Nine Things to Remember About CASTLE-AF

John Mandrola, MD


February 05, 2018

I wrote about the CASTLE-AF trial  when it was presented at the European Society of Cardiology last year. Now it has been published in the New England Journal of Medicine, let's revisit.[1]

The Study

Investigators from 33 countries randomly assigned about 360 patients with HF with reduced ejection fraction and AF to either AF ablation or guideline-directed medical therapy. All patients had a Biotronik implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT) device.[1]

Trial participants had symptomatic AF "and an absence of response to, unacceptable side effects from, or unwillingness to take antiarrhythmic drugs."  Operators chose their own ablation technique. About half of the ablation patients received pulmonary vein isolation (PVI) alone and the other half had PVI plus additional lesions. The primary endpoint was a composite of death from any cause or HF hospital admission.

My Thoughts

1. Huge benefit: The ablation group did better — far better. Ablation produced a relative reduction in the primary outcome of 38%, from 28.5% vs 44.6%. This translated to a 16% reduction in absolute terms, with a number needed to treat of 6. Ablation lowered the overall death rate by 47% (13.4% vs 25%). Importantly, ablation also reduced cardiovascular death by 51% (11.2% vs 22.3%).

2. AF persisted: Ablation reduced, but did not eliminate, episodes of AF: 63% of the ablation group vs 22% of the medical therapy group were in sinus rhythm at 60 months. AF recurred in about half of the as-treated ablation group (those who actually had ablation; average of 1.3 procedures). And 18% of patients in the ablation group had an AF burden  of 10% or greater during the study, as compared with 45% of patients in the pharmacologic group.

3. Low complication rates: There were 15 complications (8%) related to ablation but no deaths. Only one patient in the ablation group developed worsening HF tied to the procedure. This is surprising because ablation uses saline-irrigated catheters and can sometimes lead to atrial stunning. That there was so little procedural-related worsening of HF speaks to the healthiness of enrolled patients, the skill of the operators, or both.

4. Astonishing benefit size: The magnitude of mortality benefit (47%) exceeds that of any known HF therapy. Angiotensin receptor-neprilysin inhibitor drugs reduce mortality by 35%; ICDs and β-blockers do so by 30%.[2] The authors suggest that AF in the presence of systolic HF confers a terrible prognosis and reduction of AF improves survival. That is a reasonable conclusion, but a study published in JAMA in 2012 found that when studies with very large treatment effects are retested in other trials, the treatment effects often lessen.[3]

5. Unblinded study: The authors clearly state the limitations and potential biases in their trial. They note the unblinded nature of treatment assignments. Blinding is important because investigators' (and patients') knowledge of treatment assignment might influence treatment decisions and outcomes. Although superior performance of the ablation arm (more sinus rhythm) likely explains the trial's results, another possibility is underperformance of the medical arm. Patients enrolled in the medical arm had higher rates of diabetes, more use of digoxin, and a greater incidence of ischemic cardiomyopathy. About a third of the medical arm underwent attempts at medically induced rhythm control, which could be harmful. But perhaps most notable was that CASTLE-AF enrolled patients with failed (or unwanted) medical therapy to an arm of more medical therapy.

6. Consistent results add confidence: The CASTLE-AF findings move in the same direction as previous studies. The CAMERA-MRI and CAMTAF trial both found that restoration of sinus rhythm with catheter ablation in patients with HF and AF improved important surrogate outcomes.[4,5] The AATAC trial compared AF ablation and amiodarone in patients with HF (with ICDs/CRT) and symptomatic AF. Ablation proved superior for reducing AF episodes and hospital admissions, as well as a trend toward lower mortality.[6] Another observation that bolsters confidence in CASTLE-AF was the late mortality benefit. The Kaplan-Meier mortality curves separate after 3 years. If they had separated early, one would worry more about unmeasured confounders.

7. Not your typical HF patient: Translating CASTLE-AF requires intense focus on the type of patients enrolled in the trial and its methods. CASTLE-AF enrolled young predominantly male patients. The median age was 64 years, and more than 8 of 10 participants were men. The median ejection fraction was about 32%, and more than 90% of the enrolled patients were well enough to tolerate ACE inhibitors/angiotensin receptor blockers, β-blockers, and diuretics. Median left atrial diameter was less than 5 cm.

8. Don't overextrapolate: CASTLE-AF does not apply to sicker, older, and frailer patients with HF. In a subgroup analysis, patients with an ejection fraction < 25% showed a trend toward worse outcomes with ablation. The male predominance of CASTLE-AF is notable because many studies confirm that women do worse with AF ablation than do men.[7,8] Also, CASTLE-AF does not apply to asymptomatic patients.

9. Expert centers: Another crucial factor in applying these results to the real world is that these were expert centers for ablation. CASTLE-AF investigators accomplished ablation with few complications; they chose patients carefully and slowly (it took 8 years to get 360 patients), and they used a run-in period to optimize therapy. Whether these dramatic benefits can be replicated in everyday practice requires more study. A sobering analysis of nearly 94,000 AF ablation procedures done in the United States from 2000 to 2010 found that rates of complications are increasing over time, perhaps because most AF ablation is done by low-volume operators.[9]


When a young male patient with an ICD and moderate LV dysfunction develops symptomatic AF and does poorly with initial attempts at rhythm control, doing ablation rather than pushing on with drugs or rate control will likely improve outcomes. AF ablation docs sensed that this was true. CASTLE-AF confirms it.

The CASTLE-AF investigators have done their job. Now it is up to the electrophysiology community to apply this evidence wisely. Are we up to the challenge?


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