The American College of Cardiology's 70th Annual Scientific Session, an all-virtual experience, just concluded on May 17. Several groundbreaking research studies were presented during the three days of this international conference, of which two trials were noteworthy from the perspective of therapeutic management of atrial fibrillation (AF). Those were the RAFT-AF trial and the LAAOS III study.
Randomized Ablation-based atrial Fibrillation rhythm control versus rate control Trial in patients with heart failure and high burden Atrial Fibrillation (RAFT-AF) trial:
This randomized single-blinded multi-center study assigned patients with AF (all AF types included) and heart failure (HF) to rhythm control (catheter ablation plus post-ablation anti-arrhythmic drugs) versus rate control (AV nodal blockers ±ablate and bi-V pace) therapy and followed them up for five years (1). Primary endpoint of the study was a composite of time to death or HF event. The primary and secondary outcomes were evaluated in patients with reduced (≤45%) and preserved (>45%) LV ejection fraction.
Although the sample size was initially calculated to be 300 per arm, because of lower-than-expected enrollment and event rate, the study was terminated early. A total of 411 patients were randomized to Rate control (n=197) and Rhythm control group (n=214). The results showed rhythm-control strategy, although numerically favorable, to be not statistically superior to the rate-control approach for death and HF events at five years among patients with AF and HF. However, there was significant improvement in post-ablation LVEF, 6-minute walk distance, NT-ProBNP level, and quality of life compared to the rate-control group.
The above finding of non-superiority of catheter ablation in improving mortality and cardiovascular hospitalization rate was in disagreement with the AATAC and CASTLE-AF trial that demonstrated significantly lower rate of arrhythmia recurrence, death, or hospitalization for worsening of HF in patients with concomitant AF and HF (2, 3). Benefits of rhythm-control has also been shown in the CAMTAF, CAMERA-MRI, EAST-AFNET 4 and CABANA studies in the AF+HF population (4-7). The comparable outcome of catheter ablation and rate-control strategy for the composite primary endpoint in the current study can be due to the following:
- Difference in study population with LVEF cutoff at < 40% and ≤35% in AATAC and CASTLE-AF studies compared to 45% in the RAFT-AF trial. It is possible that the benefit of catheter ablation is more pronounced in patients with more severe left ventricular dysfunction at baseline.
- Inclusion of both preserved and reduced EF heart failure types: The study could have had more power if it involved either preserved or reduced HF with a larger sample size.
- There was a clear positive trend in favor of the ablation arm in the survival analysis of the primary endpoint at five years of follow-up in patients with reduced ejection fraction. It is highly plausible that the results could have been different if the study would have enrolled all 600 patients without terminating early for futility.
Therefore, I would not categorize the RAFT-AF findings as "negative" and would rather project the dataset as similar to the earlier published trials in terms of improvement in cardiovascular outcomes following catheter ablation.
Left Atrial Appendage Occlusion during Cardiac Surgery to Prevent Stroke (LAAOS III):
The LAAOS study has provided the first definitive evidence that surgical left atrial appendage (LAA) occlusion (amputation of the appendage followed by suture closure of the stump) in AF patients significantly reduces the risk of ischemic stroke (8). In this large multi-center randomized trial the thromboembolic events were reported to be 4.8% in the LAA occlusion group versus 7% in the non-occlusion group (hazard ratio: 0.67, p=0.001).
Several non-surgical studies have demonstrated similar benefits of LAA occlusion with percutaneous devices in AF patients, especially in those that receive electrical isolation of the LAA to achieve freedom from recurrent arrhythmia. Even though guidelines strongly favor lifelong anticoagulation for stroke-prophylaxis, anticoagulation is limited by problems such as poor compliance, incorrect dosing, interruption of therapy for medical reasons, and intolerance to the drugs. Therefore, the current findings from the LAAOS study make a compelling argument in favor of LAA occlusion for prevention of stroke in AF patients with high stroke risk.
References
1. Tang A, Prakash R, Rouleau J, Talajic M, Essebag V, Skanes A, Wilton S, Verma A, Healey J, Wells G. A Randomized Ablation-based atrial Fibrillation rhythm control versus rate control Trial in patients with heart failure and high burden Atrial Fibrillation - RAFT-AF. Late Breaking Clinical Trials V, ACC.21
2. Di Biase L, Mohanty P, Mohanty S, Santangeli P, Trivedi C, Lakkireddy D, Reddy M, Jais P, Themistoclakis S, Dello Russo A, Casella M, Pelargonio G, Narducci ML, Schweikert R, Neuzil P, Sanchez J, Horton R, Beheiry S, Hongo R, Hao S, Rossillo A, Forleo G, Tondo C, Burkhardt JD, Haissaguerre M, Natale A. Ablation Versus Amiodarone for Treatment of Persistent Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted Device: Results From the AATAC Multicenter Randomized Trial. Circulation. 2016 Apr 26;133(17):1637-44.
3. Marrouche NF, Brachmann J, Andresen D, Siebels J, Boersma L, Jordaens L, Merkely B, Pokushalov E, Sanders P, Proff J, Schunkert H, Christ H, Vogt J, Bänsch D; CASTLE-AF Investigators. Catheter Ablation for Atrial Fibrillation with Heart Failure. N Engl J Med. 2018 Feb 1;378(5):417-427.
4. Hunter RJ, Berriman TJ, Diab I, Kamdar R, Richmond L, Baker V, Goromonzi F, Sawhney V, Duncan E, Page SP, Ullah W, Unsworth B, Mayet J, Dhinoja M, Earley MJ, Sporton S, Schilling RJ. A randomized controlled trial of catheter ablation versus medical treatment of atrial fibrillation in heart failure (the CAMTAF trial). Circ Arrhythm Electrophysiol. 2014 Feb;7(1):31-8.
5. Prabhu S, Taylor AJ, Costello BT, Kaye DM, McLellan AJA, Voskoboinik A, Sugumar H, Lockwood SM, Stokes MB, Pathik B, Nalliah CJ, Wong GR, Azzopardi SM, Gutman SJ, Lee G, Layland J, Mariani JA, Ling LH, Kalman JM, Kistler PM. Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction: The CAMERA-MRI Study. J Am Coll Cardiol. 2017 Oct 17;70(16):1949-1961.
6. Kirchhof P, Camm AJ, Goette A, Brandes A, Eckardt L, Elvan A, Fetsch T, van Gelder IC, Haase D, Haegeli LM, Hamann F, Heidbüchel H, Hindricks G, Kautzner J, Kuck KH, Mont L, Ng GA, Rekosz J, Schoen N, Schotten U, Suling A, Taggeselle J, Themistoclakis S, Vettorazzi E, Vardas P, Wegscheider K, Willems S, Crijns HJGM, Breithardt G; EAST-AFNET 4 Trial Investigators. Early Rhythm-Control Therapy in Patients with Atrial Fibrillation. N Engl J Med. 2020 Oct 1;383(14):1305-1316.
7. Packer DL, Mark DB, Robb RA, Monahan KH, Bahnson TD, Poole JE, Noseworthy PA, Rosenberg YD, Jeffries N, Mitchell LB, Flaker GC, Pokushalov E, Romanov A, Bunch TJ, Noelker G, Ardashev A, Revishvili A, Wilber DJ, Cappato R, Kuck KH, Hindricks G, Davies DW, Kowey PR, Naccarelli GV, Reiffel JA, Piccini JP, Silverstein AP, Al-Khalidi HR, Lee KL; CABANA Investigators. Effect of Catheter Ablation vs Antiarrhythmic Drug Therapy on Mortality, Stroke, Bleeding, and Cardiac Arrest Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial. JAMA. 2019 Apr 2;321(13):1261-1274.
8. Whitlock RP, Belley-Cote EP, Paparella D, Healey JS, Brady K, Sharma M, Reents W, Budera P, Baddour AJ, Fila P, Devereaux PJ, Bogachev-Prokophiev A, Boening A, Teoh KHT, Tagarakis GI, Slaughter MS, Royse AG, McGuinness S, Alings M, Punjabi PP, Mazer CD, Folkeringa RJ, Colli A, Avezum Á, Nakamya J, Balasubramanian K, Vincent J, Voisine P, Lamy A, Yusuf S, Connolly SJ; LAAOS III Investigators. Left Atrial Appendage Occlusion during Cardiac Surgery to Prevent Stroke. N Engl J Med. 2021 May 15. doi: 10.1056/NEJMoa2101897.
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