European Heart Journal (2021) 42, 4740–4742 EDITORIAL

doi:10.1093/eurheartj/ehab695

Pace and ablate better than drugs in patients

with heart failure and atrial fibrillation: lessons

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from the APAF-CRT mortality trial
1,2,
Cecilia Linde *
1
Karolinska Institutet, Department of Medicine, Stockholm, Sweden; and 2Karolinska University Hospital, Department of Cardiology, Stockholm, Sweden

Online publish-ahead-of-print 6 October 2021

This editorial refers to ‘AV junction ablation and cardiac resynchronization for patients with permanent atrial fibrillation and
narrow QRS: the APAF-CRT Mortality Trial’, by M. Brignole et al., doi:10.1093/eurheartj/ehab569.

Atrial fibrillation in heart failure patients- advantages/disadvantages of potential therapies

PV isolation of pulmonary veins AV-junction ablation and CRT Pharmacological Rate control
pacing
Beta-blockers/digoxin/amiodarone

Younger patients Older patients Older patients

For y Severe Symptoms y
1 HF hospitalisation y
Insufficient rate control >110 bpm
whom? y Tachycardia-mediated y
HFrEF/HFmrEF/HFpEF y
HFrEF/HFmrEF/HFpEF
cardiomyopathy y
Irrespective of QRS duration y
Ability to tolerate rate control drugs
y HFrEF

y Improved mortality/morbidity y
Rate-control y
Rate control / Quality of life
Benefits y Symptoms / Qol /LV function y
Improved mortality/morbidity /QoL y
RACE and AFFIRM trials
y CASTLE-AF /RAFT-AF trials y
APAF-CRT morbidity/mortality trials

Negative Procedure related yPacemaker-dependency yInability to achieve rate control

effects complications / AF/Aflu relapse yBradycardia/hypotension

Knowledge gaps Value of PVI in HFpEF, RCT comparing PVI vs Abl+CRT, RCT comparing Abl+CRT to Abl+ His-pacing

Graphical Abstract APAF-CRT mortality study.

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
* Corresponding author. Heart, Vascular and Neurology Theme, Karolinska University Hospital, S-17176 Stockholm, Sweden. Tel: þ46 760 52 64 94, Email: cecilia.linde@.ki.se
Published on behalf of the European Society of Cardiology. All rights reserved. VC The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.
Editorial
..
Many patients with heart failure (HF) develop atrial fibrillation (AF), ..
and AF can cause HF often through high heart rates. Pulmonary vein ..
..
catheter isolation (PVI) to cure AF is recommended to improve out- ..
comes,1 but implementation has been slow. One reason may be that ..
..
the recommendation is based on small studies of relatively young HF ..
patients not resembling very much those we encounter in our every- ..
..
day practice. In the CASTLE AF- trial,2 PVI ablation reduced total mor- ..
tality and HF hospitalizations by an impressive 40% compared with ..
..
pharmacological treatment. Study patients were in their early 60s with ..
moderately symptomatic HF with reduced ejection fraction (HFrEF). It ..
..
is important to remember that 3000 patients had to be screened to ..
find 363 eligible CASTLE-AF study patients.2 When their inclusion cri- ..
..
teria were applied in a large US database,3 of 289 831 patients with AF ..
and HF, again the majority (91%) did not meet the inclusion criteria
..
..
and the benefit of PVI was modest compared with trial results. ..
Recently the equally small randomized controlled RAFT-AF trial (n =
..
..
411) comparing PVI vs. rate control failed to demonstrate a benefit in ..
the primary endpoint of HF hospitalizations and mortality. RAFT-AF
..
..
study patients were more clinically representative and were in their ..
70s with LVEF <_45% or >45%, and had moderate HF symptoms
..
..
(Tang et al., oral presentation LBT ACC 2020). Therefore, at present, ..
..
even if PVI in HF patients is appealing, the results are not consistent, ..
and with no evidence for benefits in HF patients with preserved ejec- ..
..
tion fraction (HFpEF) a growing proportion of the HF spectrum. The
results of the APAF-CRT trials4,5 indicate that atrioventricular juncion
(AVJ) ablation and cardiac resynchronizaztion (CRT) is a successful al-
ternative for those many HF patients with AF in whom rate control
cannot be achieved and who are not suitable for PVI.
AVJ ablation is technically a much simpler procedure and very suc-
cessful to obtain complete rate control in AF. The downside is that it
causes permanent damage to the conduction system and pacemaker
dependency, which can lead to HF development when delivered
through right ventricular (RV) pacing. At present, a ‘pace and ablate’
strategy comes second to rate control in the guideline recommenda-
tions for HF patients with AF.6 Many HF patients are elderly with mul-
tiple comorbidities and may not tolerate rate control regimens and/
or reach the optimal heart rate recommended to be in the order of
60–100 b.p.m.6 For them an ablate and pace strategy may be more
tolerable. Moreover, the negative effects of permanent RV pacing
may no longer be as ominous since they can be mitigated by CRT and
potentially physiological pacing.
The APAF-CRT study4,5 was an investigator-initiated randomized
controlled parallel open label study comparing two treatment strat-
egies: Abl (AVJ ablation) þ CRT and pharmacological rate control. It
comprised a morbidity trial4 and a pre-specified mortality trial5 which
is published in this issue of the European Heart Journal. This study
included patients as old as 83 years but with a median of 73–74 years
old (47% females) and with severe HF (NYHA class III in 70%), per-
manent AF, QRS duration <_100 ms, and with more than one HF hos-
pitalizations the year before randomization.
The morbidity trial4 with a median follow-up time of 16 months
showed that Abl þ CRT compared with pharmacological AF rate
control was superior for mortality and HF hospitalizations or wor-
sening of HF, the primary endpoint [hazard ratio (HR) 0.38, 95% con-
fidence interval (CI) 0.18–0.91, P = 0.013]. Significantly fewer patients
in the Abl þ CRT arm died from any cause or were hospitalized for
HF (HR 0.28, 95% CI 0.11–0.72, P = 0.008).5 Specific symptoms
4741
related to AF were reduced by 36% in the Abl þ CRT arm after
1 year of follow-up (P = 0.004).
The present mortality study5 contained more patients as calcu-
lated from the mortality data in the morbidity trial.5 A total of 133
patients with AF history of at least 1.5 years were studied. More than
a third had undergone previous cardioversion and one in 10 AF abla-
tion attempts. AF symptom scores were high, in particular concern-
ing subscores for dyspnoea and exercise intolerance. A total of 40%
had HFrEF defined as LVEF <_35% and 60% had either HFpEF or
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HFmrEF (HF with mildly reduced EF) defined as LVEF >35%. One in
four in both groups had implantable cardioverter device (ICD) ther-
apy (CRT-D or just ICD).
A total of 63 patients were assigned to the Abl þ CRT group and
70 to the pharmacological rate control group. Study patients had
many comorbidities but were well matched between groups. The
study was stopped prematurely for efficacy after a median follow-up
time of 29 months per patient. The primary endpoint was reached in
11% (n = 7) in the Abl þ CRT group compared with 29% (n = 20) in
the rate control arm (HR 0.26, 95% CI 0.10–0.65, P = 0.004).
Mortality was mostly cardiovascular. There were also impressive dif-
ferences in annual mortality between groups, with an estimated 2-
year mortality rate of 5% and 21% in the Abl þ CRT group and rate
control arm, respectively, and at 4 years this was 14% and 41%, re-
.. spectively. The mortality curves progressively diverged in favour of
.. the Abl þ CRT strategy (Graphical Abstract). The secondary endpoint
..
.. combining all-cause mortality and HF hospitalizations was also signifi-
.. cantly improved and in favour of the Abl þ CRT arm (29% n = 18 vs.
..
.. 51% n = 36; HR 0.40, 95% CI 0.22–0.73, P = 0.002). There were
.. fewer HF deaths and hospitalizations in the Abl þ CRT arm (HF
..
.. deaths n = 2 in Abl þ CRT and n = 6 in rate control; HF hospitaliza-
.. tions n = 18 in Abl þ CRT and n = 29 in rate control). Benefits from
..
.. the intervention arm were consistent across subgroups including age,
.. sex, ischaemic heart disease, heart rate at baseline, and LVEF.
..
.. The authors are to be commended for performing this important
.. study. The results are indeed impressive, with 3–4 times lower mor-
..
.. tality risk over the 4 years by Abl þ CRT vs. the rate control strategy,
.. and with a number needed to treat of only 3.7. However, to explain
..
.. the reasons for the results is not as easy, since the study compares
.. treatment strategies. Thus, to what degree rate control, heart rhythm
..
.. regularity, and ventricular synchronization contributed to the results
.. remains unclear and is very difficult to discern. As an example, in a re-
..
.. cent small study,7 the effects of irregularity and heart rate in AF were
..
.. shown to be inter-related. In 10 AF patients (with no HF), LV peak
.. strain was related to the preceding RR interval and varied more at
..
.. fast than at slower heart rates because of insufficient left ventricular
.. diastolic filling time.7
..
.. Even though initial rate control was achieved in the APAF-CRT
.. study [mean heart rate at 70 b.p.m. (IQR 70–75) in the Abl þ CRT
..
.. group and 83 b.p.m. (IQR 65–90) in the rate control group], we have
.. little information on whether rate control was maintained over the
..
.. duration of the study or if further efforts to fine-tune rate control
.. were performed. However, we do know that the crossover rate was
..
.. very high. Thus 18 patients crossed over within the first 2 months to
.. Abl þ CRT for worsening of HF or physicians’ judgement, which may
..
.. indicate that rate control could not be obtained in the control arm.
.. The analysis was based on intention to treat, meaning that patients
..
. were analysed according to the randomization, which could have
4742 Editorial

..
diluted the results. Significantly more patients in the rate control arm .. La Meir M, Lane DA, Lebeau JP, Lettino M, Lip GYH, Pinto FJ, Thomas GN,
were on digoxin but with no reported interaction with outcome. A .. Valgimigli M, Van Gelder IC, Van Putte BP, Watkins CL; ESC Scientific Document
.. Group. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation
sensitivity analysis for baseline heart rate indicated similar beneficial .. developed in collaboration with the European Association for Cardio-Thoracic
results in Abl þ CRT vs. rate control with heart rate <_102 b.p.m. .. Surgery (EACTS): The Task Force for the diagnosis and management of atrial fib-
.. rillation of the European Society of Cardiology (ESC) Developed with the special
(achieved rate control) and >102 b.p.m. (insufficient rate control ..
which occurred in n = 23/70) which seems counterintuitive. Finally, .. contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur
.. Heart J 2021;42:373–498.
CRT per se could be expected to have had a major impact on HF- .. 2. Marrouche NF, Brachmann J, Andresen D, Siebels J, Boersma L, Jordaens L,
related death and hospitalizations. CRT could also be expected to af- .. Merkely B, Pokushalov E, Sanders P, Proff J, Schunkert H, Christ H, Vogt J, Bänsch
.. D; CASTLE-AF Investigators. Catheter ablation for atrial fibrillation with heart fail-
fect quality of life, NYHA class, or NT-proBNP levels, or induce ..

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ure. N Engl J Med 2018;378:417–427.
reversed left ventricular remodelling, but these results were not
.. 3. Noseworthy PA, Van Houten HK, Gersh BJ, Packer DL, Friedman PA, Shah ND,
..
reported in this mortality study .. Dunlay SM, Siontis KC, Piccini JP, Yao X. Generalizability of the CASTLE_AF trial:

The results highlight important knowledge gaps and the need for
.. catheter ablation for patients with atrial fibrillation and heart failure in routine
.. practice. Heart Rhythm 2020;7:1057–1065.
future studies such as a randomied controlled trial to compare PVI .. 4. Brignole M, Pokushalov E, Pentimalli F, Palmisano P, Chieffo E, Occhetta E,
with Abl þ CRT in HF patients with AF. The PABA CRT trial8 from
.. Quartieri F, Calò L, Ungar A, Mont L. APAF-CRT Investigators. A randomized
.. controlled trial of atrioventricular junction ablation and cardiac resynchronization
2008 showed PVI to be superior to Abl þ CRT for symptomatic re- ..
lief but since then a randomized study comparing these treatments
.. therapy in patients with permanent atrial fibrillation and narrow QRS. Eur Heart J
.. 2018;39:3999–4008.
has not been performed, at least not to the knowledge of this author. .. 5. Brignole M, Pentimalli F, Landolina M, Quartieri F, Occhetta E, Calò L, Mascia G,
.. Mont L, Vernooy K, van Dijk V, Allaart C, Fauchier L, Gasparini M, Parati G,
However, it is more likely that the two approaches should be tailored
... Soranna D, Rienstra M, van Gelder IC, for the APAF-CRT Trial Investigators. AV
to the individual patient, taking, for example, age and HF severity into .. junction ablation and cardiac resynchronization for patients with permanent atrial
consideration. Very importantly, physiological pacing such as His- .. fibrillation and narrow QRS: the APAF-CRT Mortality Trial. Eur Heart J 2021;42:
.. 4731–4739.
pacing which mimics normal ventricular conduction should be com- .. 6. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V,
pared with Abl þ CRT. It may prove to be superior particularly when ..
.. González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C,
the intrinsic QRS is narrow, but this needs testing in a clinical trial. .. Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM,
The study results of APAF-CRT are indeed impressive and the .. Ruschitzka F, Rutten FH, van der Meer P; Authors/Task Force Members;
.. Document Reviewers. 2016 ESC Guidelines for the diagnosis and treatment of
authors are to be congratulated. With this addition to the APAF- .. acute and chronic heart failure: The Task Force for the diagnosis and treatment of
CRT morbidity trial,4 we now know that AVJ ablation combined with .. acute and chronic heart failure of the European Society of Cardiology (ESC).
.. Developed with the special contribution of the Heart Failure Association (HFA)
CRT improves mortality and HF morbidity, and thus is a superior ..
strategy to rate control in elderly HF patients with permanent AF. .. of the ESC Eur J Heart Fail 2016;18:891–975.
.. 7. Lyon A, van Mourik M, Cruts L, Heijman J, Bekkers SCAM, Schotten U, Crijns
.. HJGM, Linz D, Lumens J. Both beat-to-beat changes in RR-interval and left ven-
Conflict of interest: CL reports consulting fees from AstraZeneca, .. tricular filling time determine ventricular function during atrial fibrillation. Europace
Roche diagnostics, Bayer and speaker honoraria from Novartis, .. 2021;23(23 Suppl 1):i21–i28.
.. 8. Khan MN, Jaı̈s P, Cummings J, Di Biase L, Sanders P, Martin DO, Kautzner J, Hao
Astra, Bayer, Medtronic, Impulse Dynamics and Vifor. ..
.. S, Themistoclakis S, Fanelli R, Potenza D, Massaro R, Wazni O, Schweikert R,
.. Saliba W, Wang P, Al-Ahmad A, Beheiry S, Santarelli P, Starling RC, Dello Russo
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