Phased RF ablation in persistent atrial fibrillation John Hummel, MD, * Gregory Michaud, MD, FHRS, † Robert Hoyt, MD, FHRS, ‡ David DeLurgio, MD, § Abdi Rasekh, MD, ║ Fred Kusumoto, MD, FHRS, ¶ Michael Giudici, MD, # Dan Dan, MD, ** David Tschopp, MD, †† Hugh Calkins, MD, FHRS, ‡‡ Lucas Boersma, MD, §§ for the TTOP-AF Investigators From the * The Ohio State University, Columbus, Ohio, † Brigham and Women’s Hospital, Boston, Massachusetts, ‡ Iowa Heart Center, Des Moines, Iowa, § Emory Crawford Long Hospital, Atlanta, Georgia, ║ Texas Heart Institute at St. Luke’s Episcopal Hospital, Houston, Texas, ¶ St. Luke’s Hospital, Mayo Clinic, Jacksonville, Florida, # Genesis Medical Center, Davenport, Iowa, ** Piedmont Hospital, Atlanta, Georgia, †† Austin Heart, Austin, Texas, ‡‡ The John Hopkins Medical Institute, Baltimore, Maryland, and §§ St. Antonius Ziekenhuis, Nieuwegein, The Netherlands. BACKGROUND Persistent and long-standing persistent atrial fibrillation (AF) often requires extensive and/or repeat radiofre- quency (RF) ablation procedures. OBJECTIVE The Tailored Treatment of Persistent Atrial Fibrillation (TTOP-AF) study assessed the effectiveness and safety of the phased RF system in a randomized controlled comparison of medical therapy against phased RF ablation for the management of persistent and long-standing persistent AF. METHODS Patients who had failed at least 1 antiarrhythmic drug (AAD) were randomized (2:1) to ablation management (AM) or medical management (MM). AM patients were allowed up to 2 ablations. Index and retreatment procedures consisted of pulmonary vein isolation and ablation of complex fractionated atrial electro- grams. MM patients received AAD changes and/or cardioversion. The primary end points of the TTOP-AF study included chronic effective- ness and safety at 6 months and acute safety within 7 days of ablation. RESULTS At 6 months, a greater proportion of AM patients achieved effectiveness off AAD (77 of 138 [55.8%]) compared to MM patients (19 of 72 [26.4%]) (P o .0001). Acutely, 92.8% (128/138) of the procedures were successful while 12.3% (17/138) experienced a serious procedure and/or device-related adverse event. The prede- fined acute safety end point was not met. The proportion of patients with chronic safety events did not differ significantly between groups. CONCLUSIONS Catheter ablation of persistent/long-standing per- sistent AF with the phased RF ablation system is effective with greater reduction of AF compared with MM. More intense anti- coagulation strategies, careful attention to catheter placement relative to the pulmonary vein ostia, and elimination of electrode interaction are expected to reduce the risk of stroke, pulmonary vein stenosis, and asymptomatic cerebral emboli. KEYWORDS Phased RF; Persistent; Atrial fibrillation; Ablation; TTOP ABBREVIATIONS AAD ¼ antiarrhythmic drug; ACE ¼ asymptomatic cerebral embolus; AF ¼ atrial fibrillation; AM ¼ ablation management; CFAE ¼ Complex Fractionated Atrial Electrogram; DCCV ¼ direct current cardioversion; FDA ¼ Food and Drug Administration; INR ¼ International normalized ratio; ITT ¼ intention to treat; LA ¼ left atrial; LMWH ¼ low-molecular weight heparin; LVEF ¼ left ventricular ejection fraction; MAAC ¼ multiarray ablation catheter; MASC ¼ multiarray septal catheter; MM ¼ medical management; OAT ¼ oral anticoagulation therapy; PV ¼ pulmonary vein; PVAC ¼ pulmonary vein ablation catheter; RF ¼ radiofrequency; SR ¼ sinus rhythm; TEE ¼ transesophageal echocardiography; TTOP-AF ¼ Tailored Treatment of Persistent Atrial Fibrillation (Heart Rhythm 2014;11:202–209) I 2014 Heart Rhythm Society. All rights reserved. Introduction Symptomatic atrial fibrillation (AF) decreases quality of life and is associated with an increased risk of heart failure, stroke, and death. 1,2 Radiofrequency (RF) catheter ablation can restore sinus rhythm (SR) in patients with symptomatic persistent or long-standing persistent AF who fail antiar- rhythmic drugs (AADs). However, extensive ablation with long procedure times and repeat ablations are often required. 3,4 These issues were the impetus for the develop- ment of a multielectrode, duty-cycled RF ablation system (phased RF), which was designed to allow rapid treatment of the atrium by creating contiguous lesions using bipolar and This work was supported by Medtronic, Inc. Dr Hummel is a consultant to Medtronic and has received fellowship support and research funding from Medtronic, Boston Scientific, and St. Jude Medical. Dr Michaud and Dr Kusumoto are consultants to Medtronic. Dr Calkins is a consultant to Medtronic, Atricure, Biosense Webster, and Sanofi-Aventis. Dr De Lurgio is on an advisory board for Boston Scientific and speaker’s bureau for St. Jude Medical. Dr Rasekh is a consultant to Biosense Webster. Dr Hoyt is on speaker’s bureaus for Medtronic, St Jude Medical, Boeringer-Ingelheim, and Sanofi-Aventis. Dr Boersma is a consultant to Medtronic and Boston Scientific and is a speaker for Medtronic, Boston Scientific, and Biotronik; he is a former stockholder of Ablation Frontiers and has received research funding from Medtronic. Address reprint requests and correspondence: Dr John Hummel, The Ohio State University, 473 W 12th Avenue, Suite 200, Columbus, OH 43210. E-mail address: [email protected]. 1547-5271/$-see front matter B 2014 Heart Rhythm Society. All rights reserved. http://dx.doi.org/10.1016/j.hrthm.2013.11.009
Transcript
Phased RF ablation in persistent atrial fibrillationJohn Hummel, MD,* Gregory Michaud, MD, FHRS,† Robert Hoyt, MD, FHRS,‡
David DeLurgio, MD,§ Abdi Rasekh, MD,║ Fred Kusumoto, MD, FHRS,¶ Michael Giudici, MD,#
Dan Dan, MD,** David Tschopp, MD,†† Hugh Calkins, MD, FHRS,‡‡ Lucas Boersma, MD,§§ forthe TTOP-AF Investigators
From the *The Ohio State University, Columbus, Ohio, †Brigham and Women’s Hospital, Boston,Massachusetts, ‡Iowa Heart Center, Des Moines, Iowa, §Emory Crawford Long Hospital, Atlanta, Georgia,║Texas Heart Institute at St. Luke’s Episcopal Hospital, Houston, Texas, ¶St. Luke’s Hospital, Mayo Clinic,Jacksonville, Florida, #Genesis Medical Center, Davenport, Iowa, **Piedmont Hospital, Atlanta, Georgia,††Austin Heart, Austin, Texas, ‡‡The John Hopkins Medical Institute, Baltimore, Maryland, and §§St. AntoniusZiekenhuis, Nieuwegein, The Netherlands.
BACKGROUND Persistent and long-standing persistent atrialfibrillation (AF) often requires extensive and/or repeat radiofre-quency (RF) ablation procedures.
OBJECTIVE The Tailored Treatment of Persistent Atrial Fibrillation(TTOP-AF) study assessed the effectiveness and safety of the phasedRF system in a randomized controlled comparison of medicaltherapy against phased RF ablation for the management ofpersistent and long-standing persistent AF.
METHODS Patients who had failed at least 1 antiarrhythmic drug(AAD) were randomized (2:1) to ablation management (AM) ormedical management (MM). AM patients were allowed up to 2ablations. Index and retreatment procedures consisted of pulmonaryvein isolation and ablation of complex fractionated atrial electro-grams. MM patients received AAD changes and/or cardioversion. Theprimary end points of the TTOP-AF study included chronic effective-ness and safety at 6 months and acute safety within 7 days of ablation.
RESULTS At 6 months, a greater proportion of AM patients achievedeffectiveness off AAD (77 of 138 [55.8%]) compared to MM patients(19 of 72 [26.4%]) (P o .0001). Acutely, 92.8% (128/138) of theprocedures were successful while 12.3% (17/138) experienced aserious procedure and/or device-related adverse event. The prede-fined acute safety end point was not met. The proportion of patientswith chronic safety events did not differ significantly between groups.
This work was supported by Medtronic, Inc. Dr Hummel is a consultantto Medtronic and has received fellowship support and research funding fromMedtronic, Boston Scientific, and St. Jude Medical. Dr Michaud and DrKusumoto are consultants to Medtronic. Dr Calkins is a consultant toMedtronic, Atricure, BiosenseWebster, and Sanofi-Aventis. Dr De Lurgio ison an advisory board for Boston Scientific and speaker’s bureau for St. JudeMedical. Dr Rasekh is a consultant to Biosense Webster. Dr Hoyt is onspeaker’s bureaus for Medtronic, St Jude Medical, Boeringer-Ingelheim, andSanofi-Aventis. Dr Boersma is a consultant to Medtronic and BostonScientific and is a speaker for Medtronic, Boston Scientific, and Biotronik;he is a former stockholder of Ablation Frontiers and has received researchfunding from Medtronic. Address reprint requests and correspondence:Dr John Hummel, The Ohio State University, 473 W 12th Avenue, Suite200, Columbus, OH 43210. E-mail address: [email protected].
1547-5271/$-see front matter B 2014 Heart Rhythm Society. All rights reserved.
CONCLUSIONS Catheter ablation of persistent/long-standing per-sistent AF with the phased RF ablation system is effective withgreater reduction of AF compared with MM. More intense anti-coagulation strategies, careful attention to catheter placementrelative to the pulmonary vein ostia, and elimination of electrodeinteraction are expected to reduce the risk of stroke, pulmonaryvein stenosis, and asymptomatic cerebral emboli.
ABBREVIATIONS AAD ¼ antiarrhythmic drug; ACE ¼ asymptomaticcerebral embolus; AF ¼ atrial fibrillation; AM ¼ ablationmanagement; CFAE ¼ Complex Fractionated Atrial Electrogram;DCCV ¼ direct current cardioversion; FDA ¼ Food and DrugAdministration; INR ¼ International normalized ratio; ITT ¼intention to treat; LA ¼ left atrial; LMWH ¼ low-molecular weightheparin; LVEF¼ left ventricular ejection fraction;MAAC¼ multiarrayablation catheter; MASC ¼ multiarray septal catheter; MM¼ medicalmanagement; OAT ¼ oral anticoagulation therapy; PV ¼ pulmonaryvein; PVAC¼ pulmonary vein ablation catheter; RF¼ radiofrequency;SR ¼ sinus rhythm; TEE ¼ transesophageal echocardiography;TTOP-AF ¼ Tailored Treatment of Persistent Atrial Fibrillation
(Heart Rhythm 2014;11:202–209) I 2014 Heart Rhythm Society. Allrights reserved.
IntroductionSymptomatic atrial fibrillation (AF) decreases quality of lifeand is associated with an increased risk of heart failure,stroke, and death.1,2 Radiofrequency (RF) catheter ablationcan restore sinus rhythm (SR) in patients with symptomaticpersistent or long-standing persistent AF who fail antiar-rhythmic drugs (AADs). However, extensive ablation withlong procedure times and repeat ablations are oftenrequired.3,4 These issues were the impetus for the develop-ment of a multielectrode, duty-cycled RF ablation system(phased RF), which was designed to allow rapid treatment ofthe atrium by creating contiguous lesions using bipolar and
Figure 1 Scheduled evaluations for the ablation and medical arms atbaseline and 1, 3, and 6 months. AF ¼ atrial fibrillation; CT ¼ computedtomography; ECG ¼ electrocardiogram; MRI ¼ magnetic resonanceimaging; QoL ¼ quality of life; TEE ¼ transesophageal echocardiography;TTE ¼ transthoracic echocardiography.
203Hummel et al Phased RF Ablation in Persistent AF
unipolar energy. The objective of the Tailored Treatment ofPersistent Atrial Fibrillation (TTOP-AF) study was tocompare the effectiveness and safety of the phased RFsystem with those of AADs for the treatment of patientswith symptomatic persistent and long-standing persistentAF. Catheter ablation is not Food and Drug Administration(FDA) approved for the treatment of persistent AF in theUnited States; thus, study data were intended to support apremarket application for the phased RF system.
MethodsPhased RF ablation systemThe phased RF system, consisting of a multichannel RFgenerator and 3 multielectrode catheters (GENius, pulmo-nary vein ablation catheter [PVAC], multiarray septalcatheter (MASC), multiarray ablation catheter (MAAC),Medtronic Ablation Frontiers, Carlsbad, CA), has beendescribed previously in treating paroxysmal and persistentAF.5,6 Briefly, the multielectrode catheters are used todeliver duty-cycled phased energy via the RF generator totargeted left atrial (LA) regions. Phase-shifted energydelivery between adjacent catheter electrodes (bipolar) andreturn electrodes (unipolar) allows creation of long contig-uous lesions. Modulating unipolar to bipolar RF ratioscontrols lesion depth. RF is delivered in temperature-controlled and power-limited fashion (601C, 8 or 10 W),with a typical duration of 60 seconds.5
Study populationEligible patients were 18–70 years of age and had sympto-matic persistent AF lasting 7 days to 1 year or long-standingpersistent AF lasting 1–4 years. All had failed direct currentcardioversion (DCCV), resulting in recurrent AF within 30days. Patients failed Z1 class I or III AAD and hadcontinuous AF/atrial flutter (AFL) on baseline 48-hourHolter monitor. The study was conducted according to theDeclaration of Helsinki, approved by the institutional reviewcommittee at each of the 24 centers (23 United States and 1Europe) and patients gave informed consent. Exclusioncriteria included prior AF ablation, enrollment in otherarrhythmia study, treated ventricular tachyarrhythmia, activeinfection, history of cerebral vascular accident, pregnancy,active LA thrombus, contrast media allergy, reversible causeof AF, blood clotting abnormalities, sensitivity to heparin/warfarin, severe pulmonary disease, left ventricular ejectionfraction (LVEF ) o40%, New York Heart Association classIII or IV heart failure, severe comorbidity that precludedreliable follow-up, or significant structural heart disease.
Study designAll patients were prospectively randomized 2:1 to ablationmanagement (AM) or medical management (MM). Patientsfollowed a predefined schedule for baseline, discharge, and 1-,3-, and 6-month visits, which includedmedical history, physicalexamination, electrocardiogram, echocardiogram, computedtomography or magnetic resonance imaging, and/or Holter
monitoring (Figure 1). All Holter monitoring and imaging datawere analyzed by an independent core laboratory.
The evaluation of chronic effectiveness of AM vs MMwas performed after 6 months. Treatment success in AM wasdefined as follows:
1.
Acute procedural success is defined as all pulmonary vein(PV) isolated, 450% reduction of Complex FractionatedAtrial Electrogram (CFAE) targets, and restoration ofstable SR,
2.
Z90% reduction in the cumulative time of AF and AFLepisodes lasting Z10 minutes on 48-hour Holter monitor6 months postablation as compared to baseline, and
3.
absence of AAD therapy.
AM patients were allowed up to 2 ablation procedures toachieve success with a 6-month follow-up reset after repeatablation. Acute procedural success was required for bothablation procedures to count as treatment success for theevaluation of chronic effectiveness. Postablation AF recur-rence was managed with DCCV and/or a previously failedAAD discontinued a minimum of 5 days (28 days foramiodarone) before the 6-month visit.
Treatment success in MM patients was defined by the sameAF/AFL reduction as in AM patients. MM treatmentfailures were permitted crossover to ablation therapy 44months after randomization. Both treatment arms were pre-scribed oral anticoagulation therapy (OAT) during the follow-upperiod.
Assessment of safetyAll safety events were adjudicated by a Clinical EventsCommittee/Data Safety Monitoring Board. Serious andprobably or definitely procedure-related and/or device-related events counted toward the acute or chronic end point.
Values are presented as mean � SD and as n (%).AAD¼ antiarrhythmic drug; AF ¼ atrial fibrillation; DC¼ direct current.
*Two-sided t test for age and χ2 test for sex and race.†Two patients (05-321 and 05-315) had left to right shunts present.
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Acute safety. The primary end point was the proportion ofAM patients with at least 1 serious and procedure-relatedand/or device-related adverse event occurring within 7 daysof the index or retreatment ablation procedure. A prespeci-fied end point was defined as a 2-sided 95% upperconfidence bound of o16.0%.
Chronic safety. The primary end point was comparedbetween groups 6 months postablation for AM patients andpostrandomization for MM patients. Any serious adverseevent related to therapy (as adjudicated by the ClinicalEvents Committee/Data Safety Monitoring Board) thatoccurred 47 days and r6 months postprocedure, or afterrandomization for MM, were considered chronic safetyfailures. Acute events (r7 days) were not included in thecalculation of chronic safety.
Secondary end pointsSecondary end points in the study included AF SymptomSeverity and Quality of Life surveys.7,8 In addition, assess-ments of LA size and LVEF by echocardiography wereobtained at baseline and 6 months postablation.
Ablation procedureThe ablation procedure for phased RF ablation of persistentAF has been described previously.5 Briefly, all PVs wereisolated by using the PVAC. CFAE ablation (definition wasper operator) was performed on the left intraatrial septumwith the MASC and in the LA body using the MAAC. Theeffectiveness of CFAE ablation was determined by thereduction in local bipolar electrograms. If AF or atrialtachycardia persisted, SR was restored by DCCV at theend of the procedure. PV isolation was determined by theoperator via PVAC electrogram interpretation during SR.
Transesophageal echocardiography (TEE) was performedwithin 72 hours of the ablation procedure to rule out thepresence of a preexisting intracardiac thrombus. Periproce-dural anticoagulation was dictated by center practice standardsand monitored per individual laboratory protocol. In general,patients discontinued OAT and were bridged with low-molecular weight heparin (LMWH) or intravenous unfractio-nated heparin until the procedure or continued OAT during theprocedure. Heparin was adjusted as necessary to maintain anactivated clotting time of4300 seconds. Once vascular accesssheaths had been removed and hemostasis had been achieved,anticoagulation could be bridged, with LMWH or intravenousheparin administering after 3 hours of hemostasis until the INRwas 42.0. The exact bridging protocol during the trial wasdetermined by the individual center.
Medical management treatmentMM patients received new dosages of previously failedAAD or a new medication promptly after randomization.Patients prescribed amiodarone were allowed a loadingdosage. DCCVs, changes to AAD, and/or dosage wereallowed during the follow-up period.
Statistical analysisThe statistical analysis of all primary end points was basedon intention to treat (ITT) per randomization schedule.Patients missing 6-month data were considered failures inthe analysis. Descriptive statistics were calculated for eachquantitative and qualitative assessment. Primary end pointcomparisons were analyzed by using a χ2 test or an exactbinomial test at 1-sided α ¼ .025 level of significance.
ResultsStudy patientsFrom November 2007 through May 2010, 210 randomizedpatients (138 to AM and 72 to MM) were enrolled in thestudy (Table 1). Compliance with follow-up clinic visits,
Figure 2 Participation of the screened and randomized patients in each arm over time. F/U ¼ follow-up.
205Hummel et al Phased RF Ablation in Persistent AF
electrocardiograms, Holter monitoring, and other evaluationsexceeded 88%.
In AM, 6 patients (4.4%) were withdrawn shortly afterrandomization: 2 due to insurance denials, 2 for discovery of anunderlying medical condition during preprocedure testing, and2 for atypical anatomy (hemizygous vein and aortic valvelocation precluding safe transseptal access). One hundred thirty-two patients received index procedures, with repeat ablation in48 of 132 (36.4%), most frequently due to AF recurrence(84%). Seven additional patients (5%) exited the study becauseof withdrawn consent (n ¼ 4), investigator withdrawal (n ¼ 2;preablation stenotic PV and patient compliance), and 1 whoreceived conventional RF ablation. One patient death occurredbefore the 6-month follow-up visit. There were a total of183 (180 successful and 3 aborted) procedures in the 132 AMpatients for the evaluation of acute safety. Forty-one procedures(22.4%) were conducted with an INR Z2, 140 procedures(76.5%) with INRo2.0, and 2 (1.1%) with no INR data. Meanprocedure time was 3.18� 0.54 hours, LA dwell time was 2.43� 0.49 hours, and fluoroscopy time was 0.54� 0.23 minutes.The rate of DCCV needed to restore SR was 89.4%, with amean of 1.8 per patient. The mean number of RF applicationswas 26.6 � 10.2 for the PVAC catheter, 12.5 � 7.2 for theMAAC catheter, and 6.3 � 2.6 for the MASC catheter. Ofthe 138 patients randomized to AM, 124 (89.9%) completed thestudy through 6 months of follow-up.
Of the 72 patients randomized to MM, 6 patients exitedthe study (8.3%). There were 4 voluntary withdrawals(5.6%), 1 investigator withdrawal, and 1 lost to follow-up.Forty-three of 66 (65%) MM patients crossed over toablation after a median of 153 days (2 patients r4 monthsand 28 patients during 4–6 months) due to inadequate AADtreatment. The remaining 23 (35%) patients completed the6-month follow-up under MM (Figure 2). Patient data
obtained after crossing over was not included in the ITTanalysis. When including crossovers and reablations, 176patients underwent at least 1 study ablation attempt, with atotal of 239 procedures.
EffectivenessAblation procedures met acute success criteria for 128 of 138(92.8%) AM patients. Of note, 5 AM patients never receivedan ablation attempt, but were included per ITT analysis asacute failures (3.6%). Six months after ablation, therapy wascompleted; 77 of 138 (55.8%) AM patients met the chroniceffectiveness end point compared with 19 of 72 (26.4%) MMpatients (P o .0001; Figure 3). Treatment success forpatients with persistent vs long-standing AF did not differsignificantly (AM: 54.2% vs 59.5%; MM: 28.1% vs 20.0%).
The MM treatment failures took at least 1 new AAD,including propafenone (43.9%), flecainide (24.4%), dofeti-lide (17.1%), amiodarone (14.6%), sotalol (12.2%), quini-dine (2.4%), and disopyramide (2.4%) and underwentcardioversion. Of the 10 patients on amiodarone, 4 patients(40%) were treated successfully.
Fifty-six of 77 (73%) successfully treated AM patientswere free from AAD or DCCV in 90 days before the 6-month Holter monitoring, while 72 of 77 (93.5%) patientswere off AAD 30 days before Holter monitoring for the 6-month end point. The last DCCV was 57 days before the 6-month Holter monitoring, and the last amiodarone use was61 days before the 6-month Holter monitoring (Figure 4). Apost hoc analysis was also conducted, in which any episodeof AF/AFL lasting 430 seconds was considered a treatmentfailure. Based on this definition as well as the additionalcriteria for acute procedural success and freedom fromAADs in AM, the proportion of treatment success remained
Figure 3 Treatment success per protocol and solely AF burden reductionper treatment group, with and without antiarrhythmic drug. Treatmentsuccess per protocol (the ITT ablation group) required acute proceduralsuccess and absence of antiarrhythmic medication as well as Holter criteriafor the reduction of AF. The success rate in the ITT ablation group wasidentical when a definition of no AF 430 seconds was used. AF ¼ atrialfibrillation; ITT ¼ intention to treat.
Heart Rhythm, Vol 11, No 2, February 2014206
unchanged for both AM (56%) and MM (26%) (Figure 3).Also, a retrospective post hoc analysis was performed for107 patients who were willing to reconsent for the assess-ment of 12-month treatment success (71 AM, 24 MMcrossover, and 12 MM without crossover). Of the 95 ablatedpatients, 63 (66.3%) achieved Z90% reduction in AFburden without the use of an AAD. Seven additional patientshad treatment success on AAD, resulting in 70 of 95 (73.7%)12-month AF burden reduction Z90 for all ablated patients.Of the 12 MM patients who consented and completed the 12-month visit, all achieved the Z90% reduction in AFend point.
For all patients undergoing a complete ablation (132 AMþ 43 MM � 3 investigator crossover withdrawals), 99(57.6%) were treated successfully. Independent of acuteprocedural success and allowing use of AADs, the AFburden reduction treatment success for ITT along with allablated patients was 67.4% (93 of 138) and 70.9% (122 of172), respectively (Figure 3). There were no predictors oftreatment success, including sex, age, LA size, diabetes,hypertension, procedure time, LA dwell time, AF duration,failed DCCVs, and number of failed AADs.
Figure 4 AAD use per patient before 48-hour Holter assessment ofsuccess at 6-month evaluation in the ablation management arm. AAD ¼antiarrhythmic drug.
Secondary effectiveness end pointsThe quality of life score (Symptom Severity and Quality ofLife surveys) revealed a 6.6-point improvement in physicalwell-being in AM, which exceeded the 2.7-point improvementin MM (P ¼ .0052). Also, a 6.3-point improvement in mentalwell-being in AM exceeded the 2.1-point improvement inMM (P ¼ .0013; Figure 5). Similarly, improvement in meanAF symptom severity score was significantly greater in theAM group compared to the MM group (Po .0001; Figure 6),with each individual symptom showing improvement.
No significant difference was observed in left atrialdiameter (LAD) change between patients randomized toAM and MM (P ¼ .35). Mean LVEF increased modestlyfor both treatment groups, with AM improving from 54.7%
to 58.3% and MM patients improving from 54.9% to57.0% (P ¼ .06).
SafetyAcute safetySeventeen (12.3%) AM patients experienced a total of 21adverse events that are listed in Table 2. Of note, 12 eventsoccurred within the first 5 procedures (n¼ 72) at a site while9 occurred afterward (n ¼ 111), a rate of 0.167 and 0.081events per procedure, respectively. The upper confidencebound of the 2-sided 95% confidence interval exceeded theprespecified performance goal of 16.0% (P ¼ .1427). Noatrio-esophageal fistulae or phrenic nerve paralyses werereported. There was 1 death due to acute heart failureoccurring within 7 days of retreatment ablation. This patientunderwent a successful index ablation despite severelydepressed LVEF of 10%–15% on preablation TEE, whichwas a protocol deviation. Approximately 1 month later, thepatient underwent retreatment, with preprocedure TEEshowing LVEF recovery to 30%–35%, but moderate mitralinsufficiency. After transseptal access and initial heparin-ization but before deployment of any investigational deviceor application of RF energy, the patient suffered acutesystolic heart failure and cardiogenic shock.
Chronic safetyThe proportion of AM patients with chronic adverse safetyevents was 9 of 138 (6.5%), including 5 PV stenoses orsymptomatic narrowing, 1 stroke, 1 persistent ASD, 1symptomatic pericarditis, and 1 pericardial effusion. Theproportion of MM patients with chronic adverse safetyevents was 3 of 72 (4.2%), including 2 gastrointestinalbleeds and 1 AF with rapid ventricular response.
StrokeAcute stroke occurred in 4 of 138 (2.9%) AM patientsundergoing ablation for an ITT procedural rate of 2.2% (4 of183). Three of 4 patients with acute stroke experienced
Figure 5 Physical and mental quality-of-life outcomes in the ablation management arm vs the medical management arm.
207Hummel et al Phased RF Ablation in Persistent AF
symptoms approximately 12 hours after the ablation proce-dure, while the fourth experienced symptoms 3 hours afterthe procedure. Two patients’ symptoms have fully resolved,while the other 2 continue to experience residual strokesymptoms (visual field defect and partial left upper extremityhemiparesis). Three strokes occurred within the first 5procedures at a site. Although these 3 patients receivedLMWH postprocedure, its’ administration occurred 46hours after hemostasis with INR o 2.0. While the studysample size precludes an analysis to fully identify predictorsof periprocedural stroke, the acute stroke patients had a trendto higher CHADS2 scores (mean ¼ 1.6; 3 patients with 1,and 1 patient each with 2 and 3), larger LA, and lower INRsat the time of the procedure, as well as longer proceduretimes compared to patients who did not suffer a stroke. Onestroke was diagnosed 31 days after retreatment in AM. Noacute or chronic strokes were reported for MM patients,including ablation crossovers. Including all attempted abla-tions for both arms after crossover, the periproceduralincidence of stroke was 1.7% (4 of 239).
Figure 6 Changes in atrial fibrillation symptom severity scores frombaseline to 6 months.
Pulmonary vein stenosis/narrowingAM patients underwent computed tomography or magneticresonance imaging at baseline and 6-month follow-up. FourPV stenoses, defined as a 470% diameter reduction,occurred in the left superior PV. One resulted in symptoms,as did 1 PV narrowing (50%–70% reduction). Thus, a total of5 of 138 (3.6%) patients experienced PV stenosis. No PVinjuries required an intervention.
DiscussionThe TTOP-AF study is the only controlled, multicenter,prospective, randomized, FDA-monitored study of catheterablation compared to medical therapy in the treatment ofpersistent or long-standing persistent AF. All other studies ofthis population have been unmonitored, single-center,retrospective, uncontrolled, used inactive controls, or used
Stroke 4 (2.9%)Cardiac tamponade 2 (1.4%)Pseudoaneurysm 2 (1.4%)Heart failure resulting in death 1 (0.7%)Heart failure 1 (0.7%)Pulmonary infiltrates with fever (1 patientexperienced 2 events)*
2 (1.4%)
Drop in Hct secondary to ablation 1 (0.7%)Anesthesia reaction 1 (0.7%)UTI with prolonged hospitalization 1 (0.7%)Hypotension secondary to cardiactamponade
1 (0.7%)
Hypotension/cardiogenic shock 1 (0.7%)Pneumonia 1 (0.7%)Acute respiratory failure 1 (0.7%)Retroperitoneal bleed with right ureterobstruction
1 (0.7%)
Postprocedure pericarditis 1 (0.7%)
Total 21 events occurred in17 patients
Hct ¼ hematocrit; UTI ¼ urinary tract infection.
Heart Rhythm, Vol 11, No 2, February 2014208
subgroup analysis. The population enrolled in the trial hadsymptomatic AF and failed treatment with AAD and DCCV.The use of AM resulted in 55.8% success compared to26.4% with MM, with an ablation retreatment rate of 36%;this result compares favorably with that observed in lesscontrolled trials in similar populations.3 Importantly, medicaltherapy required multiple drug trials and DCCVs beforecrossover to AM. Effective ablation was associated with agreater improvement in quality of life and AF symptomsafter ablation compared to MM. From the standpoint ofpatient outcomes and benefit, the maintenance of SR (with-out the protocol requirements for “acute procedural success”and if one allows use of AADs) appears to be 67.4% (93 of138) for ITT and 70.5% (122 of 173) for all patients ablated.
Previous studies evaluating the phased RF system havereported similar effectiveness outcomes in this patientpopulation. By using 7-day Holter monitoring at 12-monthfollow-up, Mulder et al9 found that 50 of 89 (56.2%) patientswith persistent AF were free from AF/AFL 430 secondsafter 1.2 procedures without AAD. Scharf et al6 reported an80% reduction in AF burden on 7-day Holter monitor in 32of 50 (64%) patients after 1.5 procedures without AAD after6-month follow-up, with a notably low rate of postablationLA flutter (4%).
It is worth noting that the effectiveness results of theTTOP-AF study were achieved despite first use of theablation system in all but one investigating center and nomapping system was used to guide lesion placement.
SafetyThe acute per patient stroke rate for all ablated patientswas 2.3% (4 of 176), with per-procedure incidence of 1.7%(4 of 239). Possible explanations for the rate of strokemay lie in the operator inexperience with the system, theablation system itself, and/or inadequate periproceduralanticoagulation.
Since the completion of this trial, 2 studies comprising1805 patients treated with the study system at experiencedcenters demonstrated thromboembolic rates comparable tocryoballoon and irrigated RF catheter trials, although treatinga minority of patients with persistent AF.10,11 A recentlypublished survey from 20 European centers evaluating 2748patients (620 with persistent AF) using the study ablationsystem reported an overall complication rate of 3.9%, withstroke and TIA incidence of 1.1%.12 The authors note thatcomplications were more frequent in patients with persistentAF treated at less experienced centers. Interestingly, proce-dure and fluoroscopy durations in these prior reports arenotably shorter than those noted in the TTOP-AF study,which might be expected with greater experience using thesystem.
The study system itself could partially account for theincidence of stroke in the trial. It is plausible that multiplecatheter exchanges used in the TTOP-AF study mayincrease the risk of gaseous emboli. Recent animal studieshave suggested that air introduced via the sheath, as well as
bipolar RF interaction between the most proximal anddistal PVAC electrodes inadvertently overlapping duringablation, can increase the risk of predominantly gaseousembolic load and procedural changes to address theseissues appear to contribute to a reduction in asymptomaticcerebral embolus (ACE).13,14 Recently, a multicenterstudy reported a low incidence (1 of 60 [1.7%]) of newasymptomatic cerebral embolism in patients treated withPVAC.15 This study applied no overlap of activatedelectrodes during ablation, submerged catheter introduc-tion, careful attention to sheath management, and unin-terrupted warfarin.
Inadequate anticoagulation may also be a contributingfactor for strokes in the TTOP-AF study. Independent of LAablation, DCCV alone confers risk of thromboembolism ashigh as 1.5% under insufficient anticoagulation.16 In theTTOP-AF study, restoration of SR was required to meet theprocedural success criteria and DCCV was used in490% ofthe procedures. The INR was o2.0 in all acute strokepatients, all of whom underwent cardioversion. Notably, 3 ofthese patients did not receive a bridging dose of LWMH until46 hours postablation. Large retrospective trials publishedafter the TTOP-AF study have demonstrated superiority ofcontinuous OAT to bridging strategies in the prevention ofperiprocedural stroke.17 Interestingly, the recently presentedCOMPARE study demonstrated a periprocedural strokerate of 5.0% (29 of 561) in patients with persistent AF(1.2% [2 of 174]) or long-standing persistent AF (6.7% [26of 387]) who underwent catheter ablation with a heparin-bridging strategy while those randomized to continuouswarfarin had a remarkably lower stroke rate of only 0.33%(2 of 594).18
In the TTOP-AF study, PV injury (stenosis or sympto-matic narrowing) was confined to the left superior PV andwas seen in 4% of the patients. Prior studies have detailedpre- and postablation PV imaging with a low incidence of PVstenosis when using the study ablation system.10,19 However,De Greef et al20 recently published data showing 450%narrowing of the PVs in 15% of the patients, also with higherincidence in the left superior PV. It may be more difficult todistinguish far-field LA appendage from PV signals owing tothe wide interelectrode spacing of PVAC electrodes com-pared with that of standard circular mapping catheters. Also,if the ostium is not well defined via contrast venography,inadvertent ablation within the tubular portion of the PV maylead to stenosis. A recent description of how to correctlyidentify LAA vs PV signals on the PVAC, as well astechniques to avoid RF applications in the PV, may helpreduce the risk of PV stenosis.21,22
Thus, data published after the TTOP-AF study wasplanned and executed suggest that an opportunity exists tomitigate the risk of complications noted in this study byapplying currently accepted OAT practices and improvedtraining, and changing the phased RF ablation strategy toavoid ablation in sites with poor tissue contact or overlappingelectrodes. An acute safety trial incorporating such measuresis currently underway.23
209Hummel et al Phased RF Ablation in Persistent AF
Study limitationsThe TTOP-AF study was designed by using the FDAguidance at the time and before the publication of the 2007HRS Expert Consensus Statement on Catheter Ablation ofAtrial Fibrillation. As a result, several study end points,including the duration of follow-up and definition of treatmentsuccess, are not congruent with the consensus statement.
Recent studies indicate that ACEs on diffusion-weightedMRI can occur with all ablation technologies. In comparativenonrandomized studies, higher rates have been observedwith the phased RF system.24,25 The clinical implication ofthese emboli is still unclear. The TTOP-AF study wasdesigned before concerns of ACEs in the setting of AFablation; thus, MRIs were not performed to evaluate theincidence of silent lesions.
The population studied in this trial consisted of mostlyCaucasian men; thus, extension to other populations cannot beassumed. The significant crossover from MM to AM earlyafter drug failure could bias the study in favor of AM. Thedocumentation of INRs and heparin bridging was not system-atically performed in the trial, making definitive assignment ofstroke events to anticoagulation strategy unclear. Right atrialablations were performed in some patients but, unfortunately,not documented systematically during the trial. Thus, the roleof right atrial ablation in overall effectiveness cannot beassessed. The use of 48-hour Holter, as compared to a longermonitoring period (4- or 7-day Holter), may overestimate thetreatment effect. AF termination was not a study end point inthe TTOP-AF study; however, a comparison study of 306patients with long-standing persistent AF did not show abenefit during 2-year follow-up.26 Entrance, but not exit, blockwas required to confirm PV isolation, thus potentially leadingto an overestimation of acute success. Variability in CFAEdefinition between operators may affect the end point ofablation, thus potentially affecting treatment success. How-ever, there was no significant difference in efficacy betweensites in this study.
ConclusionsThe protocol-defined 6-month effectiveness of the multi-electrode phased RF system in patients with persistent andlong-standing AF is greater than that of MM, providinggreater reduction of AF burden. Further study with theablation system and protocol changes aiming to mitigatesafety concerns will be necessary to verify an acceptable riskprofile.
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