Despite mixed reactions among the cardiovascular community, the recently published Catheter ABlation vs ANtiarrhythmic Drug Therapy in Atrial Fibrillation (CABANA) trial should be considered positive, as it provides clear evidence that catheter ablation is a valuable option for treating patients with atrial fibrillation (AF). In CABANA, not only did catheter ablation reduce the AF burden and prolong time to first recurrence,1 but it also improved quality of life.2 Furthermore, and most importantly, it reduced all-cause mortality and cardiovascular hospitalizations (HR 0.83, 95% CI 0.74-0.93, p=0.001).1 What this means is that for every 15.6 patients randomized to catheter ablation, one death or cardiovascular hospitalization was prevented (number needed to treat [NNT] 15.6). This is an extremely informative and powerful endpoint, as it is used for showing the benefit of most interventions across the spectrum of cardiovascular disease (Figure 1). The fact that it is a secondary endpoint in CABANA does not reduce its importance.

Figure 1.

Clinical events in some of the main cardiovascular trials. (A) and (B) show the number of patients who need to be treated for a fatal event to be prevented (A), or for a fatal event or hospitalization to be avoided (B). We chose to include trials of different cardiovascular interventions that have demonstrated significant benefit in the prevention of these events. Interpretation of these graphs shows that among all these interventions whose benefit has been demonstrated in landmark trials, and most of which have led to indications in the guidelines, the interventions with more benefit, as represented by a larger number of lives saved or hospitalizations avoided, are those with a smaller number needed to treat to prevent one event. As such, interventions with most benefit as measured by the number needed to treat are those which are located closer to the origin on the x axis. Furthermore, in (A) the results of CABANA are highlighted in red for two different reasons: first, inclusion of the results of the as-treated analysis, with an NNT of 32.3, and secondly, inclusion of the results of the ITT analysis, which were not significant due to the small sample size. However, CABANA shows a larger, albeit non-significant, impact than the novel oral anticoagulants and statins in some populations. Randomized trials for: AF – CASTLE-AF and CABANA; cardiac resynchronization therapy – CARE-HF and COMPANION; beta-blockers – COPERNICUS; angiotensin-converting enzyme inhibitors – SOLVD; PARADIGM-HF – valsartan + sacubitril vs. enalapril; statins and treatment of dyslipidemia – HPS, JUPITER and IMPROVE-IT; anti-platelet agents – CURE, PLATO and TIMI-38 TRITON; anti-arrhythmic agents – ATHENA; anticoagulants – ARISTOTLE. CV: cardiovascular; CRT: cardiac resynchronization therapy; CRT-D: cardiac resynchronization therapy-defibrillator; HF: heart failure; MI: myocardial infarction; OPT: optimal pharmacologic therapy.

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The patient subgroup that derived most benefit from catheter ablation was younger individuals (less than 65 years old).1 This result is not surprising considering that most of these patients live long enough to experience a mortality benefit from the intervention.

In CABANA, no atrio-esophageal fistulas, stroke or procedure-related mortality were observed. Procedure-associated complications included myocardial infarction in <1/1000, need for pericardiocentesis in 0.8%, and vascular access complications in 3.9%. At the same time, ventricular tachycardia or ventricular fibrillation was observed in 0.8%, and thyroid dysfunction in 1.6%, in the medical treatment arm. This eases some of the concerns associated with ablation3 and illustrates that being assigned to antiarrhythmic agents is also not devoid of risk.

1. Nearly a third of patients initially randomized to treatment with antiarrhythmic agents were later treated with ablation. On the other hand, almost 10% of patients randomized to catheter ablation did not receive this treatment. These are excessively high cross-over rates, and are unequal in the two treatment arms.

2. There were weaknesses in the selection and definition of the trial's primary endpoint. This was changed during the course of CABANA, from all-cause mortality to a combined endpoint of all-cause mortality, incapacitating stroke, major bleed or cardiac arrest. Why did the investigators not choose a more widely accepted endpoint, like all-cause mortality and hospitalizations? A recent trial comparing transcatheter aortic valve replacement and surgical aortic valve replacement in low surgical risk patients has been hailed as a success, as the newer treatment reduced the rate of the composite of death, stroke, or rehospitalization at one year.4 Would not the same apply to CABANA if it had used a similar primary endpoint? It should be recalled that the intention-to-treat (ITT) analysis showed that catheter ablation significantly reduced mortality and hospitalizations, and the rate of stroke in the catheter ablation arm was numerically 50% lower, which leads one to suspect that such an endpoint would also very likely show a significant difference.

It is interesting to note that the combined primary endpoint in CABANA included events like stroke and bleeding, as well as mortality and cardiac arrest. Ablation was numerically better for all of them except bleeding, for which the event rate was the same (as would be expected as patients in both treatment arms were on anticoagulants).

3. Patients who had previously not tolerated or had relapsed on more than two antiarrhythmic drugs, or were on full-dose amiodarone, were not included in the study. CABANA therefore excluded a good percentage of real-world AF patients currently being referred for ablation.

4. To be included in CABANA, patients had to be eligible for catheter ablation.5 However, some patients who were included in the study and randomized to ablation ended up not having the procedure. In the lead author's own words, “the main reason for that is that patients changed their minds, or a physician changed their mind for them. Or if you go to China or Korea, there are other conditions that are important there.” With regard to this point, the Medscape editor responsible for the article added: “In Packer's HRS presentation, he said of these countries that often ‘if you don’t go into the hospital with a bag of money, you will not get ablated.”’6 Box III in CABANA appears to confirm this by showing that patients randomized to the ablation arm but not receiving ablation were more frequently from ethnic minorities.1 This raises several questions regarding the eligibility of these patients and the trial's organization. If money was required for patients to have an ablation procedure and they were unable to pay, should they have been considered eligible for the trial in the first place? Should centers that behaved in this way toward clinical trial patients have been allowed in the trial? In mega-drug trials, the sponsor provides the drug free of charge. Could CABANA not have done the same with the ablation treatment for these patients?

CABANA included AF patients with and without heart failure. The ITT sub-analysis of the primary endpoint for heart failure patients suggests a benefit of ablation, with a 39% risk reduction, which nearly crosses the boundary of significance. This was despite there being only 1197 patients in the study with heart failure.1

The CASTLE-AF trial suggested a clear benefit of this treatment modality in the subgroup of patients with AF and heart failure and left ventricular dysfunction.7 The NNT to save a life was 8.6, and to prevent one heart failure hospitalization it was 6.6. These results are therefore in line with the trend observed in CABANA, and with recently published systematic reviews of randomized trials that showed a similar reduction in mortality and effect size with catheter ablation in the AF population. This effect became more pronounced in sub-analyses of studies including only heart failure patients.8,9

Several factors have been suggested to explain the benefit of AF ablation in patients with heart failure, which are discussed in more detail by Kadhim et al.10 Statistical considerations concerning this subject are discussed in Box II.

Figure 1 shows the effect size, represented by the NNT, of several drugs and interventions currently used in cardiovascular medicine and recommended in international guidelines. It is interesting to note that the effect size and benefit for some of these drugs appear to be much lower than that observed with catheter ablation (Figure 1A and B). Using apixaban, one of the novel oral anticoagulants, instead of a vitamin K antagonist, we would need to treat 132 AF patients to save one life,11 while in the population with heart failure in PARADIGM-HF, the association of valsartan and sacubitril needs to be used instead of enalapril in 37.8 and 35.7 patients to save one life or prevent one heart failure hospitalization, respectively.12 This is also seen with drugs whose use is considered unquestionable in coronary artery disease, like ticagrelor instead of clopidogrel, for which the number of patients needed to treat to prevent one fatal event is 71.4.13

Even the most conservative analysis of CABANA (the ITT analysis “shows a clear significant reduction”) of the all-cause mortality and cardiovascular hospitalization endpoint (HR 0.83, 95% CI 0.74-0.93, p=0.001), which translates into an NNT of 15.6.1

The authors have no conflicts of interest to declare.