Catheter Ablation versus Standard conventional Treatment in patients with LEft ventricular dysfunction and Atrial Fibrillation

The CASTLE-AF trial

Nassir F. Marrouche MD on behalf the CASTLE AF Investigators

• Atrial fibrillation (AF) and heart failure are well intertwined

• Catheter ablation of AF in patients with heart failure has been shown feasible

Background

• Study the effectiveness of catheter ablation of 

atrial fibrillation in patients with heart failure in 

improving hard primary endpoints of mortality and

heart failure progression when compared to 

conventional standard treatment

CASTLE­AFRationale and Objective

CASTLE­AF

Primary Endpoint

• All-cause mortality

• Worsening heart failure admissions

Secondary Endpoints • All­cause mortality • Worsening of heart failure admissions• Cerebrovascular accidents • Cardiovascular mortality • Unplanned hospitalization due to cardiovascular reason • All­cause hospitalization • Quality of Life: Minnesota Living with Heart Failure and 

EuroQoL EQ­5D • Exercise tolerance (6 minutes walk test) • Number of delivered ICD shocks, and ATPs 

(appropriate/inappropriate) • LVEF• Time to first ICD shock, and time to first ATP • Number of device detected VT/VF • AF burden: cumulative duration of AF episodes • AF free interval: time to first AF recurrence after 3 months 

blanking period post ablation

• Symptomatic paroxysmal or persistent AF• Failure or intolerance to ≥ 1 or unwillingness to take AAD• LVEF ≤ 35%• NYHA class ≥ II• ICD/CRT­D with Home Monitoring  capabilities already implanted due to primary or secondary prevention

CASTLE­AFInclusion Criteria

Study Design— CASTLE­AF 

EligibilityAssessment

3013 pts

Enrolled/Randomized

397 pts

Run­in 5 weeks

Ablation

13 pts excluded

21 pts excluded

179 pts

184 pts

200 pts

197 pts

153 pts (26 cross­overs)

165 pts (18 cross­overs)

Follow­up: 3, 6, 12, 24, 36, 48, 60 months

ICD/CRT­D checkAdverse event documentationEchocardiography6­minute walk testOptimization of medication for HF­Home Monitoring programming NYHA, weight, BP, QoLPatients’ diary

Conventional

• Investigator initiated, Prospective, Multicenter ( 31 sites, 9 countries), Randomized, Controlled

• According to the ACC/AHA/ESC 2006 guidelines for treatment of AF in Heart Failure patients

• Efforts to maintain sinus rhythm in this study arm were recommended 

• In case of rate control strategy:• 60 and 80 beats per minute at rest• 90 and 115 beats per minute during moderate exercise 

• Anticoagulation was initiated, if not already started, and maintained throughout the study. The INR was maintained between 2.0 and 3.0

CASTLE­AFTreatment Protocol - Conventional Arm

• Pulmonary Vein Isolation• Additional lesions 

Øat discretion of operator

• Repeat ablation after blanking period

CASTLE AFAblation Protocol

Ablation group(179 patients)

Conventional group(184 patients)

Age – years  64 (56­71) 64 (56­73.5)New York Heart Association class        I (%) 11 11   II (%) 58 61   III (%) 29 27   IV (%) 2 1Left ventricular ejection fraction – % 32.5 (25.0­38.0) 31.5 (27.0­37.0)Current type of atrial fibrillation       Paroxysmal (%) 30 35   Persistent (%) 70 65CRT­D implanted (%) 27 28

ICD implanted (%) 73 72

Baseline Characteristics­CASTLE AF

Baseline Characteristics­CASTLE AF

Ablation group

(179 patients)

Conventional group

(184 patients)

   ACE­inhibitor or ARB – no. (%) 94 91

   Beta­blocker – no. (%) 93 95

   Diuretic – no. (%) 93 93

   Digitalis – no. (%) 18 31

   Oral anticoagulant  – no. (%) 93 96

   Antiarrhythmic drug – no. (%) 32 30

      Amiodarone – no. (%) 97 85

Results­CASTLE AFRate Versus Rhythm Control in Conventional Arm

Rate control:  Beta-blocker Digitalis  Calcium antagonist Atrioventricular node 

ablation (in 5 patients) Rhythm control:  Antiarrhythmic drug Atrial fibrillation ablation 

(18 crossover cases)

12/31/1899 12:00:00 AM

1/12/1900 12:00:00 AM

1/24/1900 12:00:00 AM

2/5/1900 

12:00:00 AM

2/17/1900 12:00:00 AM

100806040200

Follow-Up Time (Months)

Perc

ent o

f Pat

ient

s (%

)

Results­CASTLE AFAF Burden Derived from Memory of Implanted Devices

AF Burden

Percent (%) in Time

Baseline 3M 6M 12M 24M 36M 48M 60M0

10

20

30

40

50

60

70

Ablation Conventional

Results­CASTLE AFAbsolute change in LVEF from baseline

LVEF

 Change fro

m Baseline

12mo 36mo 60mo

0

5

10

15

20

-5

-10

[VALUE][VALUE]

[VALUE]

[VALUE] [VALUE] [VALUE]

Ablation Conventional

p*=0.001 p=0.055 p*=0.005

Event

Ablation Group(n=179)

 

Conventional Group(n=184)

no. patients with event (%) no. patients with event (%)

Pericardial effusion  (acute) 3 (1.7) 0 Severe bleeding (acute) 3 (1.7) 0Stroke or TIA 7 (3.9) 12 (6.7)Pulmonary vein stenosis 1 (0.6) 0Pneumonia 3 (1.7) 1 (0.5)Groin infection  1 (0.6) 0Worsening heart failure 1(0.6) 0

Results­CASTLE AFSerious Adverse Events

Results­CASTLE AFPrimary Composite Endpoint

12/31/1899 

12:00:00 AM

1/12/1900 

12:00:00 AM

1/24/1900 

12:00:00 AM

2/5/1900 

12:00:00 AM

2/17/1900 

12:00:00 AM

10.80.60.40.20

Risk Reduction: 38% Risk Reduction: 38%

Follow-Up Time (Months)

Surv

ival

Pro

babi

lity

Patients at RiskPatients at RiskAblationAblation 179179 141 141 114 114 76 76 58 58 22 22ConventionalConventional 184184 145 145 111 111 70 70 48 12 48 12

AblationAblation

ConventionalConventionalHR, 0.62 (95% CI, 0.43-0.87); P=0.007Log-rank test: P=0.006

Results­CASTLE AFAll-Cause Mortality

12/31/1899 

12:00:00 AM

1/12/1900 

12:00:00 AM

1/24/1900 

12:00:00 AM

2/5/1900 

12:00:00 AM

2/17/1900 

12:00:00 AM

10.80.60.40.20

Patients at RiskPatients at RiskAblationAblation 179179 154 154 130 130 94 94 71 71 27 27ConventionalConventional 184184 168 168 138 138 97 97 63 19 63 19

HR, 0.53 (95% CI, 0.32-0.86); P=0.011Log-rank test: P=0.009

AblationAblation

ConventionalConventional

Surv

ival

Pro

babi

lity

Follow-Up Time (Months)

Risk Reduction: 47% Risk Reduction: 47%

Results­CASTLE AFWorsening Heart Failure Admissions

12/31/1899 

12:00:00 AM

1/12/1900 

12:00:00 AM

1/24/1900 

12:00:00 AM

2/5/1900 

12:00:00 AM

2/17/1900 

12:00:00 AM

10.80.60.40.20

Patients at RiskPatients at RiskAblationAblation 179179 141 141 114 114 76 76 58 58 22 22ConventionalConventional 184184 145 145 111 111 70 70 48 12 48 12

HR, 0.56 (95% CI, 0.37-0.83); P=0.004Log-rank test: P=0.004

AblationAblation

ConventionalConventional

Surv

ival

Pro

babi

lity

Follow-Up Time (Months)

Risk Reduction: 44% Risk Reduction: 44%

Results­CASTLE AFCardiovascular Mortality

12/31/1899 

12:00:00 AM

1/12/1900 

12:00:00 AM

1/24/1900 

12:00:00 AM

2/5/1900 

12:00:00 AM

2/17/1900 

12:00:00 AM

10.80.60.40.20

Patients at RiskPatients at RiskAblationAblation 179179 154 154 130 130 94 94 71 71 27 27ConventionalConventional 184184 168 168 138 138 97 97 63 19 63 19

HR, 0.49 (95% CI, 0.29- 0.84); P=0.009Log-rank test: P=0.008

AblationAblation

ConventionalConventional

Surv

ival

Pro

babi

lity

Follow-Up Time (Months)

Risk Reduction: 51% Risk Reduction: 51%

Results­CASTLE AFCardiovascular Hospitalization

12/31/1899 

12:00:00 AM

1/12/1900 

12:00:00 AM

1/24/1900 

12:00:00 AM

2/5/1900 

12:00:00 AM

2/17/1900 

12:00:00 AM

10.80.60.40.20

Patients at RiskPatients at RiskAblationAblation 179179 127 127 95 95 60 60 42 42 17 17ConventionalConventional 184184 131 131 91 91 52 52 33 8 33 8

HR, 0.72 (95% CI, 0.52-0.99); P=0.041Log-rank test: P=0.050

AblationAblation

ConventionalConventional

Surv

ival

Pro

babi

lity

Follow-Up Time (Months)

Risk Reduction: 28% Risk Reduction: 28%

Results­CASTLE AFPrimary Endpoint-Subgroups

Ablationbetter

Conventionalbetter

Conclusion­CASTLE AF

• Catheter ablation of atrial fibrillation in patients with heart failure is associated with improved all-cause mortality and fewer admissions for worsening heart failure when compared to conventional standard of care treatment 

• Catheter ablation of atrial fibrillation in patients with heart failure is also associated with improved cardiovascular mortality and hospitalization when compared to conventional standard of care treatment 

Steering Committee

Nassir MarroucheJohannes BrachmannDietrich AndresenDietmar BänschLucas BoresmaLuc JordaensHeribert SchunkertJürgen SiebelsJuergen Vogt

The study was funded by BIOTRONIK 

Endpoint Adverse Event Committee

Heinrich Wieneke Frieder Braunschweig, Harriette F. Verwey 

Data and Safety Monitoring Board

John CammEtienne AliotWalter Lehmacher 

Hüseyin Ince, Béla Merkely,  Hüseyin Ince, Evgeny Pokushalov, Georg Nölker, Sergey PopovPrashanthan Sanders Lukasz Szumowski Dimitry Lebedev  Tamàs Szili­Török Paul Martin Eduard IvanitskiyBernhard Zrenner Anthony ChowArif Elvan, MD Ivan Diaz Remirez Thomas Pezawas Mathias Busch Zoltán CsanádiWilhelm Haverkamp Helmut Pürerfellner Andreas SchärtlBernd Lemke Stefan Schlüter Isabel Deisenhofer Jens Günther Thorsten Lawrenz Ernst Günter Vester Michael Wiedemann 

    Co­Investigators