# Catheter Ablation for Persistent Atrial Fibrillation: What the STAR AF II Trial Means for Patients SUMMARY: In this randomized trial involving 589 patients with persistent atrial fibrillation, adding extra ablation (either targeting complex electrical signals or creating additional linear scars) to standard pulmonary-vein isolation did not improve freedom from recurrent atrial fibrillation at 18 months. Success rates were 59% with isolation alone, 49% with isolation plus electrogram ablation, and 46% with isolation plus lines (P=0.15). The simpler procedure also took less time. This suggests that the extra ablation approaches may not provide additional benefit for persistent AF. # Catheter Ablation for Persistent Atrial Fibrillation: What the STAR AF II Trial Means for Patients ## Table of Contents - Key Points - What Is Persistent Atrial Fibrillation and Why Is It Harder to Treat? - How the Study Was Conducted - Key Findings: Did Extra Ablation Help? - What This Means for Patients - Study Limitations - Questions to Ask Your Doctor - Frequently Asked Questions - Source Information ## Key Points - In 589 patients with persistent atrial fibrillation, adding electrogram or linear ablation to pulmonary-vein isolation did not significantly reduce recurrent AF at 18 months. - Freedom from recurrent AF at 18 months was 59% with isolation alone, 49% with isolation plus electrograms, and 46% with isolation plus lines. - Procedure time was significantly shorter with pulmonary-vein isolation alone than with the more extensive approaches in this trial. - Serious complications were rare: tamponade, stroke or transient ischemic attack, and one atrioesophageal fistula across all groups. - Patients with persistent AF should discuss with an electrophysiologist whether isolation alone is appropriate, given individual anatomy and symptom burden. ## What Is Persistent Atrial Fibrillation and Why Is It Harder to Treat? Atrial fibrillation (AF) is an irregular, often rapid heart rhythm that originates in the upper chambers of the heart (the atria). In **paroxysmal atrial fibrillation**, episodes come and go and usually stop on their own within 7 days. **Persistent atrial fibrillation** is defined as a sustained episode lasting more than 7 days and is more difficult to treat successfully. Catheter ablation is a minimally invasive procedure in which a doctor threads a thin tube (catheter) through blood vessels to the heart and uses heat (radiofrequency energy) to create small scars. These scars block abnormal electrical signals that cause AF. For paroxysmal AF, ablation is very effective. Most triggers for paroxysmal AF come from the **pulmonary veins** — the four veins that bring oxygen-rich blood from the lungs to the left atrium. Ablation therefore focuses on creating circular scars around these veins to electrically isolate them from the rest of the heart. Persistent AF is more challenging. The abnormal signals are not only in the pulmonary veins but also throughout the left atrium, which has developed "substrate" — tissue changes that help keep AF going. Because of this, guidelines have suggested that doctors should consider more extensive ablation in addition to pulmonary-vein isolation. The two most common extra techniques are: - **Ablation of complex fractionated electrograms (CFEs):** targeting small areas in the atrium that show rapid, disorganized electrical activity. - **Linear ablation:** creating long lines of scar tissue across the roof of the left atrium and between the mitral valve and the pulmonary veins (the mitral isthmus). However, before this trial, there were limited randomized data to prove that these additional ablation strategies actually improve outcomes. The **STAR AF II** (Substrate and Trigger Ablation for Reduction of Atrial Fibrillation Trial Part II) was designed to answer this question directly. ## How the Study Was Conducted ### Trial Design and Participants The study was a multicenter, randomized trial conducted at 48 experienced centers in 12 countries. It was sponsored by St. Jude Medical, a medical device company. The trial was approved by ethics committees at each center, and all patients gave written informed consent. A total of **589 patients** with persistent atrial fibrillation were enrolled between November 2010 and July 2012. Patients were eligible if they were **18 years or older**, had **symptomatic persistent AF** (a sustained episode lasting more than 7 days), had AF that was **refractory to at least one antiarrhythmic medication**, and were undergoing ablation for the **first time**. Key exclusion criteria were: - Paroxysmal (episodic) atrial fibrillation - Sustained AF lasting more than **3 years** - A left atrial diameter of **60 mm or greater** (severely enlarged left atrium) ### Randomization and Ablation Strategies Patients were randomly assigned in a **1:4:4 ratio** to one of three ablation strategies: 1. **Pulmonary-vein isolation alone** (67 patients) — ablation around each pulmonary vein until electrical signals from the veins could not enter the atrium (entrance block) and pacing inside the vein could not exit (exit block). 1. **Pulmonary-vein isolation plus complex fractionated electrogram ablation** (263 patients) — after isolation, doctors used validated automated software to identify and ablate areas with rapid or continuous electrical activity until AF terminated or all such areas were eliminated. 1. **Pulmonary-vein isolation plus linear ablation** (259 patients) — after isolation, doctors created additional lines of scar across the left atrial roof and the mitral valve isthmus, and confirmed conduction block with pacing maneuvers. Randomization was performed using an automated telephone system and was stratified by study site. **Patients were unaware** of which ablation strategy they received. Doctors, of course, knew which procedure they were performing. ### Procedures and Follow-Up Before ablation, patients stopped taking antiarrhythmic medications and took oral anticoagulation (blood thinners) for at least 4 weeks. The ablation itself used radiofrequency energy delivered through a catheter with an open, irrigated tip, guided by a 3D mapping system (EnSite Velocity, St. Jude Medical). During the first 3 months after ablation (the "blanking period"), patients could take antiarrhythmic medications. After that, their use was discouraged. Patients with recurrent AF after the blanking period could restart antiarrhythmic drugs or undergo a repeat ablation using the same randomized strategy, which was recommended 3 to 6 months after the initial procedure. Follow-up assessments were performed at **baseline and at 3, 6, 9, 12, and 18 months**. At each visit, patients had: - Clinical assessment - 12-lead electrocardiogram (ECG) - 24-hour Holter monitor recording In addition, patients were given a **transtelephonic monitor** and were asked to transmit rhythm recordings **weekly** and any time they had symptoms like palpitations, dizziness, or shortness of breath. All ECGs and Holter readings were interpreted by clinicians who did not know the treatment assignment. Transtelephonic transmissions were read by independent core laboratory personnel, also blinded to treatment. ### Study Endpoints and Statistical Analysis The **primary endpoint** was freedom from any documented episode of atrial fibrillation lasting longer than 30 seconds after a single ablation procedure, with or without antiarrhythmic medication. Episodes within the first 3-month blanking period were not counted. A repeat left atrial ablation procedure at any time was also counted as a recurrence. Main secondary endpoints included: - Freedom from documented AF after two ablation procedures - Freedom from any atrial arrhythmia (AF, atrial flutter, or atrial tachycardia) after one and after two procedures - Use of antiarrhythmic medication - Procedure time - Incidence of repeat procedures - Incidence of periprocedural complications An independent events committee, unaware of treatment assignments, adjudicated all adverse events. Sample-size calculations were based on a pilot study. The expected freedom from AF after one procedure was **75%** for isolation plus electrograms and **45%** for isolation alone. For isolation plus lines, the expected success was estimated from the literature at **60%**. The trial was designed to have **90% power** at a one-sided alpha level of 0.025, and after accounting for a 15% dropout rate, the target enrollment was **549 patients** (61 for isolation alone and 244 each for the other two groups). Statistical comparisons among the three groups were performed using the log-rank test with two degrees of freedom, and post hoc pairwise analyses used the Holm method. A two-sided P value of less than 0.05 was considered statistically significant. ## Key Findings: Did Extra Ablation Help? ### Follow-Up and Adherence Of the 589 randomized patients, **21 patients did not receive any ablation** after randomization, and **19 more dropped out** before completing the 3-month blanking period. These patients were not included in the outcome analyses. Therefore, the primary analysis included **61 patients in the isolation-alone group, 244 in the isolation-plus-electrograms group, and 244 in the isolation-plus-lines group**. Of the patients who did receive ablation, **90% completed the 18-month follow-up**. Adherence to Holter monitoring at each visit was **85%**. Adherence to at least weekly transtelephonic transmission during the 18 months was **75%**, with no significant differences among the groups. ### Primary Outcome: Recurrence of Atrial Fibrillation After 18 months, the primary outcome — freedom from any documented AF recurrence lasting more than 30 seconds after one ablation procedure — was reported for: - **59%** of patients in the pulmonary-vein isolation alone group (36 of 61) - **49%** of patients in the isolation plus electrograms group (119 of 244) - **46%** of patients in the isolation plus lines group (112 of 244) The overall comparison among the three groups was **not statistically significant (P = 0.15)**. In other words, adding either complex fractionated electrogram ablation or linear ablation did not significantly improve freedom from recurrent AF compared to pulmonary-vein isolation alone. ### Secondary Outcomes There were also no significant differences among the three groups for the main secondary endpoints: - **Freedom from AF after one procedure without antiarrhythmic drugs:** 48% (isolation alone), 37% (isolation plus electrograms), 33% (isolation plus lines) — P = 0.11 - **Freedom from any atrial arrhythmia after one procedure with or without drugs:** 49%, 41%, and 37% — P = 0.15 - **Freedom from any atrial arrhythmia after one procedure without drugs:** 41%, 33%, and 29% — P = 0.08 - **Freedom from documented AF after two procedures:** 72%, 60%, and 58% — P = 0.18 - **Freedom from any atrial arrhythmia after two procedures:** 61%, 50%, and 48% — P = 0.24 - **Documented atrial flutter or tachycardia after one procedure:** 11%, 11%, and 14% — P = 0.57 - **Documented atrial flutter or tachycardia after two procedures:** 11%, 13%, and 12% — P = 0.98 One noteworthy post hoc finding: when the researchers specifically compared pairs of groups without adjusting for multiple comparisons using the Holm method, they found that patients assigned to **isolation plus lines** had **significantly less freedom from AF and from atrial arrhythmias without antiarrhythmic medications** than patients assigned to **isolation alone** (P = 0.04 for both comparisons). This was an unplanned analysis, so it should be interpreted cautiously, but it does suggest that adding linear ablation might actually be worse in some respects. ### Procedural Details At the time of ablation, **79% of patients were in spontaneous atrial fibrillation**. Successful pulmonary-vein isolation was achieved in **97%** of all patients, with no significant differences between groups. In the isolation plus electrograms group, complex fractionated electrograms were **successfully eliminated in 80% of patients**. In 11% of cases, the electrograms were not mapped according to protocol because AF was no longer inducible after pulmonary-vein isolation. In 9%, all complex fractionated electrograms could not be eliminated. In the isolation plus lines group, all patients had the required lines performed, but only **74%** showed complete conduction block across both lines. **Procedure time was significantly shorter for pulmonary-vein isolation alone** than for the other two procedures (P < 0.001). Exposure to fluoroscopy (X-ray imaging) was also significantly lower for isolation alone (P < 0.001 for both comparisons). Repeat ablation was performed in: - **21%** of patients in the isolation-alone group - **26%** of patients in the isolation plus electrograms group - **33%** of patients in the isolation plus lines group The difference between groups was not significant (P = 0.10). ### Complications Serious complications in the trial included: - **Tamponade** (compression of the heart due to fluid in the sac around it) — occurred in **3 patients** - **Stroke or transient ischemic attack** ("mini-stroke") — occurred in **3 patients** - **Atrioesophageal fistula** (an abnormal connection between the heart and the esophagus, a rare but very serious complication) — occurred in **1 patient** The report notes that an independent events committee adjudicated all adverse events, and the numbers above represent the total across all treatment groups. ### Baseline Patient Characteristics The three groups were well balanced at the start of the trial. Across all groups, the average age was **58 to 61 years**, **76% to 81%** of patients were male, and the average left ventricular ejection fraction (a measure of heart pumping function) was **55% to 57%**. The average left atrial diameter was **44 to 46 mm**. Time from first AF diagnosis averaged **3.6 to 4.3 years**. Medical history showed that **48% to 61%** had hypertension, **9% to 12%** had diabetes, **3% to 11%** had coronary disease, **5% to 9%** had a prior stroke or transient ischemic attack, and **4% to 6%** had heart failure. Regarding stroke risk (CHADS2 score), **31% to 46%** had a score of 0, **37% to 49%** had a score of 1, **9% to 12%** had a score of 2, and **4% to 7%** had a score greater than 2. Baseline medications included beta-blockers (56% to 64%), calcium-channel blockers (13% to 18%), amiodarone (19% to 24%), and vitamin K antagonists (72% to 82%), among others. ## What This Means for Patients The most important message from STAR AF II is that **more extensive ablation is not necessarily better** for persistent atrial fibrillation. In this large, randomized trial, adding either complex fractionated electrogram ablation or linear ablation to pulmonary-vein isolation did not reduce the rate of recurrent AF over 18 months. In fact, the numerical trend favored the simpler procedure. This is reassuring for patients who have persistent AF and are considering catheter ablation. It suggests that **pulmonary-vein isolation alone may be a reasonable first-line approach**, and that the additional time, risk, and complexity of substrate modification may not provide meaningful benefit. The significantly shorter procedure time with pulmonary-vein isolation alone is also important. A shorter procedure generally means less time under anesthesia, lower radiation exposure from fluoroscopy, and potentially fewer complications. However, the results do not mean that every patient with persistent AF should receive only pulmonary-vein isolation. Persistent AF is a complex and heterogeneous condition. Some patients may still benefit from additional ablation, particularly if pulmonary-vein isolation alone fails. The study also found that only **74%** of patients who received linear ablation achieved complete conduction block, suggesting that the technique might not have been fully effective in all cases. This could partly explain the lack of benefit. For patients, the key takeaway is to have a detailed discussion with an electrophysiologist (a heart rhythm specialist) about the risks and benefits of each ablation strategy, taking into account individual anatomy, AF duration, symptom burden, and underlying heart disease. ## Study Limitations As with any clinical trial, this study has limitations that are important to understand: - **Unblinded operators:** Although patients did not know their treatment assignment, the doctors performing the ablations obviously did. This can introduce bias, although the endpoints were adjudicated by blinded committees. - **Experienced centers only:** All procedures were performed at 48 experienced centers. Results may not be generalizable to lower-volume or less experienced centers. - **Follow-up duration:** The trial followed patients for 18 months. Longer-term outcomes may differ. - **Monitoring limitations:** Holter monitors recorded only 24 hours at each visit, and transtelephonic monitoring depended on patient adherence (75%). Some short or asymptomatic episodes of AF may have been missed. - **Specific patient population:** Patients with AF lasting more than 3 years or a left atrial diameter of 60 mm or greater were excluded. Results may not apply to those with more advanced disease. - **Variable completeness of ablation:** In the linear ablation group, complete conduction block was achieved in only 74% of patients. This could have affected the outcomes in that group. - **Sponsorship:** The trial was funded by St. Jude Medical, the manufacturer of the mapping system and catheters used. The sponsor reviewed the manuscript but was not involved in study design, writing, or submission. ## Questions to Ask Your Doctor If you have persistent atrial fibrillation and are considering catheter ablation, here are some questions based on this study that you might ask your doctor: 1. **Is pulmonary-vein isolation alone enough for my type of AF?** The STAR AF II results suggest that it may be, but your individual situation matters. 1. **Do you recommend additional ablation of complex fractionated electrograms or linear lesions?** If so, ask why — and what evidence supports that choice for your specific case. 1. **What is your success rate and complication rate?** This trial was conducted at experienced centers with a 97% success rate for pulmonary-vein isolation. 1. **What are the risks of the procedure?** In this trial, serious complications included tamponade, stroke or transient ischemic attack, and atrioesophageal fistula — all rare but possible. 1. **How long will the procedure take?** The simpler pulmonary-vein isolation procedure took significantly less time than the more extensive approaches. 1. **What is the plan for managing my stroke risk?** Anticoagulation was used before and after ablation in the trial, and should be part of your overall treatment plan. 1. **What happens if AF recurs?** In the study, repeat ablation was performed in 21% to 33% of patients, and freedom from AF after two procedures was better across all groups. The decision to undergo catheter ablation — and which type of ablation to have — is personal. This study provides strong evidence that additional substrate modification does not routinely improve outcomes for persistent AF. Discussing these findings with your care team can help you make an informed choice that aligns with your goals and values. ## Frequently Asked Questions ### What is persistent atrial fibrillation and why is it harder to treat than paroxysmal AF? Persistent atrial fibrillation is a sustained irregular heart rhythm lasting more than 7 days. It is harder to treat because abnormal electrical signals are not only in the pulmonary veins but also throughout the left atrium, which has developed tissue changes that help keep AF going. This is why doctors previously considered more extensive ablation. ### What was the STAR AF II trial testing? The trial randomly assigned 589 patients with persistent atrial fibrillation to pulmonary-vein isolation alone, isolation plus complex fractionated electrogram ablation, or isolation plus linear ablation. The goal was to see whether adding extra ablation improved freedom from recurrent atrial fibrillation compared with the simpler procedure alone. ### Did adding extra ablation help patients with persistent atrial fibrillation? No. At 18 months, freedom from recurrent atrial fibrillation was 59% with isolation alone, 49% with isolation plus electrogram ablation, and 46% with isolation plus lines. The differences were not statistically significant (P=0.15). The simpler procedure also took less time and had no worse outcomes in this trial. ### What does this trial mean for a patient considering catheter ablation for persistent AF? Pulmonary-vein isolation alone may be a reasonable first-line approach for persistent atrial fibrillation. Adding substrate modification did not improve outcomes in this trial and increased procedure time. However, persistent AF is complex, so individual anatomy, symptom burden, and underlying heart disease should be discussed with an electrophysiologist before choosing a strategy. ### What were the serious complications in this trial? Serious complications included tamponade (compression of the heart by fluid) in 3 patients, stroke or transient ischemic attack in 3 patients, and atrioesophageal fistula (an abnormal connection between heart and esophagus) in 1 patient. These events occurred across the whole trial; they are rare but possible during catheter ablation. ### What questions should I ask my doctor about persistent AF ablation? Ask whether pulmonary-vein isolation alone is enough for your type of AF, why extra ablation might be recommended for you, the doctor's success and complication rates, how long the procedure will take, how stroke risk will be managed, and what the plan is if AF returns. The trial showed repeat ablation was done in 21%–33% of patients, with better freedom from AF after two procedures. ## Source Information **Original article title:** Approaches to Catheter Ablation for Persistent Atrial Fibrillation **Authors:** Atul Verma, M.D., Chen-yang Jiang, M.D., Timothy R. Betts, M.D., M.B., Ch.B., Jian Chen, M.D., Isabel Deisenhofer, M.D., Roberto Mantovan, M.D., Ph.D., Laurent Macle, M.D., Carlos A. Morillo, M.D., Wilhelm Haverkamp, M.D., Ph.D., Rukshen Weerasooriya, M.D., Jean-Paul Albenque, M.D., Stefano Nardi, M.D., Endrj Menardi, M.D., Paul Novak, M.D., and Prashanthan Sanders, M.B., B.S., Ph.D., for the STAR AF II Investigators **Journal:** The New England Journal of Medicine, 2015;372:1812-22. Published May 7, 2015. **DOI:** 10.1056/NEJMoa1408288 **Trial registration:** ClinicalTrials.gov number, NCT01203748 **Funding:** St. Jude Medical This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and should not replace individualized advice from your healthcare provider. --- Publisher: Diagnostic Detectives Network (https://diagnosticdetectives.com) — independent multi-expert medical second opinions, worldwide, private-pay. Author byline: Anton Titov, MD, PhD. 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