Download Atrial Fibrillation and Sudden Cardiac Death

JACC: Heart Failure
Ó 2014 by the American College of Cardiology Foundation
Published by Elsevier Inc.
EDITORIAL COMMENT
Atrial Fibrillation and
Sudden Cardiac Death
Is Heart Failure the Middleman?*
Jonathan P. Piccini, MD, MHS,
James P. Daubert, MD
Durham, North Carolina
Atrial fibrillation (AF) is a world-wide epidemic, affecting
more than 33 million individuals across the globe (1).
Beyond its impact on quality of life, AF is associated with
increased risks of stroke, heart failure, cognitive impairment,
and death (2,3). Emerging evidence suggests that AF may
be associated with an increased risk of sudden cardiac death
(SCD) as well (4,5).
See page 221
Several recent observational studies have shown an association between AF and SCD. In the Cardiovascular
Health Study, the unadjusted incidence of SCD was 12 per
1,000 person-years in those with AF versus 3.8 per 1,000
person years in those without AF. Following adjustment,
AF remained associated with an increased hazard of SCD
(hazard ratio [HR]: 2.14 [95% confidence interval (CI):
1.60 to 2.87]) (4). Findings in a validation cohort of individuals ages 45 to 64 were similar (4). In the LIFE
(Losartan Intervention for Endpoint) study, hypertensive
patients with left ventricular hypertrophy and new-onset
AF were observed to have a more than 4-fold increased
risk of SCD after adjustment for multiple factors, including
heart failure (HF) (HR: 4.69 [95% CI: 2.96 to 7.45]) (5).
Finally, new-onset AF has also been associated with an
increased risk of malignant arrhythmias following myocardial infarction (6).
It is plausible that AF independently contributes to the risk
of SCD, and potential mechanistic explanations include: 1)
genetic or other propensity favoring fibrillation in the ventricles
*Editorials published in JACC: Heart Failure reflect the views of the authors and do not
necessarily represent the views of JACC: Heart Failure or the American College of
Cardiology.
From the Duke Center for Atrial Fibrillation, Electrophysiology Section, Cardiology Division, Duke University Medical Center, Durham, North Carolina. Dr. Piccini
receives research funding from ARCA biopharma, Boston Scientific, GE Healthcare,
Johnson & Johnson, and ResMed; and serves as a consultant to Biosense-Webster,
Janssen Pharmaceuticals, Medtronic, and Spectranetics. Dr. Daubert receives
research support from Boston Scientific, Gilead, Medtronic, ARCA biopharma, and
Biosense-Webster; and receives honoraria for advisory board participation or lectures
from Biosense-Webster, Boston Scientific, and Medtronic.
Vol. 2, No. 3, 2014
ISSN 2213-1779/$36.00
http://dx.doi.org/10.1016/j.jchf.2014.03.004
in those with fibrillating atria; 2) AF-related adverse myocardial remodeling; 3) tachycardia-induced tachycardia; 4)
proarrhythmic long–short sequences during AF; 5) impaired
calcium handling; or 6) repolarization abnormalities (7–10).
Alternatively, AF may be a marker for occult or more
advanced cardiovascular disease, including hypertrophy or
HF, either with reduced or preserved ejection fraction (EF).
The AF–SCD relationship may thus be a confounded one.
In the 18,000-patient RE-LY (Randomized Evaluation of
Long Term Anticoagulant Therapy) trial, 20% of deaths
were due to SCD, and these events were best predicted
by the presence of HF (HR: 2.24 [95% CI: 1.75 to 2.87],
p < 0.0001) (11). This raises the question, “Is HF the
middleman responsible for the observed increased risk of
SCD in patients with AF?”
In this issue of JACC: Heart Failure, Reinier et al. (12)
analyzed the association between AF and SCD with casecontrol methodology. The investigators compared 652
SCDs in the Oregon Sudden Unexpected Death Study
with age- and sex-matched controls. AF was much more
common in SCD cases than matched controls (27% vs. 18%,
p ¼ 0.0001). However, after adjustment using logistic
regression and propensity score matching, the AF-SCD
association was no longer significant. Patients with SCD
more frequently had HF (45% vs. 19%, p < 0.0001) and low
EF (30% vs. 14%, p < 0.001) than controls. When the prevalence of AF stratified by HF status was compared in cases
and controls, there was no difference (p ¼ 0.13). Reinier et al.
(12) conducted a host of sensitivity analyses using alternative
definitions of HF based upon left ventricular function and
brain natriuretic peptide levels, all of which failed to
demonstrate an independent association of AF and SCD.
Another interesting, but subtle, finding in Reinier et al.
(12) was the more frequent use of digoxin in SCD cases
versus controls with HF. Despite some efficacy for rate
control in AF, and symptom control in HF, digoxin is
known to have proarrhythmic effects. Digoxin has been
associated with an increased risk of SCD and all-cause
mortality in patients with AF (with and without HF)
(13–15). Furthermore, digoxin is also associated with increased risks of implantable cardioverter-defibrillator shocks,
even after adjustment for AF (16). This finding represents
yet another association that requires further investigation,
particularly given the known safety concerns surrounding
digoxin pharmacotherapy.
There are several limitations that need to be considered
when interpreting the findings from this case-control analysis. Most importantly, all of the controls in the study had
coronary artery disease, and therefore, the results may not be
generalizable to patients without coronary artery disease.
Although multiple methods of adjustment were employed,
the propensity matching was performed on different sources
of patients, using a relatively limited set of covariates
(n ¼ 5), and the potential for unmeasured confounding was
significant. Finally, all case-control studies suffer from
selection bias, and the cases described in the Oregon-SUDS
JACC: Heart Failure Vol. 2, No. 3, 2014
June 2014:228–9
(Oregon Sudden Unexpected Death Study) may not entirely
be representative of other cohorts.
The findings from Reiner et al. (12) have important implications for both cardiovascular investigators and clinicians. The relationship between AF, HF, and SCD in this
analysis serves as an important reminder of the clear and
present danger of confounding in all observational studies.
Further investigation is required to clarify whether AF
contributes to the risk of SCD. However, these data also
highlight the risks of SCD in patients with concomitant AF
and HF. Perhaps the best method for preventing SCD in
patients with AF is the prevention of HF.
Although we have many effective therapies for stroke prevention, we have little randomized evidence for the prevention
of HF in patients with AF, despite the fact that the incidence
of HF is approximately 2-fold greater than the incidence of
stroke in patients with AF (17). Moreover, the incidence of
HF in AF patients has not decreased over the last few decades
(18). Pharmacological rhythm control has so far been relatively
ineffective in preventing morbidity and mortality in AF patients with low EF (19). Limited data suggest AF ablation
can ameliorate HF in AF patients (20,21), but larger more
definitive trials are underway. More research and effective
therapies are needed for the primary prevention of HF in
patients with AF. Although the causal nature of AF in SCD
remains uncertain, it is clear that HF and AF is a bad combination that is best avoided.
Reprint requests and correspondence: Dr. Jonathan P. Piccini,
Electrophysiology Section, Duke University Medical Center, Duke
Clinical Research Institute, PO Box 17969, Durham, North Carolina
27710. E-mail: [email protected].
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Key Words: arrhythmia
ventricular fibrillation.
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cardiac arrest
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diastolic
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ejection fraction
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