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Catheter Ablation in End-Stage Heart Failure with Atrial Fibrillation

Summary Author: Lukas Lauer

Background & Impetus for the CASTLE-HTx Trial

Heart Failure (HF) affects an estimated 6.7 million people in the US and accounts for 1.2 million hospitalizations annually (1). Atrial fibrillation (Afib) is the most common dysrhythmia, affecting an estimated 3.8 million people in the US and was listed as the cause of death for 26.5K patients in 2019 (2). HF and Afib have a reciprocal relationship – HF begets Afib and Afib begets HF. Indeed, when compared with HF alone, patients with comorbid HF and Afib face increased hospitalizations and mortality (3).  

The principal goals of treatment for Afib are to reduce symptoms, prevent tachycardia mediated cardiomyopathy, and reduce the risk of stroke (4).

For Afib without comorbid HF, studies have found catheter ablation (CA) to be superior to antiarrhythmic drugs for symptomatic relief but have not assessed for reductions in cardiac or all-cause mortality (5). Thus, most professional societies still recommend CA only after a patient has failed at least one antiarrhythmic drug (6).

In 2018, Marrouche et al. found that for patients with HF and symptomatic Afib, CA with Guideline Directed Medical Therapy (GDMT) is superior to GDMT alone on its composite primary endpoint of death from any cause or hospitalization due to heart failure exacerbation. However, this study excluded patients that were eligible for heart transplantation and required patients to have already failed at least one antiarrhythmic drug (7). 

Thus, Sohns et al. conducted the CASTLE-HTx trial to answer the question: Are patients in end stage HF with symptomatic Afib less likely to die of any cause or need a Left Ventricular Assist Device (LVAD) or urgent heart transplant if they receive CA and GDMT rather than GDMT alone (8)?

    Brief Summary    

  • Design: Single center, unblinded, randomized controlled trial

    • The trial was powered to detect a hazard ratio of .5 with a sample size of 97 patients per arm. The authors considered a hazard ratio of .75 to be clinically significant 

  • Inclusion Criteria: Symptomatic Afib, HF ≥ New York Heart Association (NYHA) II, Left Ventricular Ejection Fraction ≤ 35%, impaired functional capacity as assessed by 6-minute walk test, referred to transplant center for evaluation of eligibility for transplant or LVAD implantation, dual-chamber implantable cardiac defibrillator with home monitoring capabilities already implanted

  • Time Period: November 2020 – May 2022

  • Arms: 

    • CA + GDMT

    • GDMT only

  • Primary Endpoint (PE):

    • Composite: Death from any cause or LVAD implantation or urgent heart transplant at 3 years

  • Secondary Endpoints (all components of PE):

    • Death from any cause

    • LVAD implantation

    • Urgent heart transplant

  • Crossover: Patients in the GDMT arm were allowed to crossover to the CA arm.  Their data was included with the GDMT arm per the intention to treat design 


97 patients were randomized to each arm and the median duration of follow up was approximately 18 months in both arms. A primary end-point event occurred in 8 patients (8%) in the ablation arm and 29 patients (30%) in the GDMT arm (Hazard Ratio (HR), 0.24; 95% confidence interval (CI), 0.11 to 0.52; P<0.001). For secondary endpoints, death was less likely for patients in the ablation group (HR, 0.29; 95% CI, 0.12 to 0.72), as was LVAD implantation (HR, 0.09; 95% CI, 0.01 to 0.70) and urgent heart transplant (HR, 0.15; 95% CI, 0.02 to 1.25). Procedure complications were minimal.

The trial was initially designed to analyze the cumulative incidence of the primary endpoint at three years, but on May 16, 2023, 1 year after enrollment was completed, the study ended as recommended by the Data and Safety Monitoring Board due to an unexpectedly large treatment difference favoring the CA arm. 


Sohns et al. concluded that catheter ablation with GDMT was superior to GDMT alone for end stage HF patients with symptomatic Afib. Patients in the CA arm lived longer and were less likely to require a transplant or LVAD. However, this study has limitations:

Blinding: Neither patients nor physicians were blinded to the intervention which allowed for the possibility of biasing the data as knowledge of group assignment affects behavior9. For example, physicians may have been more hesitant to offer transplantation to a patient known to be on the CA arm because they believed CA works and wanted to see a positive study result. 

Single Site: This trial was performed by two cardiac electrophysiologists at one hospital in Germany. Whether these results are reproducible across geographies and across operators remains a question. 

Patient Selection: 31% of patients were NYHA functional class II meaning they only experienced mild symptoms during everyday activity. Other reviewers have suggested that the authors should limit future studies to only those with class III or IV HF to best encompass truly end stage patients likely to require transplant or LVAD implantation. 

Additionally, the study excluded patients with certain comorbidities including uncontrolled hypertension or end stage renal disease requiring dialysis. This limits external validity and highlights the need to consider individual patient characteristics in clinical decision making. 

Early Termination: Although terminating the study early may have been necessary to maintain clinical equipoise, a shorter study period may have missed the longer-term benefits or harms of the intervention.

Crossover: In the CA arm, 81 of 97 (84%) patients underwent ablation, while in the GDMT arm, 16 of 97 (16%) patients crossed over and underwent ablation. They were still included in the GDMT only arm due to the study’s intention to treat design. This was a limitation in the execution of the trial. However, crossover makes it harder to detect a difference between study arms, so the significant result despite patient crossover actually bolsters the author’s conclusions.  

Main Takeaway

Despite the study’s limitations, Sohns et al. provide reasonably strong evidence that CA with GDMT is superior to GDMT alone for end stage HF patients with symptomatic Afib. Their findings suggest that CA may be able to delay or eliminate the need for transplant or LVAD implantation. A subsequent study with additional sites, patients, and operators as well as limiting the study to NYHA class III or IV patients is warranted to conclude definitively that CA is superior.


  1. Bozkurt B, Ahmad T, Alexander KM, Baker WL, Bosak K, Breathett K, et al. Heart failure epidemiology and outcomes statistics: a report of the heart failure society of America. J Card Fail. 2023 Oct;29:1412-1451. doi: 10.1016/j.cardfail.2023.07.006

  2. Turakhia MP, Shafrin J, Bognar K, Trocio J, Abdulsattar Y, Wiederkehr D, et al. Estimated prevalence of undiagnosed atrial fibrillation in the United States. PLoS One. 2018 Apr 12;13:e0195088. doi: 10.1371/journal.pone.0195088

  3. Lee Park K, Anter E. Atrial fibrillation and heart failure: A review of the intersection of two cardiac epidemics. J Atr Fibrillation. 2013 Jun 30;6:751. doi: 10.4022/jafib.751. 

  4. Padanilam BJ, Prystowsky EN. Atrial fibrillation: goals of therapy and management strategies to achieve the goals. Cardiol Clin. 2009 Feb;27:189-200, x. doi: 10.1016/j.ccl.2008.09.006

  5. Imberti JF, Ding WY, Kotalczyk A, Zhang J, Boriani G, Lip G, et al. Catheter ablation as first-line treatment for paroxysmal atrial fibrillation: a systematic review and meta-analysis. Heart. 2021 Oct;107:1630-1636. doi: 10.1136/heartjnl-2021-319496

  6. Calkins H, Hindricks G, Cappato R, Kim YH, Saad EB, Aguinaga L, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm. 2017 Oct;14:e275-e444. doi: 10.1016/j.hrthm.2017.05.012. 

  7. Marrouche NF, Brachmann J, Andresen D, Siebels J, Boersma L, Jordaens L, et al. Catheter ablation for atrial fibrillation with heart failure. N Engl J Med. 2018 Feb 1;378:417-427. doi: 10.1056/NEJMoa1707855

  8. Sohns C, Fox H, Marrouche NF, Crijns HJGM, Costard-Jaeckle A, Bergau L, et al. Catheter ablation in end-stage heart failure with atrial fibrillation. N Engl J Med. 2023 Oct 12;389:1380-1389. doi: 10.1056/NEJMoa2306037

  9. Schulz KF, Grimes DA. Blinding in randomised trials: hiding who got what. Lancet. 2002 Feb 23;359:696-700. doi: 10.1016/S0140-6736(02)07816-9. 

  10. Kuck KH, Brugada J, Fürnkranz A, Metzner A, Ouyang F, Chun KR, et al. Cryoballoon or radiofrequency ablation for paroxysmal atrial fibrillation. N Engl J Med. 2016 Jun 9;374:2235-45. doi: 10.1056/NEJMoa1602014

  11. Heidenreich, P, Bozkurt, B, Aguilar, D. et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2022 May, 79;e263–e421

Source Journal

Screenshot 2023-10-12 at 10.46.24 PM.png

Efficacy and Safety of Tralokinumab in Adolescents with Moderate to Severe Atopic Dermatitis

Summary Author: Nancy Shen

    Type of Study    

Original Investigation – Phase 3 RCT

    Brief Summary    

The purpose of this investigation was to evaluate the efficacy and safety of IL-13-targeted
treatment with tralokinumab monotherapy in adolescents with atopic
dermatitis (AD). This was
a 52-week-long, randomized, double-blinded, placebo-controlle
d phase 3 trial held at 72
institutions in 10 countries. The patient populatio
n included adolescents ages 12 to 17 with
moderate to severe AD based on either an Investigator’s Global Assessment (IGA) score >=3 or
an Eczema Area and Severity Index (EASI) >=16. Patients received either tralokinumab (150 or
300 mg) or placebo every 2 weeks for 16 weeks. At 16 weeks, patients found to have an IGA
score of 0 or 1 and/or 75% or higher improvement with EASI at week 16 without rescue
medication received maintenance treatment. Patients that did not meet these criteria at 16
weeks were switched to open-label tralokinumab, receiving 300 mg every two weeks.

    What did they find?    

  • Primary end points measured were proportions of patients achieving IGA score of 0 
    (clear) or 1 (almost clear) at week 16 and/or 75% or higher improvement in EASI (EASI 75) at week 16.

  • Secondary end points measured changes to Adolescent Worst Pruritus Numeric Rating
    Scale, SCORing AD, and Children’s Dermatology Life Quality Index.

  • Two hundred eighty-nine of 301 randomized patients were analyzed at final time stamp.
    A higher proportion of patients receiving tralokinumab 150 mg or 300 mg achieved an
    IGA score of 0 or 1 at week 16 compared to placebo (p <0.001). A higher proportion of
    patients in the tralokinumab group also achieved an EASI 75 without rescue medication
    at week 16 compared to placebo (p <0.001).

  •  Tralokinumab treatment was associated with statistically significant improvements in all
    key secondary end points compared with placebo (itch, sleep, anxiety/depression,
    overall quality of life).

  •  Tralokinumab was well-tolerated with a low rate of adverse effects, and it did not have
    high rates of discontinuation.


There was a small sample size and a lack of a placebo group in the maintenance phase. There
was also no direct comparison with similar immunotherapeutic treatments and whether it was
more, less, or equally effective as what was already being offered on the market. There was no
mention of cost compared to similar agents.

Main Takeaway

Tralokinumab, a monoclonal antibody directed against IL-13, is a well-
tolerated and efficacious agent in treating moderate to severe atopic dermatitis in adolescents.


Paller AS, Flohr C, Cork M, et al. Efficacy and Safety of Tralokinumab in Adolescents With
Moderate to Severe Atopic Dermatitis: The Phase 3 ECZTRA 6 Randomized Clinical Trial. JAMA
Dermatol. 2023;159(6):596–605. doi:10.1001/jamadermatol.2023.0627

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