≤ 0.05

• Intention-to-treat analysis for primary efficacy outcome.

Baseline Characteristics

• mean age was 76.8±7.6 years
• 36.1% women
• mean CHA2DS2-VASc score was 3.9±1.1

Trial Patients

• 4012 patients underwent randomization with 2015  to the apixaban group and 1997 to the aspirin group
  • Apixaban or aspirin was permanently discontinued due to the development of subclinical afib lasting > 24hrs to clinical afib in 24.3% of patients in the apixaban group and 23.8% of patients in the aspirin group (median time to discontinuation was 18.3mos).
  • The trial medication was discontinued for other reasons in 34.1 % of patients in the apixaban group and 34.9% of patients in the aspirin group.
  • 22.7% and 21.9%  of patients died during the follow-up period in the apixaban and aspirin groups, respectively.
  • The mean (±SD) duration of follow-up was 3.5±1.8 years for the intention-to-treat analysis and 2.5±1.8 years for the on-treatment analysis.

Outcomes

Primary Outcome

• The primary outcome of stroke or systemic embolism was measured in the intention to treat population (all patients who underwent randomization with censoring for the development of subclinical atrial fibrillation lasting more than 24 hours or clinical atrial fibrillation).
• This occurred at a rate of 0.78% per patient-year and 1.24% per patient-year in the apixaban and aspirin groups respectively ( HR= 0.63; 95% CI 0.45 to 0.88; P=0.007).
• The rates of ischemic or unknown stroke were similar with HR= 0.62; 95% CI, 0.43 to 0.91.

• By using the modified Rankin scale with scores of 3-6, 18 of 55 strokes in the apixaban group and 36 of 84 stroked in the aspirin group were disabling or fatal. This was 49% lower in the apixaban group (hazard ratio, 0.51; 95% CI, 0.29 to 0.88).
• Rates of death were similar between the two groups

Major Bleeding:

• The risk of major bleeding was assessed according to the definition of the International Society on Thrombosis and Haemostasis and was measured in the on-treatment population (underwent randomization and received at least one dose of the assigned drug with follow‐up censored 5 days after permanent discontinuation of trial medication for any reason)
• Major bleeding occurred at a rate of 1.71% per patient-year with apixaban and 0.94% per patient-year with aspirin (hazard ratio, 1.80; 95% CI, 1.26 to 2.57; P = 0.001).
• Most bleeding events responded to supportive care (including transfusions) and hemodynamic instability at presentation was uncommon.
• Fatal bleeding occurred in 5 patients with apixaban and 8 patients with aspirin.     

ARTESIA Conclusions

In this trial involving patients with risk factors for stroke who were found to have subclinical atrial fibrillation, apixaban resulted in a lower risk of stroke or systemic embolism than aspirin by 37%. There is also a lower risk of disabling or fatal stroke in the apixaban group by 49%. The apixaban group had a higher risk of major bleeding, but most incidents responded to supportive care.

Limitations and considerations:

• There was a high rate of discontinuation for various reasons in the trial but both the intention to treat and on treatment analysis showed a significant reduction in stroke or systemic embolism.
• Lastly, the results of this trial are only relevant to patients with implantable cardiac devices that can detect subclinical AF and it is unclear how these results will translate to patients at high risk of stroke with wearable monitors or other devices.

1. 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines | Circulation. 2024.

2. Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation. 1991;84(2).

3. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet (London, England). 1996;348(9028).

4. SJ C, J E, C J, et al. Apixaban in patients with atrial fibrillation. The New England journal of medicine. 2011;364(9).

5. S C, J P, R H, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet (London, England). 2006;367(9526).

6. SJ C, J P, RG H, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. The New England journal of medicine. 2009;360(20).

7. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet (London, England). 1994;343(8899).

8. CB G, JH A, JJ M, et al. Apixaban versus warfarin in patients with atrial fibrillation. The New England journal of medicine. 2011;365(11).

9. RP G, CT R, E B, et al. Edoxaban versus warfarin in patients with atrial fibrillation. The New England journal of medicine. 2013;369(22).

10. P K, T T, A G, et al. Anticoagulation with Edoxaban in Patients with Atrial High-Rate Episodes. The New England journal of medicine. 2023;389(13).

11. JS H, RD L, CB G, et al. Apixaban for Stroke Prevention in Subclinical Atrial Fibrillation. The New England journal of medicine. 2024;390(2).

Summary by: Dr. Ronaldo Filho @Ronaldo_CFF and Dr. Maani Kamal @Kamal_mz

Visual abstract by: Dr. Shivani Hanchate @HanchateShivani

Trial Tweets by: Dr. Paul Montana @PaulMontanaMD

Moderator of Twitter during CardsJC by: Dr. Yetunde Kemi Fatade @joyfuldockemi

Promo by: Student Doctor Shivani Reddy @ShivaniReddy_1

Under the guidance of House Chief: Dr. Gurleen Kaur @GurleenKaur_96 & Director of CardsJC Dr. Devesh Rai, @DeveshRaiMD

Supported by House Faculty: Dr. Ahmed Ghoneem @a_h_ghoneem, Dr. Colin Blumenthal @CBlumenthal2, and Dr. Sukriti Banthiya @sukritibanthiya

Faculty experts:

Dr. Hafiza Khan @HafizaKMD

Dr. Mayank Kansal @mmkansal

Dr. Kamala Tamirisa @KTamirisaMD