Early Atrial Fibrillation Ablation for Stroke Prevention in Patients With High Comorbidity Burden (EASThigh-AFNET 11)

Overview

EASThigh-AFNET 11 is an international, prospective, randomized, open, blinded endpoint assessment, multicenter trial (Treatment Strategy trial). The objective of EASThigh-AFNET 11 is to investigate whether early atrial fibrillation ablation in patients with atrial fibrillation (AF) and a high comorbidity burden (CHA2DS2-VASc ≥4) reduces cardiovascular events (stroke, cardiovascular death, or heart failure events) compared to usual care.

Detailed description

Atrial Fibrillation (AF) is associated with high morbidity and mortality. Even on optimal anticoagulation and therapy of concomitant conditions, many patients with AF suffer cardiovascular events, especially heart failure events, stroke, and cardiovascular death. Most of these events occur in elderly patients with comorbidities. Early rhythm control, mainly delivered using antiarrhythmic drugs, reduces AF-related complications when added to anticoagulation, rate control, and treatment of comorbidities when compared to current practice that offers rhythm control mainly to reduce symptoms. The outcome-reducing effect of early rhythm control is most pronounced in patients with multiple comorbidities, quantified by a CHA2DS2-VASc score ≥ 4. Attaining sinus rhythm is the key mediator for the outcome-reducing effect of early rhythm control. Atrial fibrillation ablation controls the rhythm better than drug-based rhythm control, avoids long-term antiarrhythmic drug treatment, thus reducing polypharmacy, and may therefore be the ideal rhythm control treatment in patients with AF and a high comorbidity burden. This hypothesis needs testing. The investigator-initiated EASThigh-AFNET 11 trial evaluates the effectiveness and safety of early atrial fibrillation ablation in patients with recently diagnosed AF and a high comorbidity burden.

EASThigh-AFNET 11 is a Treatment Strategy trial randomizing 2312 patients with AF and a high comorbidity burden to early atrial fibrillation ablation or usual care to achieve a fixed number of primary endpoint events of n=527. All therapies are clinically approved. The primary outcome is a composite of cardiovascular death, stroke, and hospitalization for worsening of heart failure. The primary safety outcome is a composite of all-cause death and serious complications of AF therapy. Secondary outcome parameters address safety, patient reported outcomes and cognitive function.

EASThigh-AFNET 11 was recommended for funding by the Expert Advisory Panel of the Global Cardiovascular Research Funders Forum (GCRFF).

Interventions

• Other Early atrial fibrillation ablation
  Patients randomised to early atrial fibrillation ablation will undergo pulmonary vein isolation within 2 months after randomisation.
• Other Usual Care
  Usual care will consist of optimal AF therapy based on guideline recommendations and local protocols and usage.The choice of therapies and medications follows routine care in line with medical guidelines and local policies at the discretion of the treating physician and should be based on the individual medical status of each study patient.

Primary outcome measures

• Composite of cardiovascular complications related to AF [Time frame: Throughout study completion, estimated at a mean of 4 years]
• The primary safety outcome is a composite of all-cause death and serious complications of AF therapy. [Time frame: Throughout study completion, estimated at a mean of 4 years]

Secondary outcome measures (12)

• Number of nights spent in hospital [Time frame: Throughout study completion, estimated at a mean of 4 years]
• Time from randomisation to first occurrence of each of the individual components of the primary outcome [Time frame: Throughout study completion, estimated at a mean of 4 years]
• All-cause death [Time frame: Throughout study completion, estimated at a mean of 4 years]
• Serious adverse events related to AF therapy [Time frame: Throughout study completion, estimated at a mean of 4 years]
• Time from randomisation to first cardiovascular hospitalisation [Time frame: Throughout study completion, estimated at a mean of 4 years]
• Number of cardiovascular hospitalisations (over-night stay) [Time frame: Throughout study completion, estimated at a mean of 4 years]
• Changes in left ventricular ejection fraction [Time frame: comparing baseline with 24 months follow up (FU)]
• Changes in quality of life [Time frame: comparing baseline with 12 and 24 months FU]
• Changes in quality of life [Time frame: comparing baseline with 12 and 24 months FU]
• Changes in cognitive function [Time frame: comparing baseline with 24 months FU]
• Cardiac rhythm status [Time frame: at 12 and 24 months FU]
• AF pattern [Time frame: at 12 and 24 months FU]

Eligibility criteria

Inclusion criteria

I1. AF first diagnosed within 5 years prior to enrolment and documented in body surface ECG

I2. High comorbidity estimated by CHA2DS2-VASc score of 4 or more

I3. Patient suitable for ablation using cryoballoon ablation systems or other ablation systems with comparable efficacy and safety from Medtronic

I4. Age ≥ 18 years

I5. Provision of signed informed consent

Exclusion criteria

General exclusion criteria

E1. Any disease that limits life expectancy to less than 1 year.

E2. Participation in another clinical trial, either within the 3 months prior to enrolment or still on-going (participation in potential sub-studies connected to this trial is permitted).

E3. Previous participation in EASThigh-AFNET 11.

E4. Pregnant women.

E5. Breastfeeding women.

E6. Drug abuse or clinically manifest alcohol abuse.

Exclusion criteria related to a cardiac condition

E7. Prior AF ablation or surgical therapy of AF.

E8. Patients not suitable for AF ablation.

E9. Patients with a history of stroke which occurred within 3 months prior to enrolment.

E10. Valve disease requiring specific therapy.

Exclusion criteria based on laboratory abnormalities

E11. Clinically manifested thyroid dysfunction requiring therapy.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Prevention

Study locations

Australia · 1 center

• Several sites — Multiple Locations

Canada · 1 center

• Several sites — Multiple Locations

Germany · 1 center

• Several sites — Multiple Locations

Netherlands · 1 center

• Several sites — Multiple Locations

Poland · 1 center

• Several sites — Multiple Locations

Spain · 1 center

• Several sites — Multiple Locations

United Kingdom · 1 center

• Several sites — Multiple Locations

Publications

• Kirchhof P, Camm AJ, Goette A, Brandes A, Eckardt L, Elvan A, Fetsch T, van Gelder IC, Haase D, Haegeli LM, Hamann F, Heidbuchel H, Hindricks G, Kautzner J, Kuck KH, Mont L, Ng GA, Rekosz J, Schoen N, Schotten U, Suling A, Taggeselle J, Themistoclakis S, Vettorazzi E, Vardas P, Wegscheider K, Willems S, Crijns HJGM, Breithardt G; EAST-AFNET 4 Trial Investigators. Early Rhythm-Control Therapy in Pa PMID 32865375
• Rillig A, Borof K, Breithardt G, Camm AJ, Crijns HJGM, Goette A, Kuck KH, Metzner A, Vardas P, Vettorazzi E, Wegscheider K, Zapf A, Kirchhof P. Early Rhythm Control in Patients With Atrial Fibrillation and High Comorbidity Burden. Circulation. 2022 Sep 13;146(11):836-847. doi: 10.1161/CIRCULATIONAHA.122.060274. Epub 2022 Aug 15. PMID 35968706
• Eckardt L, Sehner S, Suling A, Borof K, Breithardt G, Crijns H, Goette A, Wegscheider K, Zapf A, Camm J, Metzner A, Kirchhof P. Attaining sinus rhythm mediates improved outcome with early rhythm control therapy of atrial fibrillation: the EAST-AFNET 4 trial. Eur Heart J. 2022 Oct 21;43(40):4127-4144. doi: 10.1093/eurheartj/ehac471. PMID 36036648
• Andrade JG, Wells GA, Deyell MW, Bennett M, Essebag V, Champagne J, Roux JF, Yung D, Skanes A, Khaykin Y, Morillo C, Jolly U, Novak P, Lockwood E, Amit G, Angaran P, Sapp J, Wardell S, Lauck S, Macle L, Verma A; EARLY-AF Investigators. Cryoablation or Drug Therapy for Initial Treatment of Atrial Fibrillation. N Engl J Med. 2021 Jan 28;384(4):305-315. doi: 10.1056/NEJMoa2029980. Epub 2020 Nov 16. PMID 33197159
• Andrade JG, Deyell MW, Macle L, Wells GA, Bennett M, Essebag V, Champagne J, Roux JF, Yung D, Skanes A, Khaykin Y, Morillo C, Jolly U, Novak P, Lockwood E, Amit G, Angaran P, Sapp J, Wardell S, Lauck S, Cadrin-Tourigny J, Kochhauser S, Verma A; EARLY-AF Investigators. Progression of Atrial Fibrillation after Cryoablation or Drug Therapy. N Engl J Med. 2023 Jan 12;388(2):105-116. doi: 10.1056/NEJMo PMID 36342178
• Dickow J, Kirchhof P, Van Houten HK, Sangaralingham LR, Dinshaw LHW, Friedman PA, Packer DL, Noseworthy PA, Yao X. Generalizability of the EAST-AFNET 4 Trial: Assessing Outcomes of Early Rhythm-Control Therapy in Patients With Atrial Fibrillation. J Am Heart Assoc. 2022 Jun 7;11(11):e024214. doi: 10.1161/JAHA.121.024214. Epub 2022 May 27. PMID 35621202
• Dickow J, Kany S, Roth Cardoso V, Ellinor PT, Gkoutos GV, Van Houten HK, Kirchhof P, Metzner A, Noseworthy PA, Yao X, Rillig A. Outcomes of Early Rhythm Control Therapy in Patients With Atrial Fibrillation and a High Comorbidity Burden in Large Real-World Cohorts. Circ Arrhythm Electrophysiol. 2023 May;16(5):e011585. doi: 10.1161/CIRCEP.122.011585. Epub 2023 Mar 21. PMID 36942567

Identifiers

NCT: NCT06324188 · EASThigh-AFNET 11

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗