JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 83, NO.

9, 2024

ª 2024 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER

THE PRESENT AND FUTURE

JACC STATE-OF-THE-ART REVIEW

Implications of Atrial Fibrillation for

Guideline-Directed Therapy in
Patients With Heart Failure
JACC State-of-the-Art Review

Joshua D. Newman, MD,a Eileen O’Meara, MD,b Michael Böhm, MD, PHD,c Gianluigi Savarese, MD, PHD,d,e
Patricia R. Kelly, MD,f Orly Vardeny, PHARMD, MS,g Larry A. Allen, MD, MHS,h Patrizio Lancellotti, MD, PHD,i
Stephen S. Gottlieb, MD,j,k Zainab Samad, MBBS,l Alanna A. Morris, MD, MSC,m Nihar R. Desai, MD, MPH,n
Giuseppe M.C. Rosano, MD, PHD,o John R. Teerlink, MD,p Clara Saldarriaga Giraldo, MD,q,* JoAnn Lindenfeld, MDr,*

ABSTRACT

Atrial fibrillation (AF) and heart failure (HF) are common cardiovascular conditions that frequently coexist. Among
patients with HF, more than one-half also have AF. Both are associated with significant morbidity and mortality.
Moreover, the prevalence of each is increasing globally, and this trend is expected to continue owing to an aging pop-
ulation and increased life expectancy. Diagnosis of AF in a patient with HF is associated with greater symptom burden,
more frequent hospitalizations, and a worse prognosis. Guideline-directed medical therapy (GDMT) for HF can affect the
incidence of AF. Once present, AF can influence the efficacy of some components of GDMT for HF. In this review, we
discuss the effect of GDMT for HF across the spectrum of ejection fraction on prevention of AF as well as the benefit
of GDMT in patients with vs without AF. (J Am Coll Cardiol 2024;83:932–950) © 2024 by the American College of
Cardiology Foundation.

EPIDEMIOLOGY AND PROGNOSIS OF rise from around 5.2 million in 2010.1,3 Similar
ATRIAL FIBRILLATION AND HEART FAILURE trends are present in Europe, where the prevalence
of AF among patients >55 years is expected to in-
The prevalence of atrial fibrillation (AF) is increasing crease to 17.9 million by 2060 from 8.8 million in
worldwide due to increased life expectancy and 2010.1,2 AF accounts for up to 30% of all ischemic
improved survival from other cardiovascular condi- strokes and is associated with depression, vascular
tions. 1,2 In the United States, the prevalence of AF is dementia, impaired quality of life, and increased
forecast to increase to 12.1 million by 2030, a rapid mortality. 4

From the aEndeavor Health, Glenview, Illinois, USA; bMontreal Heart Institute and Université de Montréal, Montreal, Quebec,
Canada; cUniversity of the Saarland, Homberg/Saar, Germany; dDivision of Cardiology, Department of Medicine, Karolinska
Institute, Stockholm, Sweden; eHeart and Vascular and Neuro Theme, Karolinska University Hospital, Stockholm, Sweden;
f
Missoula Cardiology, Missoula, Montana, USA; gUniversity of Minnesota Medical School, Minneapolis, Minnesota, USA; hDivision
of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA; iUniversity of Liège,
Listen to this manuscript’s Liège, Belgium; jDivision of Cardiovascular Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA;
audio summary by k
Baltimore Veterans Administration Medical Center, Baltimore, Maryland, USA; lAga Khan University, Karachi, Pakistan; mEmory
Editor-in-Chief University School of Medicine, Atlanta, Georgia, USA; nSection of Cardiovascular Medicine, Yale School of Medicine, New Haven,
Dr Valentin Fuster on Connecticut, USA; oCenter for Clinical and Basic Research, IRCCS San Raffaele Pisana, Rome, Italy; pUniversity of California, San
www.jacc.org/journal/jacc. Francisco, California, USA; qUniversity of Antioquia, Medellin, Colombia; and the rVanderbilt Heart and Vascular Institute,
Vanderbilt University Medical Center, Nashville, Tennessee, USA. *Drs Giraldo and Lindenfeld contributed equally to this work.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.

Manuscript received September 18, 2023; revised manuscript received November 29, 2023, accepted December 18, 2023.

ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2023.12.033

JACC VOL. 83, NO. 9, 2024 Newman et al 933
MARCH 5, 2024:932–950 Atrial Fibrillation and Heart Failure GDMT

Registry, AF prevalence increased sequen- ABBREVIATIONS

HIGHLIGHTS AND ACRONYMS
tially among patients with HFrEF (ejection
 AF and HF commonly occur concurrently, fraction [EF] <40%), heart failure with mid-
AF = atrial fibrillation
and the combination is associated with range ejection fraction (HFmrEF; EF 40%-
ARB = angiotensin receptor
worse prognosis than either condition 49%), and HFpEF (EF $50%) from 53% to
blocker
14
alone. 60% to 65%, respectively. AF was also more
BB = beta-blocker
prevalent in patients with HFpEF than in
 GDMT for HF can reduce the incidence of EF = ejection fraction
those with HFrEF in the Framingham Heart
AF. GDMT = guideline-directed
Study (62% vs 55%; P ¼ 0.02). 7
medical therapy
 Further research is needed to clarify the
PATHOPHYSIOLOGY OF AF IN PATIENTS HF = heart failure
benefit of GDMT for HF in patients with
WITH HF HFmrEF = heart failure with
concomitant AF across the range of left midrange ejection fraction
ventricular ejection fractions. HF can lead to the development of AF HFpEF = heart failure with
preserved ejection fraction
through multiple mechanisms (Central
Similarly, heart failure (HF) prevalence in the HFrEF = heart failure with
Illustration). Chronically elevated left atrial
United States and Europe is expected to rise by 2030, reduced ejection fraction
pressures result in atrial fibrosis and scarring,
again owing to the advancing age of the population. 1,4 MRA = mineralocorticoid
which culminates in slowed conduction ve- receptor antagonist
Although implementation of guideline-directed
locity and shortened action potential dura-
RAAS = renin-angiotensin-
medical therapy (GDMT) is associated with a 25%
tion and effective refractory period, both of aldosterone system
reduction in all-cause death at 24 months in heart
which promote re-entry and AF perpetua- SGLT2 = sodium-glucose
failure with reduced ejection fraction (HFrEF),
tion. 11,15 Furthermore, the pulmonary veins cotransporter-2
5
morbidity and mortality remain high. Furthermore,
are an important site in the pathophysiology of AF,16
initiation of GDMT is often delayed and many pa-
and chronically elevated left atrial pressure has been
tients do not receive target doses. 6
shown to lead to alterations in pulmonary vein
Owing to mutual risk factors and interaction be-
myocyte firing, which promotes AF development and
tween the 2 conditions, AF and HF coexist in up to
propagation.17 AF may also result in mitral and
50% of patients.1 In an analysis of Framingham
tricuspid regurgitation owing to annular enlargement
Heart Study participants that developed new-onset
leading to elevated filling pressures and resultant
AF or HF, 32% of patients diagnosed with HF had
fibrosis.18,19
a previous history of AF and an additional 30%
Angiotensin II induces adverse atrial remodeling
were diagnosed with AF thereafter. Among patients
through activation of profibrotic pathways, including
with new-onset AF, 8% had a previous diagnosis of
those mediated by aldosterone. The release of
HF and an additional 28% were later diagnosed
proinflammatory cytokines, including transforming
with HF. 7 A diagnosis of AF among patients with HF
growth factor (TGF)- b1, leads to changes in the elec-
has been associated with worse outcomes
trical properties of the atrial myocytes and pre-
(Table 1).8,9
disposes to the development of AF.20,21
Atrial myocytes of patients with HF have decreased
RISK FACTORS FOR AF IN HF
expression of atrial L-type calcium channels, which
results in reduced calcium entry into the cell with
Risk factors for AF such as advancing age, coronary
myocyte depolarization and thus less calcium-
and peripheral artery disease, smoking, physical
induced calcium release from the sarcoplasmic retic-
inactivity, obesity, chronic kidney disease, hyper-
ulum. This culminates in an increased frequency of
tension, obstructive and central sleep apnea, meta-
delayed after-depolarizations and susceptibility to
bolic syndrome, and diabetes are prevalent among
10,11 arrhythmias. 17
patients with HF. Among modifiable risk factors,
hypertension accounts for the greatest population- PATHOPHYSIOLOGY OF HF IN PATIENTS WITH AF
attributable risk for both AF and HF. 12,13 Owing to
commonality among risk factors as well as the path- HF can result directly from AF in the form of
ophysiology of HF discussed below, HF is a risk factor tachycardia-induced cardiomyopathy, a diagnosis in
for incident AF and is associated with a higher risk of which left ventricular dysfunction caused by AF with
stroke in AF.11 rapid ventricular rate corrects with resolution
Among patients with HF, AF appears to be most of the tachyarrhythmia. The pathophysiology of
prevalent in heart failure with preserved ejection tachycardia-induced cardiomyopathy is complex and
fraction (HFpEF). In an analysis of the Swedish HF involves electrical remodeling and abnormalities in
934 Newman et al JACC VOL. 83, NO. 9, 2024

Atrial Fibrillation and Heart Failure GDMT MARCH 5, 2024:932–950

T A B L E 1 Atrial Fibrillation and Prognosis in Heart Failure

HR for Comparisona
P for
First Author Population Outcome Overall HFrEF HFmrEF HFpEF Interaction

Olsson et al29 CHARM trials All-cause mortality – LVEF #40% – LVEF >40% 0.041
HR: 1.38 (95% CI: 1.21-1.59) HR: 1.80 (95% CI: 1.46-2.21)
Maggioni Val-HeFT All-cause mortality – LVEF <40% – - –
et al48 HR: 1.40 (95% CI: 1.10-1.78);
P ¼ 0.005
Linssen et al31 COACH trial HF hospitalization or – LVEF <40% – LVEF $40% –
all-cause HR: 1.05 (95% CI: 0.80-1.38); HR: 1.49 (95% CI: 1.04-2.14);
mortality P ¼ 0.72 P ¼ 0.03
Eapen et al28 Medicare claims All-cause mortality HR: 1.08 LVEF <40% – LVEF $40% <0.001
data (95% CI: 1.03- HR: 1.00 (95% CI: 0.94-1.08); HR: 1.16 (95% CI: 1.08-1.25);
1.14); P ¼ 0.003 P ¼ 0.92 P < 0.001
Sartipy et al14 Swedish All-cause mortality – LVEF <40% LVEF 40%-49% LVEF $50% –
Heart Failure HR: 1.17 (95% CI: 1.11-1.23) HR: 1.22 (95% CI: HR: 1.11 (95% CI: 1.02-1.21)
Registry 1.12-1.33)
Zafrir et al27 European Society All-cause mortality or – LVEF <40% LVEF 40%-49% LVEF $50% –
of Cardiology HF hospitalization HR: 0.957 (95% CI: 0.843- HR: 1.302 (95% CI: HR: 1.365 (95% CI: 1.152-
HF long-term 1.087); P ¼ 0.502 1.055-1.608); 1.619); P < 0.001
registry P ¼ 0.014

a
Comparator for HRs in all studies was sinus rhythm.
CHARM ¼ Candesartan in Heart Failure Assessment of Reduction in Mortality and morbidity; COACH ¼ Comparison of Outcomes and Access to Care for Heart Failure; HFmrEF ¼ heart failure with midrange
ejection fraction; HFpEF ¼ heart failure with preserved ejection fraction; HFrEF ¼ heart failure with reduced ejection fraction; LVEF ¼ left ventricular ejection fraction; Val-HeFT ¼ Valsartan Heart Failure Trial.

calcium homeostasis with downstream sequelae enrolled in ENGAGE-AF TIMI 48 (Effective Anti-
resulting in left ventricular systolic dysfunction. 22 AF coagulation with Factor Xa Next Generation in Atrial
is one of the most common causes of tachycardia- Fibrillation–Thrombolysis in Myocardial Infarction
induced cardiomyopathy.11 48) found that among patients with AF, those with
AF causes HF through multiple other mechanisms HFrEF had a higher rate of hospitalizations for HF and
as well. In AF, left ventricular filling is impaired by a mortality than those with HFpEF.30
loss of effective atrial contractility and shortened AF burden also has prognostic significance among
diastolic filling times owing to an increased resting those with HF. In an analysis of >25,000 patients with
heart rate and an irregular ventricular rhythm.23 HF, increasing AF burden was associated with an
Together, these result in a reduction in cardiac increased risk of HF hospitalization and mortality. 32
output and an elevation in intracardiac pressures. Similarly, patients with HF and subclinical AF last-
Left atrial dilation from AF can result in atrial func- ing <24 hours who progressed to having clinical AF or
tional mitral regurgitation. Significant secondary subclinical AF lasting >24 hours had a higher rate of
mitral regurgitation is associated with a high symp- HF hospitalization (8.9% per year) than those without
tom burden and poor quality of life. 24,25 progression (2.5% per year). 33
Importantly, AF-induced left atrial dilation and
PREVENTION OF AF WITH GDMT AND IMPACT
atrial and ventricular fibrosis can lead directly to
26 OF AF ON EFFICACY OF GDMT
HFpEF. This may explain the increased prevalence
of AF among patients with HFpEF compared with
AF has important implications for GDMT in HF
HFrEF.7,14
(Table 2). Components of GDMT can prevent the
PROGNOSTIC IMPLICATIONS OF AF IN HF development of AF in patients being treated for HF.
Once AF develops, it appears to influence the efficacy
Among patients with HF, the presence of a secondary of some GDMT (Table 3).
diagnosis of AF is associated with greater symptom ANGIOTENSIN-CONVERTING ENZYME INHIBITORS
burden and hospitalizations across the spectrum of AND ANGIOTENSIN RECEPTOR BLOCKERS. HF is
EF (Table 1).27 AF has also been associated with characterized by excess sympathetic activity and
increased mortality, although there may be hetero- activation of the renin-angiotensin-aldosterone
geneity based on EF. While some studies suggest that system (RAAS). With activation of the RAAS,
AF portends a worse prognosis only among angiotensin II binds its receptor and leads to
patients with HFpEF and HFmrEF, others have increased systemic vascular resistance, aldosterone
identified increased mortality risk across the EF release from the adrenal cortex, sympathetic nerve
spectrum. 9,14,27-31 An analysis of >12,000 patients release of noradrenalin, and myocyte fibrosis.34
JACC VOL. 83, NO. 9, 2024 Newman et al 935
MARCH 5, 2024:932–950 Atrial Fibrillation and Heart Failure GDMT

C ENTR AL I LL U STRA T I O N Mechanisms of Atrial Fibrillation in Heart Failure

Newman JD, et al. J Am Coll Cardiol. 2024;83(9):932–950.

HF leads to AF via multiple intertwined pathways. HF activates the renin-angiotensin-aldosterone system (RAAS) and increases sympathetic activity. This results in
increased levels of angiotensin II and release of aldosterone and transforming growth factor (TGF)-b1. Aldosterone and TGF-b1 promote left atrial scarring and fibrosis
indirectly, via increases in left atrial pressure and release of endothelin-1, as well as directly. The resultant shortening of the atrial refractory period and slowed
conduction velocity caused by left atrial scarring promotes AF. Elevated left atrial pressure also stimulates release of B-type natriuretic peptide (BNP) which increases
pulmonary vein arrhythmogenesis and AF. Finally, atrial L-type calcium channels are decreased in HF, leading to less calcium entry with cell depolarization and
calcium-induced calcium release. This increases the frequency of delayed after-depolarizations and promotes AF. Guideline-directed medical therapy for HF can
counter these pathologic mechanisms at various points. ACE ¼ angiotensin-converting enzyme; AF ¼ atrial fibrillation; ARB ¼ angiotensin receptor blocker;
ARNI ¼ angiotensin receptor-neprilysin inhibitor; HF ¼ heart failure; MRA ¼ mineralocorticoid receptor agonist; SGLT2 ¼ sodium-glucose cotransporter-2.
936 Newman et al JACC VOL. 83, NO. 9, 2024

Atrial Fibrillation and Heart Failure GDMT MARCH 5, 2024:932–950

T A B L E 2 Studies Evaluating the Implications of Atrial Fibrillation for Guideline-Directed Medical Therapy in Heart Failure

LVEF
Inclusion Study
First Author Population Criteria Drug Outcome Numbers in Study Result
a
Vermes et al45 SOLVD trial from a #35% Enalapril Incidence of AF n ¼ 374 (n ¼ 186 10 (5.4%) in enalapril group vs
single center enalapril; n ¼ 188 45 (24%) in placebo group
without AF on placebo) (P < 0.0001);
baseline ECG HR: 0.22 (95% CI: 0.11-0.44);
P < 0.0001
a
Alsheikh-Ali SOLVD trial #35% Enalapril Hospitalization for n ¼ 6,797 (n ¼ 3,396 7.9 hospitalizations per 1,000
et al47 atrial enalapril; n ¼ 3,401 patient-years of follow-up in
tachyarrhythmia placebo) enalapril group vs 12.4 per
1,000 patient-years in the
placebo group;
RR: 0.64 (95% CI: 0.48-0.85);
P ¼ 0.002
a
Maggioni et al48 Val-HeFT without AF <40% Valsartan Incidence of AF n ¼ 4,395 (n ¼ 2,205 113 (5.12%) in valsartan group
on baseline ECG valsartan; n ¼ 2,190 vs 174 (7.95%) in placebo
placebo) group; P ¼ 0.0002;
HR: 0.63 (95% CI: 0.49-0.81);
P ¼ 0.0003.
b
Ducharme et al49 CHARM Program CHARM-Alternative Candesartan Incidence of new AF n ¼ 6,379 (n ¼ 3,191 Overall: 177 (5.55%) in the
without AF on and CHARM- candesartan; candesartan group vs 215
baseline ECG Added: #40%; n ¼ 3,188 placebo) (6.74%) in the placebo
CHARM-Preserved: group; OR: 0.812 (95% CI:
>40% 0.662-0.998) P ¼ 0.048.
CHARM-Added and CHARM-
Alternative: OR: 0.779
(95% CI: 0.608-0.997);
P ¼ 0.047.
CHARM-Preserved: OR: 0.894
(95% CI: 0.618-1.295).
P value for heterogeneity
between trials: 0.57.
b
Liu et al55 PARAMOUNT, No LVEF criteria Sacubitril/ Incidence of AF n ¼ 15,512 (n ¼ 7,750 694 (9.0%) in sacubitril/
PARADIGM-HF, valsartan sacubitril/valsartan; valsartan group vs 650
EVALUATE-HF, (comparator n ¼ 7,762 control) (8.4%) in the control group;
PARAGON-HF, arm: enalapril RR: 1.07 (95% CI: 0.95-1.19);
PIONEER-HF, and or valsartan) P ¼ 0.26.
OUTSTEP-HF
c
Cikes et al56 PARAGON-HF $45% Sacubitril/ Incidence of new AF n ¼ 2,219 without Intention-to-treat analysis: HR:
valsartan previous AF 1.06 (95% CI: 0.83-1.35);
P ¼ 0.64.
On-treatment analysis: HR: 1.05
(95% CI: 0.81-1.37);
P ¼ 0.70.
a
McMurray et al70 CAPRICORN #40% (3-21 days Carvedilol Incidence of AF and Overall: n ¼ 1,959 Overall: 22 (2.3%) in the
after myocardial atrial flutter (n ¼ 975 carvedilol; carvedilol group vs 53 (5.4%)
infarction) n ¼ 984 placebo); in the placebo group; HR:
Excluding preexisting AF: 0.41 (95% CI: 0.25-0.68);
n ¼ 1,789 (n ¼ 894 P ¼ 0.0003.
carvedilol; n ¼ 895 Excluding patients with
placebo) preexisting AF: 16 (1.8%)
carvedilol group vs 31 (3.5%)
placebo group; HR: 0.51
(95% CI: 0.28-0.93);
P ¼ 0.025.
a
Rienstra et al71 COPERNICUS, <35% Various beta- All-cause mortality Overall: n ¼ 8,680 Overall: 416 events in BB group,
MERIT-HF, CIBIS- blockers (n ¼ 4,482 BB; 750 events in placebo
II, and SENIORS n ¼ 4,198 placebo); group; OR: 0.68 (95% CI:
AF and HF group: 0.59-0.77); P < 0.01.
n ¼ 1,677 (n ¼ 842 AF and HF group: 114 events in
BB; n ¼ 835 placebo); BB group, 131 events in
SR and HF group: placebo group; OR: 0.86
n ¼ 7,003 (n ¼ 3,640 (95% CI: 0.66-1.13);
BB; n ¼ 3,363 P ¼ 0.28.
placebo) SR and HF group: 302 events in
BB group, 439 events in
placebo group
OR: 0.63 (95% CI: 0.54-0.73);
P < 0.01.
Continued on the next page
JACC VOL. 83, NO. 9, 2024 Newman et al 937
MARCH 5, 2024:932–950 Atrial Fibrillation and Heart Failure GDMT

T A B L E 2 Continued

LVEF
Inclusion Study
First Author Population Criteria Drug Outcome Numbers in Study Result
c
Kotecha et al72 10 randomized HF Predominantly Various beta- All-cause mortality n ¼ 17,009 AF group: HR: 0.97 (95% CI:
trials (though not blockers 0.83-1.14); P ¼ 0.73.
entirely) <50% SR group: HR: 0.73 (95% CI:
0.67-0.80); P < 0.001.
b
Nielsen et al73 Three nationwide No LVEF criteria Various beta- All-cause mortality Unmatched cohort: Unmatched cohort: 1-year
registries blockers n ¼ 39,741 mortality rate per 100
(n ¼ 19,464 BB; person-years: 37.2 in BB
20,277 non-BB); group vs 23.2 in non-BB
Propensity-matched group.
cohort: n ¼ 23,896 Propensity-matched cohort:
(n ¼ 11,948 BB; 1-year mortality rate per 100
n ¼ 11,948 non-BB) person-years: 17.8 in BB
group vs 10.8 in non-BB
group; HR: 0.75 (95% CI:
0.71-0.79).
a
Cadrin-Tourigny AF-CHF #35% with AF Various beta- All-cause mortality Propensity-matched 95 (42%) in the non-BB group
et al74 blockers cohort: n ¼ 655 vs 136 (31%) in the BB
(n ¼ 426 BB; n ¼ 229 group;
non-BB) HR: 0.72 (95% CI: 0.549-
0.945); P ¼ 0.018.
a
Swedberg et al88 EMPHASIS-HF #35% Eplerenone Incidence of new- n ¼ 1,794 (n ¼ 911 New-onset AF:
onset AF; eplerenone, n ¼ 883 25 (2.7%) in eplerenone group
Effect of AF on study placebo) vs 40 (4.5%) in placebo
drug efficacy group; HR: 0.58 (95% CI:
0.35-0.96); P ¼ 0.034.
Death from cardiovascular
causes or hospitalization for
HF:
No AF at baseline: HR: 0.70
(95% CI: 0.57-0.85);
AF at baseline: HR: 0.60
(95% CI: 0.46-0.79);
P for interaction ¼ 0.41.
c
Neefs et al89 TOPCAT $45% without Spironolactone Risk of new-onset AF No previous history of AF: Incidence of new-onset AF:
permanent AF or recurrence of n ¼ 2,228 (n ¼ 1,111 58 (5.2%) in spironolactone
AF spironolactone; group vs 49 (4.4%) in
n ¼ 1,117 placebo); placebo group; P ¼ 0.41;
Previous AF: n ¼ 505 HR: 1.19 (95% CI: 0.81-1.74);
(n ¼ 260 P ¼ 0.38.
spironolactone; AF recurrence: 30 (11.5%) in
n ¼ 245 placebo) spironolactone group vs 29
(11.8%) in placebo group;
P ¼ 1.00.
HR: 0.94 (95% CI: 0.57-1.58);
P ¼ 0.83.
c
Cikes et al90 TOPCAT (North and $45% Spironolactone Incidence of new- No previous history of AF: Incidence of new-onset AF: HR:
South American onset AF; n ¼ 1,005 (n ¼ 503 0.98, (95% CI: 0.68-1.42);
patients) CV mortality, aborted spironolactone; P ¼ 0.92.
cardiac arrest, n ¼ 502 placebo); No AF: HR: 0.79 (95% CI: 0.62-
and HF History of AF alone: 1.00); P ¼ 0.047.
hospitalization n ¼ 314 (n ¼ 169 History of AF alone: HR: 1.06
spironolactone; (95% CI: 0.70-1.59);
n ¼ 145 placebo); P ¼ 0.80.
AF at enrollment: AF at enrollment: HR: 0.80
n ¼ 446 (n ¼ 214 (95% CI: 0.58-1.10)
spironolactone; P ¼ 0.17;
n ¼ 232 placebo) P for interaction ¼ 0.49.
Continued on the next page

41
Angiotensin-converting enzyme (ACE) inhibition and promotes cardiac fibroblast proliferation. Experi-
angiotensin receptor blockade have been shown to mental animal models suggest that the atria are more
reduce morbidity and mortality in patients with susceptible to TGF- b 1–induced fibrosis than the ven-
HFrEF35-39 and are recommended for patients with HF tricles.42 Second, the increase in systemic vascular
who are unable to take an angiotensin receptor– resistance, sympathetic activity, and myocardial
neprilysin inhibitor. 4,40 fibrosis induced by angiotensin II results in elevations
There are multiple mechanisms by which angio- in left atrial pressures. Elevations in left atrial pres-
tensin II mediates AF. First, binding of angiotensin II sures affect the atrial myocyte action potential,
to its receptor results in production of TGF- b1, which including a shortening of atrial refractory periods,
938 Newman et al JACC VOL. 83, NO. 9, 2024

Atrial Fibrillation and Heart Failure GDMT MARCH 5, 2024:932–950

T A B L E 2 Continued

LVEF
Inclusion Study
First Author Population Criteria Drug Outcome Numbers in Study Result
a
Butt et al9 DAPA-HF #40% Dapagliflozin Incidence of new- No previous history of AF: Incidence of new-onset AF: 66
onset AF; n ¼ 2,834 (n ¼ 1,419 (4.7%) in placebo group and
Effect of AF on study dapagliflozin; 57 (4.0%) in dapagliflozin
drug efficacy n ¼ 1,415 placebo); group; HR: 0.86 (95% CI:
History of AF: n ¼ 1,910 0.60-1.22).
(n ¼ 954 Worsening HF or cardiovascular
dapagliflozin; n ¼ 956 death (events per 100
placebo) person-years):
No AF at baseline: 10.8 in
dapagliflozin group vs 14.7
placebo group; HR: 0.74
(95% CI: 0.62-0.88);
AF at baseline: 12.7 in
dapagliflozin group vs 16.9
in placebo group; HR: 0.75
(95% CI: 0.62-0.92).
P for interaction ¼ 0.88.
c
Filippatos et al102 EMPEROR- $40% Empagliflozin Incidence of new- No previous history of AF: Incidence of new-onset AF: 116
PRESERVED onset AF; n ¼ 2,853 (n ¼ 1,417 (8.0%) in empagliflozin
Effect of AF on study empagliflozin; group vs 119 (8.1%) in
drug efficacy n ¼ 1,427 placebo); placebo group; HR: 1.00
History of AF: n ¼ 3,135 (95% CI: 0.77-1.29);
(n ¼ 1,576 P ¼ 0.98.
empagliflozin; First HF hospitalization or CV
n ¼ 1,559 placebo) death (events per 100
patient-years):
No AF: 5.91 in empagliflozin
group vs in 7.74 placebo
group; HR: 0.78 (95% CI:
0.64-0.95);
AF: 7.72 in empagliflozin group
vs 9.57 in placebo group;
HR: 0.78 (95% CI: 0.66-
0.93);
P for interaction ¼ 0.96.
c
Butt et al103 DELIVER $40% Dapagliflozin Effect of AF on study No previous history of AF: CV death or worsening HF
drug efficacy n ¼ 2,709 (n ¼ 1,372 (events per 100 person-
dapagliflozin; years):
n ¼ 1,337 placebo); No AF: 7.2 in empagliflozin
History of AF: n ¼ 3,552 group vs 8.1 in placebo
(n ¼ 1,758 group; HR: 0.89 (95% CI:
dapagliflozin; 0.74-1.08);
n ¼ 1,794 placebo) Any AF: 8.3 in empagliflozin
group vs 10.8 in placebo
group; HR: 0.78 (95% CI:
0.67-0.90);
P for interaction ¼ 0.426.
b
Whitbeck et al108 AFFIRM No LVEF restriction, Digoxin All-cause mortality n ¼ 1,076 HR: 1.41 (95% CI: 1.09-1.84);
analysis limited to P ¼ 0.010.
enrolled patients
with HF
b
Gheorghiade AFFIRM No LVEF restriction Digoxin All-cause mortality Propensity-matched Propensity-matched analysis
et al105 cohort: n ¼ 1,756 (not limited to HF patients):
(n ¼ 878 digoxin 124 (14%) in digoxin group
[n ¼ 140 HF]; n ¼ 878 vs 118 (13%) in nondigoxin
nondigoxin [n ¼ 147 group; HR: 1.06 (95% CI:
HF]) 0.83-1.37); P ¼ 0.64.
Subgroup analysis of matched
cohort limited to HF
patients: 38 (27%) in digoxin
group vs 39 (27%) in
nondigoxin group; HR: 1.08
(95% CI: 0.69-1.69);
P ¼ 0.74.
a
Swedberg et al111 SHIFT #35% Ivabradine Incidence of AF n ¼ 6,558 (n ¼ 3,268 306 (9%) ivabradine vs 251
(safety outcome) ivabradine; n ¼ 3,200 (8%) placebo; P ¼ 0.012.
placebo)
Continued on the next page
JACC VOL. 83, NO. 9, 2024 Newman et al 939
MARCH 5, 2024:932–950 Atrial Fibrillation and Heart Failure GDMT

T A B L E 2 Continued

LVEF
Inclusion Study
First Author Population Criteria Drug Outcome Numbers in Study Result
c
Komajda et al116 EDIFY $45% Ivabradine Incidence of AF n ¼ 179 (n ¼ 95 7 (7.4%) ivabradine vs 6 (7.1%)
(safety outcome) ivabradine; n ¼ 84 placebo; P ¼ nonsignificant.
placebo)
a
Ponikowski et al8 VICTORIA <45% Vericiguat Incidence of new- No AF: n ¼ 2,661; Incidence of new-onset AF
onset AF; History of AF alone: (events per 100 person-
Effect of AF on study n ¼ 992; years):
drug efficacy AF on ECG at enrollment: 7.5 in vericiguat group vs 8.7 in
n ¼ 1,357; placebo group; HR: 0.93
Any AF: n ¼ 2,349 (95% CI: 0.75-1.15); P ¼ 0.51.
CV death or HF hospitalization
(events per 100 person-
years):
No AF: 31.2 in vericiguat group vs
36.2 in placebo group; HR:
0.84 (95% CI: 0.74-0.96);
P ¼ 0.001;
History of AF: 36.6 in vericiguat
group vs 40.6 in placebo
group; HR: 0.90 (95% 0.74-
1.11); P ¼ 0.33;
AF on ECG at enrollment:
36.7 in vericiguat group vs 37.8
in placebo group; HR: 0.97
(95% CI: 0.81-1.16);
P ¼ 0.77;
Any AF: 36.6 in vericiguat group
vs 39.0 in placebo group; HR:
0.94 (95% CI: 0.83-1.08);
P ¼ 0.40.
P for interaction ¼ 0.45.
a
Solomon et al123 GALACTIC-HF #35% Omecamtiv Time to first HF event No AF: n ¼ 5,987 No AF: 981 (33%) in omecamtiv
mecarbil or CV death (n ¼ 2,974 omecamtiv mecarbil group vs 1,103
mecarbil; n ¼ 3,013 (36%) in placebo group; HR:
placebo); 0.87 (95% CI: 0.80-0.95);
AF: n ¼ 2,245 (n ¼ 1,146 AF: 542 (47%) in omecamtiv
omecamtiv mecarbil; mecarbil group vs 504
n ¼ 1,099 placebo) (46%) in placebo group; HR:
1.05 (95% CI: 0.93-1.18);
P for interaction ¼ 0.012.
No AF, no digoxin: 854 (32%)
omecamtiv mecarbil vs 948
(35%) placebo; HR: 0.88
(95% CI: 0.81-0.97);
AF, no digoxin: 370 (45%)
omecamtiv mecarbil vs 365
(48%) placebo; HR: 0.94
(95% CI: 0.81-1.09);
No AF, digoxin: 127 (36%)
omecamtiv mecarbil vs 155
(44%) placebo; HR: 0.74
(95% CI: 0.58-0.93);
AF, digoxin: 172 (50%)
omecamtiv mecarbil vs 139
(40%) placebo; HR: 1.34
(95% CI: 1.07-1.69);
P for interaction ¼ 0.007.
b
Packer et al130 CABANA No LVEF criteria, Ablation Death, disabling n ¼ 778 (n ¼ 378 Primary composite endpoint: 34
analysis limited to stroke, serious ablation; n ¼ 400 (9%) in ablation group vs 49
enrolled patients bleeding, or medical therapy) (12.3%) in drug therapy
with HF cardiac arrest group; HR: 0.64 (95% CI:
0.41-0.99).
Death from any cause: 23 (6.1%)
in ablation group vs 37
(9.3%) in drug therapy
group; HR: 0.57 (95% CI:
0.33-0.96).
Continued on the next page
940 Newman et al JACC VOL. 83, NO. 9, 2024

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T A B L E 2 Continued

LVEF
Inclusion Study
First Author Population Criteria Drug Outcome Numbers in Study Result
a
Marrouche et al131 CASTLE-AF #35% Ablation Death from any cause n ¼ 363 (n ¼ 179 Primary endpoint: 51 (28.5%) in
of HF ablation; n ¼ 184 ablation group vs 82
hospitalization medical therapy) (44.6%) in medical therapy
group; HR: 0.62 (95% CI:
0.43-0.87); P ¼ 0.007.
All-cause mortality: 24 (13.4%)
in ablation group vs 46
(25.0%) in medical therapy
group; HR: 0.53 (95% CI:
0.32-0.86); P ¼ 0.01.
a
Sohns et al132 CASTLE-HTx Advanced HF Ablation Death from any n ¼ 194 (n ¼ 97 ablation Primary endpoint: 8 (8%) in
referred for cause, group; n ¼ 97 medical ablation group vs 29 (30%)
transplant implantation of a therapy) in medical therapy group;
evaluation left ventricular HR: 0.24 (95% CI: 0.11-
assist device, or 0.52); P < 0.001.
urgent heart Death from any cause: 6 (6%) in
transplantation ablation group vs 19 (20%)
in medical therapy group;
HR: 0.29 (95% CI: 0.12-
0.72).
b
Rillig et al135 EAST-AFNET 4 No LVEF criteria Rhythm control Composite of CV n ¼ 798 (n ¼ 396 early Primary endpoint: 94 (23.7%) in
(56% HFpEF, death, stroke, or rhythm control group; early rhythm control group
27% HFmrEF, hospitalization n ¼ 402 usual care) vs 130 (32.3%) in usual care;
17% HFrEF) for HF or acute HR: 0.74 (95% CI: 0.56-0.97);
coronary P ¼ 0.03.
syndrome
c
Chieng et al134 AF Ablation for $50% Ablation Difference in peak n ¼ 31 (n ¼ 16 ablation Ablation group: peak PCWP on
HFpEF: A pulmonary group; n ¼ 15 medical baseline exercise RHC 30.4
Randomized capillary wedge therapy group)  4.2 mm Hg vs 25.4 
Controlled Trial pressure (PCWP) 4.5 mm Hg at 6 mo;
on exercise right P < 0.01.
heart Medical therapy group: peak
catheterization PCWP on baseline exercise
(RHC) from RHC 29.5  3.9 mm Hg vs
baseline to 6 mo 28.9  5.3 mm Hg at 6 mo;
P ¼ 0.68.

a
HFrEF. bVariable LVEF. cHFmrEF/HFpEF.
AF-CHF ¼ Atrial Fibrillation and Congestive Heart Failure; AFFIRM ¼ AF Follow-Up Investigation of Rhythm Management; BB ¼ beta-blocker; CABANA ¼ Catheter Ablation vs Antiarrhythmic Drug Therapy
for Atrial Fibrillation; CAPRICORN ¼ Carvedilol Post-Infarct Survival Control in LV Dysfunction; CASTLE-AF ¼ Catheter Ablation versus Standard Conventional Therapy in Patients with Left Ventricular
Dysfunction and Atrial Fibrillation; CASTLE-HTx ¼ Catheter Ablation for Atrial Fibrillation in Patients with End-Stage Heart Failure and Eligibility for Heart Transplantation; CIBIS-II ¼ Cardiac Insufficiency
Bisoprolol Study II; COPERNICUS ¼ Carvedilol Prospective Randomized Cumulative Survival; CV ¼ cardiovascular; DAPA-HF ¼ Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; DELIVER ¼
Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure; EAST-AFNET 4 ¼ Early Treatment of Atrial Fibrillation for Stroke Prevention Trial;
ECG ¼ electrocardiogram; EDIFY ¼ Preserved left ventricular ejection fraction chronic heart failure with ivabradine study; EMPEROR-Preserved ¼ Empagliflozin Outcome Trial in Patients with Chronic Heart
Failure with Preserved Ejection Fraction; EMPHASIS-HF ¼ Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure; EVALUATE-HF ¼ Effects of Sacubitril-Valsartan vs Enalapril on Aortic
Stiffness in Patients with Heart Failure with Reduced Ejection Fraction; GALACTIC-HF ¼ Global Approach to Lowering Adverse Cardiac Outcomes through Improving Contractility in Heart Failure;
HFmrEF ¼ heart failure with midrange ejection fraction; HFpEF ¼ heart failure with preserved ejection fraction; HFrEF ¼ heart failure with reduced ejection fraction; MERIT-HF ¼ Metoprolol CR/XL
Randomised Intervention Trial in Congestive Heart Failure; OUTSTEP-HF ¼ Randomized Study Using Accelerometry to Compare Sacubitril/Valsartan and Enalapril in Patients with Heart Failure; PARADIGM-HF
¼ Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure; PARAGON-HF ¼ Prospective Comparison of ARNI with ARB Global Outcomes in HF with
Preserved Ejection Fraction; PARAMOUNT ¼ Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection Fraction; PIONEER-HF ¼ Comparison of Sacubitril/Valsartan
versus Enalapril on Effect on NT-proBNP in Patients Stabilized from an Acute Heart Failure Episode; SENIORS ¼ Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart
Failure; SHIFT ¼ Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial; SOLVD ¼ Studies of Left Ventricular Dysfunction; TOPCAT ¼ Treatment of Preserved Cardiac Function Heart Failure with
an Aldosterone Antagonist; VICTORIA ¼ Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction.

which increases susceptibility to AF.41,43 Finally, trandolapril among patients with left ventricular
angiotensin II may directly affect atrial myocyte systolic dysfunction following myocardial infarction
electrophysiology.41 found that among patients in sinus rhythm at the
While ACE inhibitors are of unclear benefit in pre- time of study entry, randomization to the trandolapril
venting AF among patients with hypertension, 44 group was associated with a reduction in incident
secondary analyses of HF trials provide evidence AF.46 In a separate analysis of the SOLVD trial, ACE
that ACE inhibitors prevent new-onset AF. In an inhibitors reduced clinically significant AF that
analysis of 374 patients without a previous history of resulted in hospitalizations and mortality. 47
AF enrolled in the SOLVD (Studies of Left Ventricular Similar findings have been reported for patients
Dysfunction) trial from a single center, patients ran- with HFrEF receiving angiotensin receptor blockers
domized to enalapril were less likely to develop new (ARBs). Among 4,395 patients in sinus rhythm at the
onset AF. 45 Similarly, a study investigating time of enrollment into Val-HeFT (Valsartan Heart
JACC VOL. 83, NO. 9, 2024 Newman et al 941
MARCH 5, 2024:932–950 Atrial Fibrillation and Heart Failure GDMT

T A B L E 3 Therapies With Mortality Benefit in HF and Interactions With AF

HFrEF HFmrEF and HFpEF

Decrease Decrease Decrease Decrease Decrease Decrease

AF Incidence Mortality in SR Mortality in AF AF Incidence Mortality in SR Mortality in AF

ACEI U U NR/U NR/U X X

ARB U U U U X X
ARNI X (compared with U U X (compared with Ua X
ACEI or ARB) ACEI or ARB)
BB U U NR/U NR/U Ua NR/U
MRA U U U X Ua U
SGLT2i X U U X U U
Rhythm control U N/A U U N/A U
Ablation U N/A U U N/A Ongoing clinical trial

a
Benefit may exist primarily in the lower range of preserved EF spectrum.
U ¼ data exist supporting use of the drug class for achieving the specified endpoint; ACEI ¼ angiotensin-converting enzyme inhibitor; AF ¼ atrial fibrillation;
ARB ¼ angiotensin receptor blocker; ARNI ¼ angiotensin receptor–neprilysin inhibitor; BB ¼ beta-blocker; HFmrEF ¼ heart failure with midrange ejection fraction; HFpEF ¼
heart failure with preserved ejection fraction; HFrEF ¼ heart failure with reduced ejection fraction; MRA ¼ mineralocorticoid receptor antagonist; N/A ¼ not applicable; NR/
U ¼ not reported/uncertain, ie, insufficient evidence to determine whether the drug class achieves the specified endpoint; SGLT2i ¼ sodium-glucose cotransporter-2 inhibitor;
SR ¼ sinus rhythm; X ¼ no data exist supporting use of the drug class for achieving the specified endpoint.

Failure Trial), 5.12% in the valsartan arm developed study, mice underwent rapid atrial pacing to simulate
AF compared with 7.95% of patients assigned to pla- AF and were randomized to either sacubitril/valsar-
cebo (HR: 0.63; 95% CI: 0.49-0.81; P ¼ 0.0003).48 In a tan for 3 weeks or control. Mice that received sacu-
composite analysis of the CHARM (Candesartan in bitril/valsartan had less atrial and ventricular
Heart Failure Assessment of Reduction in Mortality remodeling and fibrosis, longer atrial refractory pe-
and morbidity) trials, patients assigned to cande- riods, and lower levels of collagen and N-terminal
sartan were less likely to develop AF during follow-up pro–B-type natriuretic peptide (NT-proBNP).54
49
across the spectrum of EF. In a meta-analysis of 6 studies of patients with HF
The comparative effectiveness of ACE inhibitors on (regardless of EF), sacubitril/valsartan did not result in
morbidity and mortality among patients with vs a lower incidence of AF compared with either enalapril
without AF has not been reported in post hoc ana- or valsartan.55 Similarly, an analysis of PARAGON-HF
lyses of large randomized controlled trials. However, (Prospective Comparison of ARNI with ARB Global
an analysis of the CHARM Program found that can- Outcomes in HF with Preserved Ejection Fraction)
desartan reduced cardiovascular death or hospitali- found that randomization to sacubitril/valsartan did
zation due to HF regardless of the presence or not result in a lower incidence of AF among those
absence of AF at the time of enrollment. 29 without a previous history of AF at the time of enroll-
ANGIOTENSIN-NEPRILYSIN INHIBITORS. Sacubitril/ ment.56 However, smaller studies suggest that there
valsartan is a combination of an ARB and a neprilysin may be benefit to sacubitril/valsartan in promoting
inhibitor. Neprilysin in an endopeptidase that is reverse atrial remodeling among patients with AF. In a
involved in degradation of bradykinin, natriuretic study which randomized 64 patients to receive either
peptides, angiotensin II, and adrenomedullin, some 160 mg/d valsartan or 200 mg/d sacubitril/valsartan
of which counter the deleterious consequences of after catheter ablation for AF, patients that received
sympathetic overactivation characteristic of HF. 50 sacubitril/valsartan had a decrease in atrial size, find-
Sacubitril/valsartan has been shown to be superior ings which were not present in the valsartan group.57
to ACE inhibitors in decreasing morbidity and mor- Similarly, in a retrospective study of patients with AF
tality among patients with HFrEF. 50 Sacubitril/val- being treated with either sacubitril/valsartan or val-
sartan also has benefit among patients with HFpEF sartan alone who underwent transesophageal and
and HFmrEF, particularly among those patients with transthoracic echocardiography on the same day, pa-
an EF on the lower end of this spectrum.51 tients treated with sacubitril/valsartan had higher left
Calcium mishandling is a key contributor to the atrial peak systolic strain, left atrial appendage
development of AF. 52 Nonhuman animal models have emptying velocity, and left atrial appendage EF and a
shown that sacubitril/valsartan enhances function of lower incidence of spontaneous echo contrast. In a
the ryanodine receptors and thus can decrease cal- mouse model, investigators replicated these findings
cium mishandling.53 Sacubitril/valsartan may also and demonstrated a reduction in fibrotic area size
provide benefits for patients already in AF. In one among mice treated with sacubitril/valsartan. 58
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The morbidity and mortality benefits of sacubitril/ in incident AF from 39 to 28 events per 1,000 patient-
valsartan among patients with HFrEF were not years. 69 It remains uncertain whether BBs reduce
attenuated by the presence of AF in PARADIGM-HF incident AF in patients with HFmrEF and HFpEF.
(Prospective Comparison of ARNI with ACEI to Whether the mortality benefits of BBs in HFrEF are
Determine Impact on Global Mortality and Morbidity attenuated by the presence of AF remains uncertain. In
in Heart Failure).51 Similarly, the treatment effects of a meta-analysis of patients enrolled in COPERNICUS
sacubitril/valsartan were not affected by AF in a sec- (Carvedilol Prospective Randomized Cumulative Sur-
ondary analysis of PARAGON-HF.56 vival), MERIT-HF (Metoprolol CR/XL Randomised
BETA-BLOCKERS. Certain beta-blockers (BBs) decrease Intervention Trial in Congestive Heart Failure),
mortality, hospitalizations, and symptom burden in CIBIS-II (Cardiac Insufficiency Bisoprolol Study II),
HFrEF and are associated with an improvement in and SENIORS (Study of the Effects of Nebivolol Inter-
EF.59-61 Thus, carvedilol, metoprolol succinate, and vention on Outcomes and Rehospitalisation in Seniors
bisoprolol are recommended for all patients with with Heart Failure), BBs did not reduce HF hospitali-
HFrEF unless contraindicated. 4,40 These benefits zations or mortality among patients with AF at the time
likely extend to patients with HFmrEF. 62 Notably, of study entry, suggesting that the benefit of BBs is
evidence from studies enrolling patients with limited to those in sinus rhythm.71 In a patient-level
HFpEF both with and without AF suggest that BBs meta-analysis from the Beta-Blockers HF Collabora-
may worsen symptoms in the HFpEF cohort. 63,64 tive Group that included >18,000 patients from 10
Among patients with AF, BBs are commonly used randomized trials, beta-blockade was associated with
for rate control and are recommended for use in a significant reduction in mortality among patients
patients with AF regardless of EF. 10,65 with HFrEF in sinus rhythm (HR for all-cause mortal-
Binding of ligand to the b-adrenergic receptor re- ity: 0.73; 95% CI: 0.67-0.80) but not among those in AF
sults in activation of adenyl cyclase and production of (HR: 0.97; 95% CI: 0.83-1.14; P ¼ 0.73).72
cyclic adenosine monophosphate (AMP) via a G-pro- Observational studies have challenged these find-
tein–mediated mechanism. Cyclic AMP activates ings. In a nationwide cohort study of patients with AF
protein kinase A, which leads to increased intracel- and HFrEF, HFmrEF, or HFpEF from Nielsen et al, BBs
lular calcium and positive chronotropic and inotropic were associated with a reduction in all-cause mor-
effects. HF is characterized by excess activation of the tality.73 A secondary analysis of the AF-CHF (Atrial
sympathetic nervous system and resultant down- Fibrillation and Congestive Heart Failure) study that
regulation of myocardial b-adrenergic receptors and propensity-matched patients who did not receive BBs
uncoupling of the receptors from their G-protein– to those who did found that patients treated with BBs
mediated effects. Chronic BB therapy results in had a significantly lower risk of all-cause mortality
increased b-adrenergic receptor signal density and (HR: 0.72; 95% CI: 0.55-0.95) but not of hospitaliza-
restoration of receptor–G-protein coupling.66 tions (HR: 0.886; 95% CI: 0.72-1.10). 74
BBs are first-line therapies for rate control in AF. 67 The reason for these divergent results likely relates
Beta-blockade exerts benefit via negative chrono- to the limitations of each study. In the trials included
tropic effects which aid in rate control. BBs may also in each of the meta-analyses, patients were classified
prevent AF via numerous proposed mechanisms. BBs to AF vs sinus rhythm based on a single electrocar-
prevent adverse remodeling and promote positive diogram at the time of enrollment. This raises the
remodeling which can result in a reduction in left atrial possibility that patients with paroxysmal AF may have
pressure, a common trigger for AF. Similarly, excess been misclassified to the sinus rhythm group. Notably,
sympathetic drive promotes atrial arrhythmias and is the prevalence of AF was fewer than 20% at baseline in
opposed by beta-blockade. Stimulation of the b- both meta-analyses despite registry studies suggest-
adrenergic receptors results in a shortening of action ing AF is present in >50% of patients with HF. 14,71,73
potential duration which is a potential trigger for the Each observational study also has important limi-
initiation and maintenance of AF, and experimental tations. The study by Nielsen et al73 included patients
data suggest that BBs may reverse these changes.68 with HFrEF, HFmrEF, and HFpEF, but the in-
Finally, BBs may prevent atrial ischemia and fibrosis. 69 vestigators were unable to separate these patients
In the CAPRICORN (Carvedilol Post-Infarct Sur- into different categories. Importantly, BBs exert
vival Control in LV Dysfunction) trial, patients ran- different degrees of benefit among patients with
domized to carvedilol experienced a lower incidence HFrEF, HFmrEF, and HFpEF, so this distinction is
of AF and atrial flutter.70 An antiarrhythmic effect of important. 59-61,63,64,75 Furthermore, the registry did
BBs in HF was further supported in a meta-analysis of not include data on NYHA functional classification or
nearly 12,000 patients that demonstrated a reduction BB dose, both of which influence patient outcomes.
JACC VOL. 83, NO. 9, 2024 Newman et al 943
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The study by Cadrin-Tourigny et al74 was a sec- electrophysiologic mapping demonstrated prolonga-
ondary analysis of the AF-CHF trial, which randomized tion of P-wave duration, total right atrial activation
patients with HFrEF and AF to either rate or rhythm time, and local conduction times. Histologic exami-
control. The investigators propensity-matched pa- nation revealed excess atrial fibroblasts and intersti-
tients that received BB therapy to those that did not to tial collagen in the aldosterone group, suggesting that
determine whether BBs improved outcomes in AF and aldosterone provides a substrate for AF via alter-
HFrEF. Before propensity matching, patients that ations in atrial conduction and fibrosis, without a
received BBs were younger and more likely to have significant impact from hemodynamic de-
nonischemic cardiomyopathy, receive oral anti- rangements.87 Numerous animal studies have shown
coagulation, and have an implantable cardioverter- that MRAs decrease atrial fibrosis and AF.78
defibrillator. Each of these factors has been associated In a secondary analysis of EMPHASIS-HF
with a better outcome, thus raising concern that re- (Eplerenone in Mild Patients Hospitalization and
sidual confounding factors influenced the results even Survival Study in Heart Failure), eplerenone signifi-
after propensity matching. 76 cantly reduced the frequency of incident AF compared
Given ongoing uncertainty surrounding the bene- with placebo. Similarly, eplerenone reduced the
fits of BB in patients with AF and HF, a randomized composite endpoint of death from cardiovascular
trial examining this question may be warranted, causes or hospitalization for HFrEF among patients
although further data from large registries may help with and without AF at the time of study enrollment. 88
to clarify this issue. In contrast, spironolactone did not reduce incident or
MINERALOCORTICOID RECEPTOR ANTAGONISTS. In recurrent AF in patients with HFpEF in a secondary
HF, RAAS activation results in excess aldosterone analysis of TOPCAT. 89 A separate analysis of the same
release with resultant binding to the mineralocorticoid trial that included only patients randomized from
receptor. This has numerous deleterious conse- North and South America also reported no difference
quences including salt and water retention, increased in postrandomization incident AF between spi-
blood pressure, and activation of proinflammatory and ronolactone and placebo. In that analysis, beneficial
profibrotic pathways.77,78 ACE inhibition results in effects of spironolactone persisted regardless of AF
transient reductions in aldosterone levels, although status.90 The IMPRESS-AF (Improved Exercise Toler-
after 1 year, aldosterone is increased compared with ance in Heart Failure With Preserved Ejection Fraction
baseline.79 Among patients with HFrEF, mineralocor- by Spironolactone on Myocardial Fibrosis in Atrial
ticoid receptor antagonists (MRAs) result in a reduc- Fibrillation) trial randomized 250 patients with HFpEF
tion in HF hospitalizations and mortality. 80-82 MRAs and AF to either spironolactone or placebo and found
did not reduce the primary composite outcome of no difference in maximal oxygen consumption on
death from cardiovascular outcomes, aborted cardiac cardiopulmonary exercise testing, 6-minute walk dis-
arrest, or HF hospitalizations in the HFpEF trial TOP- tance, or E/e 0 ratio. Notably, there was a nonsignificant
CAT (Treatment of Preserved Cardiac Function Heart reduction in hospitalizations in the spironolactone
Failure with an Aldosterone Antagonist).83 However, a group (15% vs 23%).91
subgroup analysis suggested there was benefit when Among patients with diabetes mellitus type 2 and
evaluating only data from North and South America,84 chronic kidney disease, the MRA finerenone was
and a post hoc analysis suggested that patients with an shown to reduce both incident AF92 and HF. 93 Whether
EF on the lower end of normal may derive benefit.85 finerenone has clinical benefits among patients with
The incidence of AF is significantly increased HFpEF is being explored in the ongoing FINEARTS-HF
among patients with hyperaldosteronism, which led (Study to Evaluate the Efficacy [Effect on Disease] and
to a hypothesis of aldosterone involvement in the Safety of Finerenone on Morbidity [Events Indicating
pathogenesis of AF.86 To further elucidate a potential Disease Worsening] & Mortality [Death Rate] in Par-
mechanism, investigators implanted rats with os- ticipants With Heart Failure and Left Ventricular
motic minipumps that continuously delivered either Ejection Fraction [Proportion of Blood Expelled Per
aldosterone or a nonactive control. After 8 weeks, Heart Stroke] Greater or Equal to 40%; NCT04435626).
burst pacing resulted in AF in 11/11 rats that received SODIUM-GLUCOSE COTRANSPORTER-2 INHIBITORS.
aldosterone infusion compared with only 2/9 rats Sodium-glucose cotransporter-2 (SGLT2) inhibitors
randomized to control (P ¼ 0.03). In vivo right and reduce HF hospitalizations and cardiovascular mor-
left heart catheterization and ex vivo pressure- tality among patients with HFrEF, HFmrEF, and
volume loop analysis in isolated working hearts did HFpEF regardless of diabetic status.94-98 The precise
not demonstrate differences in ventricular function mechanism of benefit of SGLT2 inhibitors in HF is
or atrial pressures between groups. In contrast, unknown but likely multimodal. The natriuretic
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effects of SGLT2 inhibitors result in a reduction in atrioventricular conduction from increased vagal tone,
intravascular volume and blood pressure. The resul- digoxin is useful for rate control in patients with AF. 105
tant reduction in preload and afterload decreases re- In the DIG (Digitalis Investigation Group) trial, pa-
flex sympathetic hyperactivity. They also exert tients with HF and EF #45% in sinus rhythm ran-
benefit by augmenting myocardial energy supply by domized to digoxin had fewer hospitalizations but no
increasing circulating ketones, which is a more reduction in mortality. 106 Similar findings were noted
effective myocardial energy source, and increasing in a subset of patients enrolled with HF and EF
levels of erythropoietin and thus hemoglobin, >45%. 106 Notably, a subsequent post hoc analysis
thereby improving myocardial oxygen supply. suggested that there was mortality benefit among
Furthermore, direct inhibition of the myocardial patients randomized to digoxin with serum digoxin
sodium-hydrogen exchanger improves mitochondrial concentration (SDC) 0.5-0.9 ng/mL.107 Although AF
function and reduces oxidative stress and arrhyth- was not a specified endpoint in the DIG trial, hospi-
mias. There is evidence that SGLT2 inhibitors talization for supraventricular arrhythmias was lower
decrease sympathetic and increase parasympathetic among patients randomized to digoxin.106
99
activity. Increased thickness of epicardial adipose In one post hoc analysis of the AFFIRM (AF Follow-
tissue has been associated with an increased Up Investigation of Rhythm Management) trial that
incidence and severity of AF. 100 In a population of used propensity matching, there was an increased risk
diabetic patients with coronary artery disease, dapa- of all-cause, cardiovascular, and arrhythmic mortality
gliflozin reduced epicardial adipose tissue volume. 101 among patients that received digoxin. This excess risk
In a secondary analysis of the DECLARE-TIMI 58 of all-cause mortality remained when limiting the
(Dapagliflozin Effect on Cardiovascular Events– analysis to only patients with HF. 108 Notably, that
Thrombolysis in Myocardial Infarction 58) trial, AF analysis was limited because patients in AFFIRM were
and atrial flutter events were significantly reduced randomized to rate or rhythm control, but not to a
among patients randomized to dapagliflozin, a specific rate-controlling agent.105 Furthermore, pa-
finding which was consistent regardless of the pres- tients on digoxin in the AFFIRM trial were encouraged
ence or absence of HF at baseline.100 In contrast, to aim for SDC $1 ng/mL, whereas the aforementioned
incident AF was not reduced among patients ran- post hoc analysis of the DIG trial suggested optimal
domized to dapagliflozin in DAPA-HF (Dapagliflozin dosing of digoxin at SDC 0.5-0.9 ng/mL.105,107 A sepa-
and Prevention of Adverse Outcomes in Heart rate propensity-matched analysis of the same trial
Failure), although the benefits on dapagliflozin in found no difference in mortality, hospitalization, or
terms of the primary outcome of death from cardio- arrhythmic endpoints among patients taking
vascular causes or HF hospitalization, as well as all- digoxin. 105 In an analysis of the Swedish HF Registry,
cause mortality and quality-of-life endpoints, were digoxin was associated with a reduction in HF hospi-
consistent among patients with and without AF at talizations and mortality among patients with HF and
baseline. 9 In EMPEROR-Preserved (Empagliflozin AF. Conversely, patients with HF but no history of AF
Outcome Trial in Patients with Chronic Heart Failure receiving digoxin demonstrated an increased risk of
with Preserved Ejection Fraction), empagliflozin did HF hospitalization and mortality. 109
not reduce the frequency of incident AF among pa- Digoxin is frequently prescribed to patients with
tients with HFpEF without a previous history of AF at more advanced HF, and this may be difficult to ac-
the time of study enrollment, but the beneficial ef- count for even with propensity matching. There are 2
fects of the study drug in terms of the primary com- ongoing clinical trials evaluating the efficacy of
posite outcome of HF hospitalizations or digoxin among patients with HF while targeting lower
cardiovascular death was present regardless of AF SDCs. These trials are enrolling patients in sinus
status.102 Similar findings were evident in an analysis rhythm and AF (DIGIT-HF [Digoxin to Improve Out-
of the DELIVER (Dapagliflozin Evaluation to Improve comes in Patients with Advanced Chronic Heart
the Lives of Patients with Preserved Ejection Fraction Failure] [EudraCT 2013-005326-38], DECISION
Heart Failure) trial.103 [Digoxin Evaluation in Chronic Heart Failure: Inves-
DIGOXIN. Digoxin inhibits the sodium-potassium tigational Study In Outpatients in the Netherlands];
adenosine triphosphatase of myocardial cells, which NCT03783429).110
promotes activity of the sodium-calcium exchanger, IVABRADINE. Ivabradine is a selective inhibitor of
increased intracellular calcium, and increased force of the hyperpolarization-activated cyclic nucleotide–
myocardial contraction. Digoxin additionally has gated channels that produce the If current. Ivabra-
vagomimetic effects that slows sinoatrial and atrio- dine does not have activity against other cardiac re-
ventricular conduction.104 Owing to a reduction in ceptors or channels and thus imparts only negative
JACC VOL. 83, NO. 9, 2024 Newman et al 945
MARCH 5, 2024:932–950 Atrial Fibrillation and Heart Failure GDMT

chronotropic effects. 111 It was previously thought that Vericiguat is an oral soluble guanylate cyclase
hyperpolarization-activated cyclic nucleotide–gated stimulator. In the VICTORIA (Vericiguat Global Study
channels were present only in the sinoatrial node, in Subjects with Heart Failure with Reduced Ejection
but subsequent studies have demonstrated they are Fraction) trial, patients with HF and EF #45% were
also expressed in other cardiac tissue, including the randomized to either vericiguat or placebo on a back-
atrioventricular node. 112 In a small trial that ran- ground of GDMT. Patients that received vericiguat had
domized patients with uncontrolled permanent AF a lower incidence of a composite outcome of death
despite BB or calcium channel blocker therapy to the from cardiovascular causes and first hospitalization for
addition of ivabradine or digoxin, ivabradine HF. 120 A post hoc analysis revealed that treatment with
decreased the mean daytime heart rate by 11.5% but vericiguat did not reduce the incidence of AF compared
was less effective than digoxin.113 with placebo (7.5 vs 8.7 events/100 person-years;
In the SHIFT (Systolic Heart Failure Treatment adjusted HR: 0.93; P ¼ 0.51), however the beneficial
with the If Inhibitor Ivabradine Trial), patients with effects of vericiguat on the primary composite
HF and EF #35% on maximally tolerated BBs with a outcome persisted regardless of baseline AF status. 8
resting heart rate $70 beats/min were randomized to Omecamtiv mecarbil is a cardiac contractility
ivabradine or placebo. Patients with a history of modulator that acts by selectively binding to cardiac
persistent AF were excluded. Those that were ran- myosin and increasing the number of myosin heads
domized to ivabradine had a reduction in the com- available for interaction with actin. In GALACTIC-HF
posite outcome of hospital admission for worsening (Global Approach to Lowering Adverse Cardiac
HF or cardiovascular death. Notably, patients who Outcomes through Improving Contractility in Heart
received ivabradine were more likely to develop AF or Failure), omecamtiv mecarbil resulted in a lower
atrial flutter during the study period (9% in ivabra- incidence of a first HF event or cardiovascular death,
dine group vs 8% in placebo group; P ¼ 0.01). 111 A but no significant difference in all-cause mortality or
meta-analysis that included data from >40,000 pa- quality of life among patients with HFrEF. 121 In a
tients found that ivabradine was associated with a prespecified analysis, the benefit of omecamtiv
>15% increased risk of AF. 114 Ivabradine affects I f mecarbil was limited in those with AF at baseline.122
channels in the pulmonary veins, an important When stratified for baseline digoxin use and AF, pa-
structural substrate for AF initiation and mainte- tients with AF who were taking digoxin and ome-
nance, thus providing a potential mechanism for this camtiv mecarbil had worse outcomes in terms of the
finding. 115 In the HFpEF trial EDIFY (Preserved left primary composite outcome. In contrast, patients in
ventricular ejection fraction chronic heart failure with sinus rhythm at study entry derived benefit from the
ivabradine study), which examined use of ivabradine study drug, including the subgroup taking digoxin.123
for patients with EF $45%, AF incidence was not Why omecamtiv mecarbil led to harm in patients with
increased among patients assigned to the study drug, AF taking digoxin but not in patients in sinus rhythm
although the trial was relatively small (n ¼ 179) and taking digoxin is uncertain.110,123 Of note, omecamtiv
may have been underpowered for that endpoint.116 mecarbil was not approved for use by the U.S. Food
Although patients with AF were excluded from and Drug Administration.
clinical trials evaluating ivabradine in HF populations In the STEP-HFpEF (Subjects with Obesity-related
because of a presumed lack of benefit, subsequent HFpEF) trial, patients with HFpEF randomized to the
studies have revealed that ivabradine has heart rate– glucagon-like peptide-1 (GLP-1) receptor agonist
lowering effects in AF.112,113,117 Whether benefits of semaglutide had a greater improvement in quality of
ivabradine in terms of HF hospitalization and car- life and 6-minute walk distance compared with pla-
diovascular mortality are present among patients cebo. More than 50% of enrolled patients had AF at
with preexisting persistent AF who otherwise fit the baseline. Notably, patients randomized to semaglu-
SHIFT enrollment criteria is unknown. tide had a lower rate of serious adverse events related
OTHER MEDICATIONS. The combination of hydral- to AF (1.1% vs 3.4%). 122 In contrast, liraglutide failed
azine and nitrates for African-American patients with to improve clinical stability among patients with
HFrEF resulted in a significant improvement in the HFrEF and a recent HF hospitalization124 and was
composite endpoint of death from any cause, hospi- associated with an increased risk of a serious cardiac
talization for HF, and quality of life in the A-HeFT events (10% vs 3%; P ¼ 0.04) among stable out-
(African-American Heart Failure Trial). 118 This combi- patients with HFrEF. 125
nation was found to have consistent benefits across a Studies have shown that GLP-1 receptor agonists
variety of subgroups, including those with AF the time are associated with an increase in heart rate.126
of study enrollment.119 Whether use of these agents may incite new AF is a
946 Newman et al JACC VOL. 83, NO. 9, 2024

Atrial Fibrillation and Heart Failure GDMT MARCH 5, 2024:932–950

topic of uncertainty. In a meta-analysis of trials 6 months follow-up. One-half of patients in the

evaluating the cardiovascular safety of albiglutide, ablation arm no longer met criteria for HFpEF on
patients receiving the study drug had an increased exercise right heart catheterization at 6 months. 134
127
risk of AF. In contrast, a subsequent meta-analysis Importantly, while a large body of data supporting
that included trials evaluating albiglutide and other use of catheter ablation of AF among patients with HF
GLP-1 agonists showed no increased risk of AF.128 exists, rhythm control by means of antiarrhythmic
drug use is also of benefit. A secondary analysis of
RHYTHM CONTROL: A NEW FORM OF GDMT?
EAST-AFNET 4 (Early Treatment of Atrial Fibrillation
for Stroke Prevention Trial) found that patients with
There is mounting evidence that rhythm control is
signs or symptoms of HF (regardless of EF) random-
associated with a decrease in morbidity and mortality
129 ized to early rhythm control had a significantly lower
among patients with AF, and this benefit extends to
risk of death from cardiovascular causes, stroke, or
those with concomitant HF. In a secondary analysis of
hospitalization for HF or acute coronary syndrome.135
the CABANA (Catheter Ablation vs Antiarrhythmic
Importantly, most patients assigned to rhythm con-
Drug Therapy for Atrial Fibrillation) trial, 130 patients
trol in that analysis were treated with antiarrhythmic
with HF (79% HFpEF, 12% HFmrEF, 9% HFrEF) ran-
drugs (31% amiodarone, 33% flecainide, 10% drone-
domized to catheter ablation had a 36% relative
darone), and fewer than 10% underwent ablation.135
reduction in the primary composite endpoint of death,
Notably, many antiarrhythmic agents are contra-
disabling stroke, serious bleeding, or cardiac arrest,
indicated among patients with HF because of struc-
and a 43% relative risk reduction in all-cause mortality.
tural heart disease, coronary artery disease, reduced
These findings were similar to those in CASTLE-AF
EF, or NYHA functional class III or IV symptoms,
(Catheter Ablation versus Standard Conventional
frequently leaving amiodarone as the only available
Therapy in Patients with Left Ventricular Dysfunction
antiarrhythmic drug.10 In a randomized trial of pa-
and Atrial Fibrillation), which demonstrated a 38%
tients with HFrEF and AF randomized to ablation or
relative risk reduction in the composite outcome of
amiodarone, patients who underwent ablation had
death from cardiovascular causes and hospitalization
greater freedom from AF, a lower rate of unplanned
for HF, and a 47% relative risk reduction in all-cause
hospitalization, and decreased mortality.136
mortality among patients randomized to catheter
The mechanism by which rhythm control exerts
ablation. 131 In CASTLE-HTx (Catheter Ablation for
benefit in HF remains uncertain. Given that BBs may
Atrial Fibrillation in Patients with End-Stage Heart
not have the same benefit among patients with HFrEF
Failure and Eligibility for Heart Transplantation), pa-
in AF, one possibility is that rhythm control restores
tients with advanced HF and symptomatic AF ran-
the morbidity- and mortality-lowering benefits of BBs.
domized to catheter ablation (compared with patients
In CASTLE-AF, the point estimate for the HR for the
randomized to rhythm and/or rate control) had a sig-
primary outcome was lower among patients receiving
nificant reduction in the composite endpoint of death
BBs, although it was not statistically different from
from any cause, implantation of a left ventricular assist
those not receiving BBs.131 Similarly, the mortality-
device, or urgent heart transplantation (HR: 0.24;
lowering benefits of cardiac resynchronization ther-
95% CI: 0.11-0.52; P < 0.001).132
apy have been shown to be attenuated in the presence
A prospective registry of patients with AF and
of AF,137 providing another possible mechanism by
EF $50% found that patients with HFpEF at the time
which rhythm control may improve outcomes. Among
of ablation experienced more AF recurrence, AF-
patients with permanent AF and concomitant HF
related rehospitalization, and need for repeated AF
(regardless of EF) with at least 1 hospitalization in
ablation than those without HF. Furthermore, while
the preceding year, a strategy of atrioventricular
patients without HFpEF who underwent AF ablation
nodal ablation and cardiac resynchronization ther-
were found to have improvement in both physical
apy was shown to improve quality of life, reduce
component summary score and mental component
HF hospitalizations, and decrease mortality
summary score, no such improvement was noted for
compared with pharmacologic rate control. 138,139
those with HFpEF. 133 In contrast, a small trial ran-
domized 31 patients with HFpEF and AF to medical CONCLUSIONS
therapy alone or ablation. Compared with those in the
medical therapy group, patients randomized to abla- AF is common among patients with HF and is associ-
tion demonstrated a reduction in peak exercise ated with worse outcomes. Many components of
wedge pressure and improvement in peak VO 2, NT- GDMT may reduce incident AF among patients with
proBNP, and Minnesota Living with HF Score at HF. GDMT maintains its morbidity- and mortality-
JACC VOL. 83, NO. 9, 2024 Newman et al 947
MARCH 5, 2024:932–950 Atrial Fibrillation and Heart Failure GDMT

reducing benefits regardless of AF status among pa- committee member for DAPA-ACT and GARDEN-HF (TIMI group and
AstraZeneca), for HEART-FID (steering committee member, American
tients with HFrEF, although data are conflicting for
Regent), CARDINAL-HF (steering committee member, Cardurion),
whether this statement is true of BBs. Similarly, med- and HERMES (national lead investigator, Novo Nordisk); and has
ical therapies for HFmrEF and HFpEF maintain their received consulting or speaker fees from AstraZeneca, Boehringer
beneficial effects in patients with and without AF. Ingelheim, Bayer, and Novartis. Dr Savarese has received grants and
personal fees from Vifor, AstraZeneca, Pharmacosmos, and Novartis;
Studies have evaluated patients with AF and EF $40%
has received grants from Boehringer Ingelheim, Boston Scientific,
as 1 cohort. Thus, although some data suggest that Merck, and Bayer; has received personal fees from Servier, Cytoki-
angiotensin receptor–neprilysin inhibitors and SGLT2 netics, Medtronic, Edwards Lifesciences, Teva, and Abbott; and re-
inhibitors exert differential benefit across the spec- ceives funding through the EU Horizon Programme and the Swedish
51,140 Heart and Lung Foundation. Dr Vardeny has received research sup-
trum of midrange and preserved EFs, it is un-
port (paid to institution) from the National Institutes of Health, the
known whether this gradient of benefit is present for Food and Drug Administration, AstraZeneca, Bayer, and Cardurion;
patients with AF and HFmrEF or HFpEF. There is a and has received personal consulting fees from Cardior and Cytoki-

large body of evidence suggesting that rhythm control netics. Dr Allen has received grant funding from the Patient-Centered
Outcomes Research Institute and the National Institutes of Health; and
and catheter ablation for AF improves outcomes for
has received consulting fees from ACI Clinical, Boston Scientific, Cy-
patients with HFrEF. Preliminary studies suggest tokinetics, Novartis, and Quidel. Dr Gottlieb has received consulting
symptomatic and hemodynamic improvements for fees from Cytokinetics. Dr Zainab serves on the Heart Failure Publica-
tion Committee of Cytokinetics. Dr Morris has received consulting fees
patients with HFmrEF and HFpEF who undergo AF
or honoraria from Abbott, Acorai, BI Lilly, Cytokinetics, Edwards,
ablation, though there may be increased AF recurrence Ionis, Merck, Novo Nordisk, and Regeneron. Dr Desai works under
and need for repeated ablation among those with contract with the Centers for Medicare and Medicaid Services to
HFpEF. Whether catheter ablation reduces cardiovas- develop and maintain performance measures used for public reporting
and pay for performance programs; and has received research grants
cular endpoints such as HF hospitalization and mor-
and consulting for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim,
tality in HFpEF is being evaluated in the ongoing Bristol Myers Squibb, Cytokinetics, Merck, Novartis, SCPharmaceut-
CABA-HFPEF study (Catheter-Based Ablation of icals, and Vifor. Dr Teerlink has received consulting fees from Cytoki-
Atrial Fibrillation Compared to Conventional Treat- netics. Dr Saldarriaga-Giraldo has served as a speaker for AstraZeneca,
Novartis, Servier, Abbott, Medtronic, Pfizer, Roche, Sanofi, Boehringer
ment in Patients with Heart Failure with Preserved
Ingelheim, Elly Lilly, Bayer, and Merck; has served as a principal
Ejection Fraction; NCT05508256). investigator for Amgen, Novartis, Merck, and Bayer; and has served as
The development of AF in a patient with HF is both an advisor for Medtronic, Novartis, Bayer, AstraZeneca, Boehringer
a common occurrence and a significant clinical event Ingelheim, Servier, and Novo Nordisk. Dr Lindenfeld has received
grant funding from the National Institutes of Health, the Patient-
associated with poor outcomes. GDMT and rhythm
Centered Outcomes Research Institute, and AstraZeneca; and has
control improve morbidity and mortality in patients received consulting fees from Abbott, Alleviant, AstraZeneca, Axon,
with AF and HF across the spectrum of EF. Therefore, Bayer, Boehringer Ingelheim, Boston Scientific, CVRx, Edwards Life-

clinicians caring for patients with concomitant HF sciences, Merck, Medtronic, VWave, and Vascular Dynamics. All other
authors have reported that they have no relationships relevant to the
and AF should initiate GDMT and consider a rhythm
contents of this paper to disclose.
control strategy.

FUNDING SUPPORT AND AUTHOR DISCLOSURES

ADDRESS FOR CORRESPONDENCE: Dr JoAnn
Dr O’Meara is supported by the Montreal Heart Institute’s Carolyn & Lindenfeld, Vanderbilt University Medical Center
Richard J. Renaud Chair for Research in Heart Failure, with fees paid
East, South Tower, 1215 21st Avenue South, Suite 5209,
through her institution for this chair, for a Canadian Heart Function
Alliance (CHFA) Team Grant, funded by the CIHR (steering committee Nashville, Tennessee 37232-8802, USA. E-mail: joann.
member), and for involvement in the following trials as a steering [email protected]. @LindenfeldJoann.

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