Paroxysmal atrial fibrillation is associated with worse clinical outcomes than persistent/ permanent atrial fibrillation in patients with heart failure and reduced ejection fraction

JJV McMurray1, UM Mogensen1,2, PS Jhund1, WT Abraham3, AS Desai4, K

Dickstein5, M Packer6, JL Rouleau7, SD Solomon4, K Swedberg8, MR Zile9,

Lars Køber2 for the PARADIGM-HF and ATMOSPHERE investigators.1University of Glasgow, UK; 2Copenhagen University Hospital, Denmark; 3Ohio State

University, USA; 4Brigham and Women's Hospital, Boston, USA; 5Stavanger

University Hospital, Norway; 6Baylor University Medical Center, Dallas, USA 7Université de Montréal, Canada; 8University of Gothenburg, Sweden; 9Medical

University of South Carolina, USA.

Background and introduction

• There is controversy about whether AF is an independent prognostic factor

in HFrEF. In existing studies:

• AF was inconsistently defined, with some using medical history and others using the

baseline ECG to identify AF.

• Type of AF at baseline (paroxysmal versus persistent/permanent) has not been

related to outcome. Similarly, the relationship between incident AF and outcomes

has rarely been examined.

• The completeness of clinical data available for adjustment of outcomes has

varied between studies

• Including, medical history, comorbidity and physiological and laboratory

measurements.

• Notably, no study in chronic HFrEF included measurement of natriuretic peptides, the

most powerful independent predictor of outcomes.

Methods (1)

• The databases of the Prospective comparison of ARNI with ACEI to

Determine Impact on Global Mortality and morbidity in Heart Failure trial

(PARADIGM-HF NCT01035255) and the Aliskiren Trial to Minimize Outcomes

in Patients with Heart Failure trial (ATMOSPHERE NCT00853658), the two

most recent and largest global multicenter randomized trials in patients with

HFrEF, were pooled.

• The trials had an almost identical design and detailed clinical data, plasma NT

proBNP and a 12 lead ECG were recorded/measured at baseline.

• Investigators asked about history of AF (and if yes, whether the AF was

paroxysmal or persistent/permanent) and whether or not the baseline ECG

showed AF.

• Cardiovascular events during follow-up, including new-onset AF, were

adjudicated by the same endpoint committee.

Methods (2)

• The primary outcome of both trials was a composite of CV death or HF

hospitalization. We investigated the association between AF and risk of the

primary outcome, each of its components, all-cause mortality, and stroke.

• The cumulative incidence functions for outcomes of interest were compared

according to AF status at randomization.

• HR with 95% CI for outcomes according to type of AF were calculated using

Cox proportional hazard models using no AF as reference. To assess the

prognostic significance of new-onset AF during follow-up, AF was included

as a time-dependent variable.

• Final models included adjustment for randomized treatment and baseline

characteristics: age, sex, region, race, NYHA class, LVEF, HR, SBP, eGFR,

diabetes, BMI, time since HF diagnosis, history of HF hospitalization,

stroke, MI, and log NT-proBNP.

Results

• 15415 patients randomized in both trials

• 5481 patients (35·6%) had a history of AF. Of these, 3770 patients

(68·8%) had persistent/permanent AF and 1645 (30·0%)

paroxysmal AF (66 had undefined AF).

• A total of 4251 (27·6%) patients had AF on their baseline ECG and

384 patients developed new-onset AF during follow-up.

No AFParoxysmal

AF

Persistent/

Permanent AF

New-onset

AF

P (parox.vs

pers/perm)

History of (%)

Heart failure >5 years 27 38 37 39 .86

Hypertension 62 72 76 64 ·01

Diabetes 32 32 31 26 ·25

Myocardial infarction 46 49 30 49 <·001

HF hospitalization 59 66 66 60 ·73

Stroke 6·5 11 10 5·5 ·47

COPD 11 16 14 12 ·04

Kidney disease 11 22 17 13 <·001

NT-proBNP (pg/ml) 1037 1151 1631 1535 <·001

Results: Baseline characteristics (2)

Risk associated with baseline AF (Primary endpoint)

P<0.001

Risk associated with baseline AF (Cardiovascular death)

P=0.116

Risk associated with baseline AF (Heart failure hospitalization)

P<0.001

Risk associated with baseline AF (Stroke)

P=0.021

Risk associated with baseline AF (fully adjusted HR)

Risk associated with incident AF (Primary endpoint)

AF at randomization

No AF

New onset AF

Risk associated with AF

Summary and conclusions

• Paroxysmal, but not persistent/permanent AF, was associated with a

higher risk of the composite outcome of HF hospitalization or CV death,

even after adjustment for other prognostic variables, including NT proBNP.

• This was primarily related to an elevated risk of HF hospitalization.

• Paroxysmal AF was also associated with a higher adjusted risk of stroke

but persistent/permanent AF was not.

• New-onset (incident) AF conferred the greatest risk of all - associated with

a higher risk of each of hospitalization, death and stroke.

• These findings underline the importance of anticoagulant therapy for these

patients. New-onset AF should prompt immediate consideration of

anticoagulant therapy as well as close surveillance for evidence of

decompensation and treatment as appropriate.