A Randomized Multicenter Comparison of Radiofrequency Ablation and Antiarrhythmic Drug Therapy as First Line Treatment in 294

Patients with Paroxysmal Atrial Fibrillation

Jens Cosedis Nielsen, Professor, MD, DMSc,

Aarhus, Denmark

on behalf of the MANTRA-PAF investigators

MANTRA-PAF Investigators

• Arne Johannessen Gentofte University Hospital, CPH, Denmark• Pekka Raatikainen Oulu University Hospital, Finland• Gerhard Hindricks Leipzig University Hospital, Germany• Håkan Walfridsson University Hospital Linköping, Sweden• Ole Kongstad Lund University Hospital, Sweden• Steen Pehrson Rigshospitalet, Copenhagen, Denmark• Anders Englund University Hospital, Örebro, Sweden • Juha Hartikainen Kuipio University Hospital, Finland• Leif Spange Mortensen UNI-C, Denmark (Datamanagement and

statistics)• Peter Steen Hansen Aarhus University Hospital, Skejby, Denmark

(Chair, investigator committee)• Jens Cosedis Nielsen Aarhus University Hospital, Skejby, Denmark

(Coordinating investigator)

Funding: The trial was supported by unrestricted grants from the Danish Heart Foundation and from Biosense Webster and Johnson&Johnson

Aim

• To compare radiofrequency ablation (RFA) with antiarrhythmic drug therapy (AAD) as first-line treatment in patients with paroxysmal atrial fibrillation (AF).

Methods

• Randomized controlled multicenter trial

• Antiarrhythmic drug therapy (Class IC or III) (AAD) versus pulmonary vein isolation (RFA)

• Power calculation: Assumed freedom from AF after 24 months in 75% (RFA) versus 60% (AAD) of the patients, α=0.05, 1-β=0.80, N=150 patients in each group

• Follow-up with 7-day Holter recordings after 3, 6, 12, 18 and 24 months

• Intention-to-treat analysis

Endpoints

• Primary endpoints:– Cumulative burden of AF– AF-burden at each 7-day Holter recording

• Secondary endpoints:– Freedom from any AF after 24 months– Freedom from symptomatic AF after 24 months– Burden of symptomatic AF after 3, 6, 12, 18, and 24 months – Atrial flutter– Quality of Life after 12 and 24 months– Serious adverse events

294 Patients Randomized

146 Assigned to RFA140 Underwent RFA (96%)

148 Assigned to AAD146 Started AAD (99%)

After 24 months

N=140; 223 RFA procedures (1.6±0.7)

On AAD: N=13/138 (9%) (IC: 10, III: 3)

Withdrawn N=5 Died N=3

666 7D Holter recordings

After 24 months

N=54; 87 RFA procedures (1.6±0.7)

On AAD: N=100 /137 (73%) (IC: 86, III:14)

Withdrawn N=7 Died N=4

665 7D Holter recordings

69 underwent repeated RFA

Treatment with1.24±0.48 AAD’s

Baseline Characteristics I RFA AADN 146 148

Age (years) 56±9 54±10

Male gender 100 (68%) 106 (72%)

Body Mass Index 27±4 27±4

Hypertension 43 (29%) 53 (36%)

Coronary artery disease 6 (4%) 2 (1%)

Valvular disease 7 (5%) 15 (10%)

Previous stroke or TIA 6 (4%) 5 (3%)

Diabetes 6 (4%) 10 (7%)

Chronic lung disease 8 (5%) 6 (4%)

Pacemaker 5 (3%) 6 (4%)

Thyroid disease 10 (7%) 10 (7%)

Previous Cardioversions

0 103 100

1 8 17

2 11 6

3 7 4

4 2 6

>4 15 15

Baseline Characteristics II RFA AADDuration of usual AF episodes

≤1 hour 27 29

>1 hour, ≤7 hours 57 57

>7 hours, ≤24 hours 43 45

>24 hours, ≤2 days 14 8

>2 days, ≤7 days 3 7

Average interval between AF episodes

0-7 days 82 87

>7 days, ≤1 month 48 41

>1 month, ≤6 months 14 18

>6 months 1 0

Left atrial size (echo), mm 40±6 40±5

Left ventricular ejection fraction

>60% 116 121

40-60% 29 26

Medication last week before randomization

Warfarin 69 (47%) 65 (44%)

Betablocker 106 (73%) 107 (72%)

Calcium channel blocker 28 (19%) 16 (11%) *

Digoxin 17 (12%) 13 (9%)

* p<0.05

Without AF: 61 66 97 91 112 103 120 106 122 109 124 105 77 65

Baseline 3 months 6 months 12 months 18 months 24 months Cumulated

0

10

20

30

40

50

60

70

80

90

100

Atr

ial F

ibril

latio

n B

urd

en

(%)

A D A D A D A D A D A D A D

Mann-Whitney TestMean rank 149 146 145 150 144 151 141 154 141 154 138 157 140 155

P-value 0.72 0.49 0.34 0.08 0.07 0.007 0.10

AF Burden

A: RFAD: AAD

AF after 24 Months

Num

ber o

f pati

ents

P=0.012P=0.004

Quality of Life (SF-36)

Physical Component Summary (PCS) Mental Component Summary (MCS)

Mean values of PCS and MCS

p=0.01 p=0.02ns ns

Atrial Flutter

P=0.25

Num

ber o

f pati

ents

Serious Adverse Events RFA AADDeath 3 4

Stroke 1 0

Transient ischemic attack 1 1

Pulmonary vein stenosis 1 0

Tamponade 3 0

Pericardial effusion, no puncture 0 1

Suspected perforation at transseptal puncture 1 0

Atrial flutter, 1:1 AV conduction 0 2

Atrial flutter or atrial tachycardia 3 3

Cardiac incompensation 0 2

Perimyocarditis 1 0

Bradycardia with need of pacemaker 0 1

Ventricular tachycardia and need for ICD 1 0

Hematoma related to anticoagulation 1 0

Retroperitoneal bleeding, coiling of small artery 1 0

Chest discomfort 1 0

Discomfort probably due to medication 0 2

Cancer 6 4

Other (Rotator cuff rupture, Arthroscopy, Gallbladder surgery) 1 2

Total 25 22

Conclusions

• At 24 months AF-burden and occurrence of any and symptomatic AF were significantly lower in the RFA group than in the AAD group.

• No significant difference was observed in the cumulative burden of AF between AAD and RFA.

• QOL (PCS) better in the RFA group after 12 and 24 months.

• These data support RFA as a first-line treatment in patients with paroxysmal AF.

Discussion

• Selected patient population.

• Not an argument for offering all patients with paroxysmal AF radiofrequency ablation!

• Both strategies should be discussed with the patients and considered by patients and physicians when rhythm control for symptomatic paroxysmal AF is indicated.

• The results of the MANTRA-PAF trial support the idea of early ablation for AF to avoid progression of AF on the long term.