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
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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:
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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 RFA
140 Underwent RFA (96%)
69 underwent
repeated RFA
665 7D Holter
recordings
After 24 months
148 Assigned to AAD
146 Started AAD (99%)
666 7D Holter
recordings
Treatment with
1.24±0.48 AAD’s
After 24 months
N=140; 223 RFA procedures (1.6±0.7)
N=54; 87 RFA procedures (1.6±0.7)
On AAD: N=13/138 (9%) (IC: 10, III: 3)
On AAD: N=100 /137 (73%) (IC: 86, III:14)
Withdrawn N=5
Died N=3
Withdrawn N=7
Died N=4
Baseline Characteristics I
RFA
AAD
N
146
148
Age (years)
56±9
54±10
100 (68%)
106 (72%)
27±4
27±4
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%)
0
103
100
1
8
17
2
11
6
3
7
4
4
2
6
>4
15
15
Male gender
Body Mass Index
Hypertension
Previous Cardioversions
Baseline Characteristics II
RFA
AAD
≤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
0-7 days
82
87
>7 days, ≤1 month
48
41
>1 month, ≤6 months
14
18
>6 months
1
0
40±6
40±5
>60%
116
121
40-60%
29
26
Warfarin
69 (47%)
65 (44%)
Betablocker
106 (73%)
107 (72%)
Calcium channel blocker
28 (19%)
16 (11%) *
Digoxin
17 (12%)
13 (9%)
Duration of usual AF episodes
Average interval between AF episodes
Left atrial size (echo), mm
Left ventricular ejection fraction
Medication last week before randomization
* p<0.05
AF Burden
100
90
80
70
60
50
40
30
20
10
0
Without AF:
Mann-Whitney Test
Mean rank
P-value
61 66
A D
Baseline
97 91
A D
3 months
112 103
A D
6 months
120 106
A D
12 months
122 109
A D
18 months
124 105
A D
24 months
77 65
A D
Cumulated
149 146
145 150
144 151
141 154
141 154
138 157
140 155
0.72
0.49
0.34
0.08
0.07
0.007
0.10
A: RFA
D: AAD
AF after 24 Months
Number of patients
P=0.004
P=0.012
Quality of Life (SF-36)
Physical Component Summary (PCS)
p=0.01
p=0.02
Mean values of PCS and MCS
Mental Component Summary (MCS)
ns
ns
Atrial Flutter
Number of patients
P=0.25
Serious Adverse Events
RFA
AAD
Death
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.