The CABANA Trial in AF: A Quiz and a Practice Question

June 11, 2018

Results of the CABANA study (atrial fibrillation) are up for evaluation. How did the trial work and could it change your thoughts on AF treatment?

One of the most long-awaited trials in cardiology, the atrial fibrillation CABANA1 trial made its debut at the Heart Rhythm Society meeting (May 9-12) in Boston earlier this year. The trial has generated almost as much discussion as the sham-controlled ORBITA trial did at the American College of Cardiology meeting, ie, some are calling CABANA a “game-changer” while others say the results won't impact their practice. 

Test your knowledge of the CABANA trial here and consider your own opinion of the results.

1. Which of the following questions did the CABANA trial address in patients with atrial fibrillation who are symptomatic?

A. Should left atrial appendage ligation be done at the time of cardiac surgery to reduce stroke and all-cause mortality?

B. Are rate and rhythm control equivalent strategies in reducing risk of death?

C. Is catheter-based ablation superior to rate/rhythm control for management of atrial fibrillation?

D. Which is more effective: lenient rate control (resting HR<110 beats/min) or strict rate control (resting HR<80 beats/min and HR during moderate exercise <110 beats per minute).

Please click below for answer and discussion.

Answer: C. Is catheter-based ablation superior to rate/rhythm control for management of atrial fibrillation?

CABANA1 (Catheter Ablation versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial) asked whether percutaneous catheter ablation therapy for eliminating AF was superior to pharmacologic therapy (with either rate or rhythm control). Option A is the question posed by a recent trial published in JAMA2 that showed that surgical ligation of the LAA at the time of concurrent cardiac surgery reduced the risk of stroke and all-cause mortality. Option B reflects the AFFIRM trial,3  which concluded that management of atrial fibrillation with the rhythm-control strategy was equivalent to the rate-control strategy, with potential for fewer adverse drug side effects. Option D is the question at the center of the RACE-2 trial,4 which concluded that in patients with permanent atrial fibrillation, lenient rate control is as effective as strict rate control and is easier to achieve.

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2. What was the primary endpoint of the CABANA trial?

A. Overall mortality.

B. Stroke and systemic embolism.

C. A composite of cardiovascular death, MI, and stroke.

D. A composite of overall mortality, disabling stroke, major bleeding, and cardiac arrest.

Please click below for answer and discussion.

Answer: D. A composite of overall mortality, disabling stroke, major bleeding, and cardiac arrest.1

As a result of slow enrollment in the study and a lower than expected event rate, the investigators expanded their primary endpoint, (initially  mortality only), to include a composite of overall mortality, disabling stroke, major bleeding, and cardiac arrest (initially the secondary endpoint).1

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3. The CABANA trial randomized 2200 patients in an open label 1:1 fashion to either catheter ablation with pulmonary vein isolation or drug therapy.

Which of the following was NOT one of the key inclusion criteria for the study?A. Age ≥65 years.

B. Age <65 years plus one risk factor for a cerebrovascular accident (ie, HTN, DM, CHF, prior CVA)

C. Patients with new onset or undertreated paroxysmal, persistent or longstanding persistent AF who warrant therapy.

D. Patients eligible for catheter ablation and ≥1 sequential rhythm control and/or ≥2 rate control drugs.

Please click below for answer and discussion.

Answer: D. Patients eligible for catheter ablation and ≥1 sequential rhythm control and/or ≥2 rate control drugs.

Options A, B, and C were key inclusion criteria. With respect to option D, the inclusion criteria were: Patients eligible for catheter ablation and ≥2 (not ≥1) sequential rhythm control and/or ≥2 rate control drugs.

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4. Patients in the CABANA trial ablation arm were not mandated to receive oral anticoagulation if normal sinus rhythm was restored.

A. True

B. False

Please click below for answer and discussion.

Answer: B. False.

Both arms of the CABANA trial (either ablation or pharmacologic therapy) were required to receive “guideline mandated oral anticoagulation” before, during, and after the ablation procedure. For example, those with persistent and long-standing persistent AF were anticoagulated as follows:

Before – INR 2-3 with TEE at time of ablation to exclude LAA thrombus;

During – ACT maintained 300 and 400 seconds

After – IV heparin or LMWH 4-6 hours after all sheaths removed with resumption of warfarin the evening after intervention.

There were ~2200 patients with a median age of 67 years, with 37% women and about half with persistent or long-standing persistent AF, balanced for other baseline characteristics.

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Question 5. What were the outcomes of the CABANA trial?

A. No significant difference in the composite clinical primary endpoint or mortality in an intention to treat (ITT) analysis.

B. Reduction in the ablation group for the time to first AF recurrence in an ITT  analysis.

C. Reduction in mortality in the ablation group in an “on-treatment” analysis.

D. None of the above.

E. All of the above.

Please click below for answer and discussion.

Answer: E. All of the above.

The most interesting discussion of the results from the CABANA trial centered around the fact that a large number of patients were considered “crossover” patients and that caused “dirty results.” There were 102 (9.2%) patients in the ablation arm who received medications alone (mostly due to patient choice) and 301 (27.5%) patients who crossed over and received ablation. So, when the data were analyzed according to “assigned treatment arm” (ITT, regardless of whether completed or not), results were quite different versus when data were analyzed by actual treatment received (“on-treatment” or “per protocol”) or when those patients who crossed over were eliminated.

ITT group - No difference in primary endpoint (death, disabling stroke, serious bleeding, cardiac arrest)

- 47% reduction in time to first AF recurrence in ablation compared with drug therapy.

On-treatment or per protocol group- 33% reduction in primary endpoint (death, disabling stroke, serious bleeding, cardiac arrest) in those who underwent ablation excluding dropouts.
- 40% reduction in mortality in those with ablation compared to drug therapy when crossover patients were excluded.
- 17% reduction in death or cardiovascular hospitalization

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6. So, will you change your practice based on the results of the CABANA trial?A. Yes

B. No

C. I’m not sure!

Please click below for discussion.

Answer: None of the above and it's your choice!  

For some, this trial offered interesting insights into which patients may benefit the most from ablation. Subgroup analysis showed that patients younger than age 65 years and those with heart failure appeared to benefit more from ablation. [HR for the primary end point among patients younger than 65 years was 0.52 (95% CI, 0.27 - 1.00). It was 0.41 (95% CI, 0.20 - 0.85) in the per-protocol analysis]. Conversely, benefit of AF ablation seemed to be lacking in older patients.

For other more skeptical practitioners, any decision on how to proceed is being reserved until the full results are published. Some have raised concern about emphasizing the on-treatment analysis in a trial that was obviously unblinded (both team and patient knew whether an ablation was received) and wherein ITT analysis was negative for the primary endpoint.

One thing is certain, though … the cardiology/electrophysiology community is increasingly embracing ablation as an emerging therapy for atrial fibrillation. The procedure, based on this randomized, first-of-its-kind trial, appears to be a safe alternative for AF patients and to be at least equivalent to and in some selected patients, superior, to pharmacologic therapy.

Stay tuned.

References:

1. Packer DL, Mark DB, Robb RA, et al. Catheter Ablation vs. Antiarrhythmic Drug Therapy For Atrial Fibrillation: The Results Of The Cabana Multicenter International Randomized Clinical Trial. Heart Rhythm Society (HRS) 2018 Scientific Sessions. Abstract B-LBCT01-05. Presented May 10, 2018.

2. Yao X, Gersh BJ, Holmes DR, et al. Association of surgical left appendage occlusion with subsequent stroke and mortality among patients undergoing cardiac surgery. JAMA. 2018;319:2116–2126.

3. The AFFIRM investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347:1825-1833.

4. Van Gelder IC, Groenveld HF, Crijns HJGM, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med 2010; 362:1363-1373.