Introduction

Atrial fibrillation (AF) is a cause of significant morbidity and mortality.¹ Studies show that individuals with AF have an increased risk of death and an increased risk of cardiovascular and renal disease.^2-4 Catheter ablation for AF has emerged as an effective form of rhythm control for patients with symptomatic AF and is the recommended rhythm control strategy in selected patients with paroxysmal and persistent AF after treatment with at least one antiarrhythmic drug has failed.⁵ Several reports have suggested that ablation therapy is more effective than antiarrhythmic drug therapy to maintain sinus rhythm.^6,7 A mortality benefit has been consistently shown in the setting of heart failure with reduced ejection fraction.⁸ Recently, the findings of the largest AF ablation trial, the CABANA (Catheter Ablation versus Antiarrhythmic Drug Therapy in Atrial Fibrillation) trial, were reported.

The CABANA Trial

The CABANA trial illustrated that compared with antiarrhythmic drug therapy, catheter ablation did not significantly reduce the primary composite endpoint of death, disabling stroke, serious bleeding, or cardiac arrest in patients with AF.^9,10 However, the trial confirmed that patients who get the procedure experience much greater symptom relief and significantly improved quality of life at 1 year without increasing complications than those who get only drugs.

This open-label, multicenter, randomized trial enrolled 2,204 patients with symptomatic AF between November 2009 and April 2016. Patients with both paroxysmal and non-paroxysmal AF were randomized in a 1:1 fashion. The catheter ablation group (n = 1,108) underwent pulmonary vein isolation, with additional ablative procedures at the discretion of site investigators. The drug therapy group (n = 1,096) received standard rhythm and/or rate control drugs guided by contemporaneous guidelines. The primary endpoint was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. The 3 secondary endpoints included in the main report were all-cause mortality, total mortality or cardiovascular hospitalization, and AF recurrence. Patients were followed-up for a median duration of 48.5 months.

The investigators reported a neutral study result obtained from intention-to-treat (ITT) analysis. They found no significant difference in the incidence of primary endpoint in catheter ablation (8.0%) versus the drug therapy (9.2%) population (hazard ratio [HR] 0.86; 95% confidence interval [CI], 0.65-1.15; p = 0.30). Secondary endpoints showed no benefit in all-cause mortality (5.2% vs. 6.1%; HR 0.85; 95% CI, 0.60-1.21; p = 0.38), but there was a benefit in total mortality or cardiovascular hospitalization (HR 0.83; 95% CI, 0.74-0.93; p = 0.001) and AF recurrence (49.9% vs. 69.5%; HR 0.52; 95% CI, 0.45-0.60; p < 0.001) in the catheter ablation versus drug therapy group, respectively.

Considering the sizable number of treatment crossovers observed during the study—102 (9.2%) patients randomized to ablation never received the ablation, and 301 (27.5%) patients randomized to the drug group crossed over during their follow-up to receive an ablation—the authors also reported as-treated and per-protocol analyses, which showed decreased incidence of the primary endpoint in patients undergoing catheter ablation.

The choice of primary endpoint is crucial for any randomized clinical trial (RCT) designed to demonstrate evidence of treatment benefit comparing therapies or interventions. It is particularly important in the CABANA trial, which shifted during the study from a solo primary endpoint of all-cause mortality to a "mixed" composite of death, disabling stroke, serious bleeding, or cardiac arrest. The rationale for this unusual mid-study modification by the study steering committee was to allow the study to have adequate power with a reasonable sample size. However, use of a composite endpoint in an RCT follows certain critical assumptions:¹¹

• Are the component endpoints of similar importance to patients?
• Did the more- and less-important endpoints occur with similar frequency?
• Are the component endpoints likely to have similar relative risk reductions?

This mixed primary endpoint, where there is major disparity in clinical importance among components of a composite endpoint, could pose a major challenge. Composite endpoints are often assessed as the time to first occurrence of any one of the components. When the components correspond to distinct events, and usually those are not mutually exclusive to occur, reaching the outcome on an individual component can appear as achieving the endpoint multiple times during the study. This produces a serious problem in interpreting the results when the endpoints have major disparity in terms of clinical importance. As such, if more clinically relevant components occur less frequently than the less clinically relevant ones, such as major bleeding versus death, the composite endpoint becomes less informative (serious bleeding occurred in 3.2% of the catheter ablation group and 3.3% of the drug group, incidence of disabling stroke was 0.3% and 0.6%, and cardiac arrest was 0.6% and 1.0%, respectively).¹² Thus, if not chosen carefully, the use of the composite endpoint does not always lead to an increase in the evidence for treatment benefit.

The fundamental principle in assessing the treatment effect is that the groups must be alike in important aspects and differ only in the treatment received.¹³ RCTs serve to achieve this by randomly assigning patients to receive the novel intervention or stay in the control group. Use of the ITT principle has been considered the de facto standard for comparing the treatment effect of RCTs, but it can be problematic under certain circumstances.¹⁴ Comparing therapies or interventions from RCTs by using ITT principle is generally straightforward to analyze, but the analysis and interpretation are complicated when individuals do not comply with their assigned treatments.¹⁵ This had significant impact on the ITT findings of the CABANA trial. In such instances, patients' non-compliance with the assigned treatment is known to undermine the effect of randomization and potentially bias the estimated effect.¹⁶ The authors did attempt to overcome this potential limitation during trial planning, however, projecting up to 25% treatment crossover from drug therapy to ablation (the actual crossover was higher than this: 27.5%) while maintaining the desired 90% level of statistical power.

Therefore, different analysis methods have been suggested (i.e., as-treated, per-protocol, and instrumental variable analyses) if one wants to know the average causal effect of receiving the treatment. It is of primary importance for a patient to see the expected benefit of receiving a novel therapy when deciding whether to accept it; as such, the as-treated analysis becomes relevant and worthy of continuous discussion.

Summary

The CABANA trial showed that there was no difference in the primary outcome (death, disabling stroke, serious bleeding, or cardiac arrest); however, the secondary outcomes, including total mortality or cardiovascular hospitalization and AF recurrence, not surprisingly, favored catheter ablation. Additionally, and probably the main result from the CABANA trial, is that in patients with symptomatic AF, catheter ablation led to clinically important and significant improvements in quality of life at 12 months without increasing the risk of complications compared with medical therapy.

References

1. Writing Group Members, Mozaffarian D, Benjamin EJ, et al. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation 2016;133:e38-360.
2. Benjamin EJ, Wolf PA, D'Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998;98:946-52.
3. Vidaillet H, Granada JF, Chyou PH, et al. A population-based study of mortality among patients with atrial fibrillation or flutter. Am J Med 2002;113:365-70.
4. Odutayo A, Wong CX, Hsiao AJ, Hopewell S, Altman DG, Emdin CA. Atrial fibrillation and risks of cardiovascular disease, renal disease, and death: systematic review and meta-analysis. BMJ 2016;354:i4482.
5. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014;130:2071-104.
6. Wilber DJ, Pappone C, Neuzil P, et al. Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial. JAMA 2010;303:333-40.
7. Jaïs P, Cauchemez B, Macle L,, et al. Catheter ablation versus antiarrhythmic drugs for atrial fibrillation: the A4 study. Circulation 2008;118:2498-505.
8. Briceño DF, Markman TM, Lupercio F, et al. Catheter ablation versus conventional treatment of atrial fibrillation in patients with heart failure with reduced ejection fraction: a systematic review and meta-analysis of randomized controlled trials. J Interv Card Electrophysiol 2018;53:19-29.
9. Packer DL, Mark DB, Robb RA, et al. 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;321:1261-74.
10. Mark DB, Anstrom KJ, Sheng S, et al. Effect of Catheter Ablation vs Medical Therapy on Quality of Life Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial. JAMA 2019;321:1275-85.
11. Montori VM, Permanyer-Miralda G, Ferreira-González I, et al. Validity of composite end points in clinical trials. BMJ 2005;330:594-6.
12. McCoy CE. Understanding the Use of Composite Endpoints in Clinical Trials. West J Emerg Med 2018;19:631-4.
13. Bang H, Davis CE. On estimating treatment effects under non-compliance in randomized clinical trials: are intent-to-treat or instrumental variables analyses perfect solutions? Stat Med 2007;26:954-64.
14. Sheiner LB, Rubin DB. Intention-to-treat analysis and the goals of clinical trials. Clin Pharmacol Ther 1995;57:6-15.
15. Little RJ, Long Q, Lin X. A comparison of methods for estimating the causal effect of a treatment in randomized clinical trials subject to noncompliance. Biometrics 2009;65:640-9.
16. Ye C, Beyene J, Browne G, Thabane L. Estimating treatment effects in randomised controlled trials with non-compliance: a simulation study. BMJ Open 2014;4:e005362.

Keywords: Atrial Fibrillation, Pulmonary Veins, Anti-Arrhythmia Agents, Sample Size, Confidence Intervals, Risk, Control Groups, Research Personnel, Follow-Up Studies, Quality of Life, Intention to Treat Analysis, Random Allocation, Stroke Volume, Catheter Ablation, Heart Failure, Stroke, Cross-Over Studies, Heart Arrest, Hospitalization, Arrhythmias, Cardiac

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