Europace (2019) 21, 993–994 EHRA POSITION PAPER

doi:10.1093/europace/euz055

EHRA White Paper: knowledge gaps in

arrhythmia management—status 2019
Andreas Goette1,2,*, Angelo Auricchio3, Giuseppe Boriani4, Frieder Braunschweig5,

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Josep Brugada Terradellas6, Haran Burri7, A. John Camm8, Harry Crijns9,
Nikolaos Dagres10, Jean-Claude Deharo11, Dobromir Dobrev12, Robert Hatala13,
Gerhard Hindricks10, Stefan H. Hohnloser14, Christophe Leclercq15,
Thorsten Lewalter16,17, Gregory Y.H. Lip18,19, Jose Luis Merino20, Lluis Mont6,
Frits Prinzen21, Alessandro Proclemer22, Helmut Pürerfellner23, Irina Savelieva8,
Richard Schilling24, Jan Steffel25, Isabelle C. van Gelder26, Katja Zeppenfeld27,
Igor Zupan28, and Hein Heidbüchel29
ESC Scientific Document Group: Serge Boveda (Review Coordinator)30,
Pascal Defaye31,Michele Brignole32, Jongi Chun33, Jose M. Guerra Ramos34,
Laurent Fauchier35, Jesper Hastrup Svendsen36,37,Vassil B. Traykov38,
Frank R. Heinzel39
1
St. Vincenz-Krankenhaus GmbH, Cardiology and Intensive Care Medicine, Am Busdorf 2, 33098 Paderborn, Germany; 2Working Group Molecular Electrophysiology, University
Hospital Magdeburg, Magdeburg, Germany; 3Department of Cardiology, Fondazione Cardiocentro Ticino, Lugano (Ticino), Switzerland; 4Cardiology Division, Department of
Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Policlinico di Modena, Modena, Italy; 5Department of Cardiology, Karolinska University
Hospital, Stockholm, Sweden; 6Department of Cardiology, Hospital Clinic, University of Barcelona, Barcelona, Spain; 7Department of Cardiology, University Hospital of Geneva,
Geneva, Switzerland; 8St. George’s, University of London, Molecular and Clinical Sciences Research Institute, London, UK; 9Department of Cardiology and Cardiovascular
Research Institute Maastricht (CARIM), Maastricht UMCþ, Maastricht, The Netherlands; 10Department of Electrophysiology, Heart Center Leipzig at University of Leipzig,
Leipzig, Germany; 11Department of Cardiology, Aix Marseille Université, CHU la Timone, Marseille, France; 12University Duisburg-Essen, Institute of Pharmacology, Essen,
Germany; 13Department of Cardiology and Angiology, National Cardiovascular Institute, NUSCH, Bratislava, Slovak Republic; 14Division of Clinical Electrophysiology,
Department of Cardiology, J.W. Goethe University, Frankfurt, Germany; 15Univ Rennes, CHU Rennes, LTSI-UMR1099, Rennes, France; 16Department of Cardiology and
Intensive Care, Hospital for Internal Medicine Munich South, Munich, Germany; 17Department of Cardiology, University of Bonn, Bonn, Germany; 18Liverpool Centre for
Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, UK; 19Aalborg Thrombosis Research Unit, Department of Clinical Medicine,
Aalborg University, Aalborg, Denmark; 20Hospital Universitario La Paz, Arrhythmia and Robotic EP Unit, Madrid, Spain; 21Department of Physiology, Maastricht University,
Maastricht, Netherlands; 22Cardiology Division, University Hospital Udine, Udine, Italy; 23Department of Cardiology, Ordensklinikum Linz Elisabethinen, Academic Teaching
Hospital, Linz, Austria; 24Barts Heart Centre, Barts and the London NHS Trust, London, UK; 25University Heart Center Zurich, Zurich, Switzerland; 26Department Of
Cardiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands; 27Department of Cardiology, Leiden University Medical Center (Lumc),
Leiden, Netherlands; 28Department Of Cardiology, University Clinical Centre Ljubljana, Ljubljana, Slovenia; 29Antwerp University and Antwerp University Hospital, Antwerp,
Belgium; 30Cardiology Department, Clinique Pasteur, 31076 Toulouse, France; 31CHU Hôpital Albert Michalon, Unité de Rythmologie Service De Cardiologie, FR-38043
Grenoble Cedex 09, France; 32Department of Cardiology, Ospedali Del Tigullio, Via Don Bobbio 25, IT-16033 Lavagna (GE), Italy; 33CCB, Cardiology Department, Med. Klinik
Iii, Markuskrankenhaus, Wilhelm Epstein Str. 4, DE-60431 Frankfurt, Germany; 34Unitat d’Aritmies, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 35Service de
Cardiologie, Centre Hospitalier Universitaire Trousseau et Université de Tours, Faculté de Médecine, Tours, France; 36Department of Cardiology, The Heart Centre,
Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; 37Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen,
Copenhagen, Denmark; 38Department of Invasive Electrophysiology and Cardiac Pacing, Clinic of Cardiology, Acibadem City Clinic Tokuda Hospital, Sofia, Bulgaria; and
39
Charité University Medicine, Campus Virchow-Klinikum, 13353 Berlin, Germany

Received 4 March 2019; editorial decision 4 March 2019; accepted 15 March 2019; online publish-ahead-of-print 18 March 2019

Clinicians accept that there are many unknowns when we make diagnostic and therapeutic decisions. Acceptance of uncertainty is essen-
tial for the pursuit of the profession: bedside decisions must often be made on the basis of incomplete evidence. Over the years, physi-
cians sometimes even do not realize anymore which the fundamental gaps in our knowledge are. As clinical scientists, however, we have
to halt and consider what we do not know yet, and how we can move forward addressing those unknowns. The European Heart Rhythm
Association (EHRA) believes that scanning the field of arrhythmia / cardiac electrophysiology to identify knowledge gaps which are not yet
the subject of organized research, should be undertaken on a regular basis. Such a review (White Paper) should concentrate on research

* Corresponding author. Tel: þ49 5251 861651; fax: þ49 5251 861652. E-mail address: [email protected]
C The Author(s) 2019. For permissions, please email: [email protected].
Published on behalf of the European Society of Cardiology. All rights reserved. V
994 A. Goette et al.

which is feasible, realistic, and clinically relevant, and should not deal with futuristic aspirations. It fits with the EHRA mission that these
White Papers should be shared on a global basis in order to foster collaborative and needed research which will ultimately lead to better
care for our patients. The present EHRA White Paper summarizes knowledge gaps in the management of atrial fibrillation, ventricular
tachycardia/sudden death and heart failure.
...................................................................................................................................................................................................
Keywords European Heart Rhythm Association • White Paper • Arrhythmia • Fibrillation • Tachycardia •
Heart failure

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Table of content More fundamental reviews of areas for future research which
might prove potentially valuable for increasing our knowledge and
Introduction: Knowledge gaps—why are they so important . . . . . .994 expanding the evidence base for future therapeutics are rarely under-
Atrial fibrillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .994 taken. This is in marked contrast to commercial diagnostic, pharma-
Pathophysiology and screening. . . . . . . . . . . . . . . . . . . . . . . . . . . . .994 ceutical and device companies that regularly update their
Pharmacological therapies in atrial fibrillation, rate and understanding and appreciation of the research data to optimize their
rhythm control. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 994b potential corporate contribution. Not unreasonably, these delibera-
Stroke prevention, anticoagulation: strategies and risk tions are usually confidential. The European Heart Rhythm
stratification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 994b Association (EHRA) believes that scanning the field of arrhythmia/
Catheter/surgical ablation of atrial fibrillation . . . . . . . . . . . . . 994e cardiac electrophysiology to identify knowledge gaps which are not
Device therapies in atrial fibrillation . . . . . . . . . . . . . . . . . . . . . . . 994f yet the subject of organized research, should be undertaken on a reg-
Atrial fibrillation in orphan diseases. . . . . . . . . . . . . . . . . . . . . . . .994g ular basis. Such a review should concentrate on research, which is
Ventricular arrhythmia and sudden death . . . . . . . . . . . . . . . . . . . 994h feasible, realistic, and clinically relevant, and should not deal with fu-
Risk prediction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 994h turistic aspirations. It fits with the EHRA mission that these reviews
Pharmacological therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 994i should be shared on a global basis in order to foster collaborative
Device therapies to prevent ventricular tachycardia / and needed research which will ultimately lead to better care for our
sudden cardiac death and lead management . . . . . . . . . . . . . . . 994j patients. It might also be useful for governmental organizations, health
Catheter ablation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 994k care providers, and medical companies.
Heart failure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 994k The number of unanswered questions that you will find in the text
Pharmacological therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 994k below is impressive. It should not intimidate but motivate the clinician
New monitoring devices/technologies . . . . . . . . . . . . . . . . . . . 994k and/or clinical scientist in the quest for better personalized care.
Pacing technologies and cardiac resynchronization
therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 994p
Assist devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .994s Task Force
This Task Force was convened by EHRA, with the remit to perform a
comprehensive review and critical assessment of the current state of
Introduction: Knowledge gaps— the evidence base for arrhythmia management, to identify areas and
why are they so important aspects of arrhythmia therapies that have not been studied or have
been insufficiently explored, to evaluate the need for and feasibility of
Clinicians accept that there are many unknowns when we make diag- studies to fulfil the missing evidence, and to provide guidance on pri-
nostic and therapeutic decisions. Acceptance of uncertainty is essen- oritized research. It is an EHRA policy to sponsor position papers
tial for the pursuit of the profession: bedside decisions must often be and guidelines without commercial support, and all members volun-
made on the basis of incomplete evidence in order to move forward. teered their time. Thus, all members of the Task Force as well as
Over the years, we sometimes even do not realize anymore which reviewers have disclosed any potential conflict of interest in detail, at
the fundamental gaps in our knowledge are. As clinical scientists, the end of this document.
however, we have to halt and consider what we do not know yet,
and how we can move forward addressing those unknowns.
The knowledge base for clinical and translational aspects of cardiac Atrial fibrillation
electrophysiology and arrhythmology is regularly reviewed during
the process of producing clinical guidelines and recommendations. Pathophysiology and screening
Major knowledge gaps are often mentioned in the text, and may even Arrhythmia mechanisms are not generally evaluated on an individual
form level of evidence C recommendations. Recently, guidelines task patient basis and are not specifically targeted therapeutically.1
forces have begun to include short sections at the end of their docu- Mechanistic targeting (Table 1) has the potential to sharpen and im-
ments in which knowledge gaps, predominantly those that are close prove therapeutic choices.2–4 Current imaging/mapping techniques
to being filled by known ongoing research, are mentioned. do not allow the differentiation between ectopic (triggered) activity
EHRA White Paper: knowledge gaps in arrhythmia management 994a

Table 1 Knowledge gaps in AF pathophysiology

Knowledge gaps Less than More than Limited knowl- Resolution of gap Upcoming trials
10 case 11 case edge (small trials (in principle) in the field
reports reports or registries, but feasible (Clinical Trial.gov)
no RCT)
....................................................................................................................................................................................................................
Defining actionable patient-specific molecular ar- None Yes None
rhythmia mechanisms
Identifying and targeting key dynamic modulators None Yes None
Achieving atrial targeting of specific molecular ar- None Yes None

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rhythmic mechanisms with drugs
Integrated studies of specific molecular/cellular AF None Low feasibility at pre- Biobank data are be-
pathophysiology, genetics, and external factors sent, but theoreti- ing accumulated,
cally feasible using but means of
‘big data’ and AI analysis are limited

AF, atrial fibrillation; RCT, randomized controlled trial.

and/or re-entry and other cellular/molecular mechanisms.4–11 related to both the underlying disease and AF itself, but a significant
Techniques that track cellular metabolic state, such as Raman spec- heterogeneity in the rate and severity of AF progression has been
troscopy, could be applied to assess the effectiveness of therapies noted in a small proportion of patients who exert yet unexplained
designed to reverse atrial fibrillation (AF)-related metabolic ‘protection’ from AF progression, despite accumulating age-related
abnormalities.1 risk factors and comorbidities. Mechanistic parameters might also be
Currently, our understanding of the dynamic factors (autonomic of interest to define new AF classifications such as pulmonary vein
fluctuations, atrial stretch, circadian rhythm, ischaemia, inflammation, (PV)-dependent AF vs. non-PV-dependent AF. Medical treatment has
etc.) that modulate AF risk is based on associations and clinical obser- yet to demonstrate clinical efficacy in preventing progression, and the
vations, with limited information about underlying mechanisms.12–18 response to antiarrhythmic therapies remains poorly predictable.
The characterization of these dynamic modulators, their interactions, This may be due to multiple factors ranging from the genetic back-
mechanistic basis, and relevance for diverse subgroups of AF-patients ground and ‘high-risk’ atrial structure to environmental modifiers and
is expected to improve AF management. A major challenge to molec- to the late implementation of treatment. These issues have been ex-
ular therapeutics is finding a way to modify molecular pathways effec- tremely difficult to address with the existing epidemiological studies,
tively, safely, and specifically in human atria.19,20 Recent advances in but the advent of the ‘big data’ and artificial intelligence may make
adeno-associated virus-based vector technology and targeted deliv- these studies possible.58
ery techniques allow for efficient, safe and long-term gene transfer to Furthermore, primary prevention of AF may encompass the char-
the heart.21–23 Gene knockdown with the use of RNA-interference acterization of a so called pre-AF-state without an established atrial
technology might also be exploited therapeutically.24 In the future arrhythmia. The pre-AF state may be expressed and measured on
photoacoustic imaging might be applied to evaluate the role of intra- the different scale, including atrial irritability (the electrical compo-
cellular Ca2þ or reactive oxygen species changes in AF occurrence.1 nent) and atrial myopathy (the structural component). A variety of
The current definition of the type of AF—paroxysmal, persistent, other measures are likely to be incorporated into the assessment and
long-standing persistent, and permanent—is based on duration of AF quantification of the pre-AF state, such as blood biomarkers or echo-
episodes.25 While this classification does carry some prognostic cardiographic strain parameters. The relative weight of these compo-
weight, for example regarding the risk of stroke as well as mortal- nents has not yet been evaluated to develop the risk stratification
ity,26–29 it falls short in many other regards.30 Importantly, the success score, which should the subject of future research.59,60
of AF ablation both in patients with paroxysmal as well as in persis- Ten percent of AF-related strokes are a first clinical manifestation
tent AF is highly variable.31–33 The same is true with respect to the of the arrhythmia. Consequently, the development of an effective AF
rate of progression of AF, both from a symptomatic point of view as screening strategy should be a public health priority.61 On the con-
well as regarding the ‘burden of AF’.34–37 Hence, a more refined clas- trary, a recent report concludes that there is still a lack of evidence to
sification of AF is highly desirable both from a prognostic point of assess a proper risk/benefit balance of systematic screening for AF us-
view as well as to better be able to individually tailor antiarrhythmic ing ECG monitoring in asymptomatic adults.62 The incidence of
therapies including catheter ablation. Incorporation of clinical param- screen-detected AF varies between 1.4% and 7.4%63–66 depending
eters (including symptom duration, duration of AF, AF burden),38–40 on the duration of ECG screening, the age and the comorbidities of
electrocardiogram (ECG) parameters,41 biomarkers,42–48 atrial struc- the screened population. There is a lack of data concerning the most
ture (including invasive assessment of low voltage areas),49 atrial car- appropriate patient profile to enhance AF detection. As of today, we
diomyopathy,50 and imaging parameters51–54 will be of importance in do not know whether ECG based screening detects more AF cases
this regard.55–57 Atrial fibrillation is generally considered a progres- than screening by pulse palpation. There is uncertainty on the optimal
sive disease, attributed to electrical and structural remodelling duration and the most appropriate tool for screening. The role of
994b A. Goette et al.

Table 2 Knowledge gaps in AF screening

Knowledge gaps Less than More than Limited knowl- Resolution of gap Upcoming trials in the
10 case 11 case edge (small trials (in principle) field (Clinical Trial.gov)
reports reports or registries, but feasible
no RCT)
.........................................................................................................................................................................................................................
AF screening with stroke as a secondary endpoint Yes AFOSS (NCT 03589170)
VITAL-AF (NCT 03515057)
LOOP (NCT02036450)
Ideal MD (NCT 02270151)

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AF screening with stroke as a primary outcome Yes STROKESTOP II (NCT
02743416)
AF screening after stroke Yes Yes SAFAS (NCT 03570060)
Stroke risk in device identified AHRE/subclinical Yes Yes NOAH-AFNET 6 (NCT
AF 02618577)
ARTESIA (NCT 01938248)
Biological and clinical significance and difference Low feasibility Post hoc analyses of NOAH
between subclinical AF and device-detected Trial (NCT 02618577) and
arrhythmias ARTESiA (NCT 01938248)

AF, atrial fibrillation; AHRE, AF as opposed to device-detected arrhythmia; RCT, randomized controlled trial.

consumer cardiac monitoring using wearables in combination with Head-to-head comparisons of various drugs against each other in
apps is completely undefined. In cardiac device, patients atrial high well-powered trials are missing, however. An individualized approach
rate episodes labelled as subclinical AF (SCAF) occur in around 30– for antiarrhythmic therapy in accordance to the underlying atrial pa-
60% of patients.67,68 However, there is a lack of knowledge on the thology is also lacking (Table 3).71,72 Furthermore, combined of
stroke risk in SCAF, which might occur rarely and last only a short rate-control medications such as beta-blockers or calcium-channel
duration. Even more important, we do not know whether earlier de- blockers with/without digitalis glycosides have also not been systemati-
tection of SCAF improves clinical outcomes. It is unassessed whether cally studied. There is a new arrange of AADs under development that
AF screening by any means is cost-effective (Table 2). exploit new targets (e.g. SK channel inhibitors) or new combinations
of targets, not necessarily confined to ion channel inhibition (OMT 28;
Subclinical atrial fibrillation, atrial high rate episodes, and NCT03078738). The relative and added value of these drugs requires
device detected arrhythmias considerable research, some of which is ongoing. However, AAD-
There are controversies due to knowledge gaps that are widely recog- based research focused on irreversible hard outcomes, such as mortal-
nized, but not addressed appropriately as yet, partly due to the diffi- ity and stroke, although successfully pioneered with dronedarone, are
culty conducting the relevant studies (large number of participants are not yet considered for other agents, including new compounds.73
required, relatively low diagnostic yield, need for long, e.g. 5 years, Furthermore, there are many knowledge gaps with regard to cardio-
follow-up, which all increase costs). These knowledge gaps include the version of AF. The true incidence of stroke in patients with AF <48 h
poorly understood biological and clinical significance of SCAF as op- vs. >48 h has not systematically been studied. In addition, it is unclear if
posed to device-detected arrhythmias (AHREs), the unknown ‘optimal’ all AF patients with a CHA2DS2VASc score of zero need to be anticoa-
threshold for the duration of a SCAF or AHRE episode that determine gulated during the cardioversion period. The prognostic impact of elec-
the need for anticoagulation and the dependence of this threshold on trical/pharmacological cardioversion of AF vs. spontaneous conversion
the clinical thromboembolic risk, whether duration, frequency, cluster- is also unclear so far.74 Furthermore, the pre-treatment period with
ing of SCAF episodes plays a role and whether the concept of a ‘tem- oral anticoagulants (3 weeks) before cardioversion without the need
poral relationship’ between an AF episode and thromboembolic event for a transesophageal echocardiography screening has not been clearly
is viable. The main frequently asked, but not answered question is assessed.
whether these episodes are markers of risk or risk factors?69,70
Stroke prevention, anticoagulation:
Pharmacological therapies in atrial strategies and risk stratification
fibrillation, rate and rhythm control Risk stratification
Pharmacological therapy is the cornerstone for the majority of AF Stroke prevention is central to the management of AF.25,75,76 While
patients. Although the impact of antiarrhythmic drugs (AADs) with re- the risk of stroke is increased five-fold in AF, the risk is not homoge-
gard to overall outcome is uncertain for most compounds, such agents neous and depends on various stroke risk factors. The more common
are widely used to stabilize sinus rhythm. For some drugs, and validated clinical risk factors have been used to formulate stroke
recent observational trials have provided opposite results with a re- risk stratification schemes, which are of varying complexity. Simple
duction of stroke and myocardial infarction during long-term use. schemes such as CHADS2 and CHA2DS2VASc have been used in
EHRA White Paper: knowledge gaps in arrhythmia management 994c

Table 3 Knowledge gaps in pharmacological therapy of AF

Knowledge gaps Less than More than Limited knowledge (small Resolution of Upcoming trials in the
10 case 11 case trials or registries, but no gap (in princi- field (Clinical Trial.gov)
reports reports RCT) ple) feasible
......................................................................................................................................................................................................................
Optimal rate control therapy: use of Very small RCTs with Feasible RATE-AF (NCT 02391337)
digoxin insufficient endpoints BRAKE-AF (NCT03718273)
Optimal therapy in acute symptomatic AF Lack of studies on rhythm vs. Feasible ACWAS (NCT 02248753)
rate control in patients with
acute symptomatic AF

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Early rhythm control in AF No RCTs Feasible EAST (NCT 01288352)
Rate vs. rhythm control for post-opera- No RCTs Feasible No acronym
tive AF NCT 02132767
Rate vs. rhythm control in atrial flutter/ No RCTs Feasible None
atrial tachycardia
IV sotalol for cardioversion of AF No RCTs Feasible None
Structural (pathological) effects of antiar- No RCT None
rhythmic drugs in atrial tissue
Systematic combination of antiarrhythmic Yes Feasible None
drugs to improve efficacy
Impact of antiplatelet and antithrombotic Yes Feasible None
therapy on atrial tissue structure
(remodelling)
Stroke rate in patients undergoing cardio- Yes Feasible None
version of AF <48 h without
anticoagulation

AF, atrial fibrillation; RCT, randomized controlled trial.

clinical guidelines. They have also been used to artificially categorize abnormalities excluding rheumatic mitral valve disease/stenosis and
patients into low-, moderate-, and high-risk strata. All clinical scores metallic prosthetic valves, has not been well-established, although
only have modest predictive value for identifying the high-risk patients they are indicators of poorer outcome with regard to stroke and
that sustain events (e.g. c-index 0.63).2 Attempts to improve predic- bleeding. The role of echocardiography in risk stratification remains
tion with more complex clinical scores only result in modest improve- under-appreciated.80 The knowledge gaps in risk stratification sys-
ments in prediction (e.g. c-index 0.65). The addition of biomarkers tems include the no ‘zero’ thromboembolic risk in low-risk patients
(‘biological markers’ whether blood, urine, or imaging)77,78 improve (CHA2DS2VASc 0), wide heterogeneity in stroke rates among
on prediction, but again, predictive value remains modest (c-index patients CHA2DS2VASc 1 due to the differential impact of individual
<0.7). Many of the recent biomarker studies have been tested in se- components (e.g. age vs. other risk factors), lack of accounting for ‘ad-
lected anticoagulated clinical trial cohorts, however, to precisely as- ditional’ risk factors, and inability to quantify the ‘residual’ risk.81
sess the value of biomarkers for stroke prediction, studies in non-
anticoagulated populations are needed.79 Given that the majority of
high-risk AF patients are anticoagulated, the feasibility of such a study Anticoagulation strategies
remains uncertain. It is unknown if biomarker-based scores may prac- The approach to stroke prevention has changed with the introduction
tically help in refining stroke risk assessment especially in patients with of the non-vitamin K antagonist oral anticoagulants (NOACs), which
low CHA2DS2VASc scores. offer better efficacy, safety, and convenience compared with warfa-
Thus, existing risk stratification scores for thromboembolic risk in- rin.82,83 Observational studies suggest that there may be only marginal
clude traditional risk factors and do not account for so-called emerg- benefits of the NOACs on stroke prevention when compared with
ing risk factors such as obesity, sleep apnoea, borderline very well managed warfarin with good anticoagulation control (high in-
hypertension, and, apart from less widely accepted scores (e.g. dividual TTR, >75%), but serious bleeding may be lower with
ATRIA), renal impairment. It is also noteworthy that relatively easily NOACs.84 It is uncertain if NOACs can be used in patients with signifi-
obtainable echocardiography-derived parameters have not been in- cant valvular heart disease, or severe renal impairment (including
corporated in the stratification systems, apart from left ventricular those with renal replacement therapy). While small pharmacokinetic
ejection fraction (LVEF), and studies on the additive value of different studies are ongoing, large outcome randomized controlled trials
echo-derived parameters have been small and suboptimally designed (RCTs) are lacking. The pivotal Phase 3 randomized trials excluded
and reports have not been consistent. The impact of valvular patients with creatinine clearance (CrCl) <30 mL/min (25 mL/min for
994d A. Goette et al.

Table 4 Knowledge gaps in anticoagulation and stroke prevention in AF

Knowledge gaps Less than More than Limited knowl- Resolution of gap Upcoming trials in the field
10 case 11 case edge (small trials (in principle) (Clinical Trial.gov)
reports reports or registries, but feasible
no RCT)
...................................................................................................................................................................................................................
LAA occluder vs. NOAC Yes Feasible CLOSURE-AF NCT03463317
LAA occluder in high-risk patients vs. best Registries, single arm Feasible (1) Closure AF (NCT03463317)
medical care and propensity- (2) ASAP TOO (NCT02928497)
matched cohorts (3) A3ICH (NCT03243175)

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(4) SAFE-LAAC (NCT03445949)
(5) Occlusion-AF (NCT03642509)
(6) PRAGUE-17 (NCT02426944)
Combined procedure: AF ablation þ LAA Yes Feasible: larger RCT None
occluder vs. AF ablation only trial needed
LAAO post-procedural antithrombotic Yes RCT comparing None focusing on post-implant
treatment: ASS vs. no treatment vs. NOAC vs. APT vs. treatment
low-dose NOAC? no treatment
Head-to-head comparison of different None Feasible None
LAAO devices/technologies
Optimal therapeutic approach for stroke None Feasible None
prevention in AF dependent on LAA
morphology, LAA blood flow velocity,
and endocardial remodelling
parameters
Assessment of stroke and bleeding risk in Yes Yes Feasible VIALE (NCT02069132)
patients with valvular abnormalities DECISIVE (NCT02982850)
Rivaroxaban compared with vitamin
K antagonist upon development
of cardiovascular calcification
(NCT02066662)
CAPTURE (NCT03488420)
Assessment of stroke and bleeding risk in Yes Yes Feasible Dabigatran in patients with atrial fi-
patients undergoing biological brillation and mitral biological
prosthesis prostheses (NCT03183843)
RIVER (NCT02303795)
Rivaroxaban or aspirin for biological
aortic prosthesis (NCT02974920)
CAREAVR (NCT02626871)
Risk stratification for stroke and the use Yes Yes Feasible Apixaban vs. warfarin for the man-
of OAC in patients with post-operative agement of post-operative atrial
AF fibrillation (NCT02889562)
Can the ‘residual’ stroke risk be better Yes Theoretically feasible None
quantified or reduced and by what
means?

AF, atrial fibrillation; LAA, left atrial appendage; LAAO, left atrial appendage occlusion; NOAC, non-vitamin K antagonist oral anticoagulants; OAC, oral anticoagulants; RCT,
randomized controlled trial.

apixaban).82 Also, whether NOACs can be prospectively started in prospective clinical trials. In addition, new therapeutic options for
the early phase after an ischaemic stroke, or in those patients who had stroke prevention such as factor XI inhibitors (NCT00890812) or
sustained an intracranial haemorrhage (ICH) is not proven. In the tecafarin (NCT00691470) have to be studied in prospective RCTs.
RCTs, NOACs were associated with lower ICH rates compared with
warfarin, but patients with prior ICH were excluded from entering the Left atrial appendage occlusion
trials (Table 4). Furthermore, anticoagulation regimes for different At this point, data are lacking on whether left atrial appendage occlu-
types of atrial flutter or atrial tachycardia are not established by
sion (LAAO) can be compared against NOACs. Current practice is
EHRA White Paper: knowledge gaps in arrhythmia management 994e

Table 5 Knowledge gaps in ablation of AF

Knowledge gaps Less than More than Limited knowledge (small Resolution of gap Upcoming trials in the
10 case 11 case trials or registries, but (in principle) field (Clinical Trial.gov)
reports reports no RCT) feasible
......................................................................................................................................................................................................................
Effect on mortality, bleeding, and stroke Registries, small studies, and Yes CABANA NCT00911508
meta-analysis EAST NCT01288352
Early intervention; timing of ablation Small prospective and observa- Yes EAST NCT01288352
tional clinical trials
Anticoagulation after ablation Retrospective registry data; Yes OCEAN NCT02168829

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small observational studies
Substrate-based ablation intervention Yes DECAAF I; small prospective Yes DECAAF II NCT02529319
studies
Complications; atrio-oesophageal fistula Yes Yes Small observational trials Yes OPERA NCT03246594
AV node ablation and ventricular pacing Yes Retrospective trials, small pro- Yes CAAN-AF
as alternative to PVI in AF subgroups spective trials, meta-analyses, NCT01522898
registries, and observational JAVA-CRT
data NCT02946853

AF, atrial fibrillation; AV, atrioventricular; PVI, pulmonary vein isolation; RCT, randomized controlled trial.

to continue antiplatelet therapy post-LAAO implantation, however, veins (PVI). However, recurrence rate of AF after ablation is high and
this therapy has not been fully established with regard to post-proce- more than 50% of patients treated may not experience freedom
dural stroke prevention. Randomized controlled trials and observa- from AF after a single ablation intervention, particularly in persistent
tional studies suggest that NOACs are superior for stroke AF.86 Despite the introduction of multiple scores prediction of recur-
prevention to aspirin in non-valvular AF patients with additional rence risk is complex and currently not sufficiently possible. In a sub-
CHA2DS2VASc risk parameters, with no difference in major bleeding stantial number of patients AF is promoted by structural changes of
or ICH risk. Ongoing trials (Table 4) will address some of these issues. the atrial myocardium as suggested by magnetic resonance imaging
In addition to the listed larger registries, there are other ongoing (MRI) and/or left atrial voltage mapping.50,87 These areas have been
studies dealing with the effect of LAAO in various conditions or sub- identified as targets for catheter ablation. The pathophysiology un-
groups: (i) Left Atrial Appendage Occlusion vs. New Oral derlying atrial fibrosis, fatty infiltrates,57 amyloidosis, dynamics of dis-
Anticoagulants for Stroke Prevention in Patients With Non-valvular ease progression, and the potential influence of catheter ablation on
Atrial Fibrillation, (ii) Evaluation of WATCHMAN Left Atrial these pathologies are unknown.50
Appendage Occlusion Device in Patients With Atrial Fibrillation vs. Multiple studies/trials (CABANA, CASTLE AF etc.) have shown
Rivaroxaban, (iii) A Pilot Study of Edoxaban in Patients With Non- that catheter ablation when compared with AAD therapy significantly
Valvular Atrial Fibrillation and Left Atrial Appendage Closure, (iv) improves quality of life in patients with symptomatic AF.86
Optimal Antiplatelet Therapy Following Left Atrial Appendage Observational studies and registries suggest a reduced incidence of
Closure (SAFE-LAAC), (v) Safety and Efficacy of Left Atrial stroke and also a lower mortality after catheter ablation.88 However,
Appendage Closure vs. Antithrombotic Therapy in Patients With no randomized study could show an effect on outcomes including
Atrial Fibrillation Undergoing Drug-Eluting Stent Implantation Due to morbidity, cardiovascular mortality, stroke, or total mortality. In a re-
Complex Coronary Artery Disease, (vi) Avoiding Anticoagulation cent large scale randomized clinical trial (CABANA) comparing cath-
After IntraCerebral Haemorrhage (A3ICH), and (vii) eter ablation and drug therapy quality of life was significantly better in
AMPLATZERTM AmuletTM LAA Occluder Trial (Amulet IDE). patients undergoing ablation, while the study primary endpoint (mor-
Nevertheless, some simple issues assessing the interaction of left tality, major bleeding, and stroke) was neutral.89 In AF patients and
atrial appendage (LAA) and stroke are still not evaluated. The impact heart failure with reduced ejection fraction catheter ablation signifi-
of LAA antatomy on LAA thrombogenesis, of endocardial remodel- cantly improved ejection fraction.90 There are no adequately pow-
ling on the outcome after LAAO and of thrombogenic markers on ered trials for the endpoint of mortality. No conclusive data are
LAAO are unclear.85 available on the role of catheter ablation for patients with asymptom-
atic AF or AF and heart failure with preserved ejection fraction.
In addition, the concept of atrioventricular(AV) node ablation with
Catheter/surgical ablation of atrial consecutive right and/or left ventricular pacing deserves further eval-
fibrillation uation. Proper indication of AV node ablation, particularly in elderly
Atrial fibrillation catheter ablation has been shown to be an effective patients with AF or in patients who failed multiple PVI procedures, is
rhythm control strategy in patients with paroxysmal and persistent clinically important. The APAF-CRT trial (Atrioventricular Junction
AF. Cornerstone of treatment is durable isolation of the pulmonary Ablation and Biventricular Pacing for Atrial Fibrillation and Heart
994f A. Goette et al.

Failure; NCT 02137187) demonstrated differences in outcomes in The role of surgical ablation needs to be defined as a stand-alone
heart failure patients with AF: Ablation þ CRT was superior to phar- procedure or in combination with other cardiac surgeries. Trials
macological therapy in reducing heart failure and hospitalization and studying this may set the basis to compare PVI by catheter ablation
improving quality of life in elderly patients with permanent AF and and surgical PVI as a stand-alone procedure in subsequent trials.
narrow QRS (Brignole et al.91). Overall, comparative trials evaluating Finally, as for catheter ablation the impact of surgical ablation on hard
potential effects on outcome benefits (heart failure, stroke, cardio- endpoints needs to be clarified. Furthermore, optimal therapy of
vascular mortality, and total mortality) need to be evaluated in dou- patients with failed AF ablation needs to be defined.
ble blind studies including sham controls or in studies enrolling
asymptomatic patients (Table 5). Device therapies in atrial fibrillation
Current guidelines for indications for AF catheter ablation use Whether PM implantation and atrioventricular node (AVN) ablation
ECG-phenotyped groups (paroxysmal AF, persistent AF) for recom- should be done as a single or in staged procedures is not well deter-

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mendations as well as lack of efficacy of AADs.25 Such phenotype- mined. Retrospective series have been published.96–99 The prospective
based grouping does not reflect the complex spectrum of pathophys- Ablate and Pace Trial reported prospective data on patients using both
iology and pathology underlying AF and trials evaluating personalized strategies, but the respective numbers and outcomes are not de-
and pathology-based indications are needed. Experimental and clini- tailed.100 Only few data on simultaneous leadless PM implantation and
cal data support the perspective that patients with higher burden and AVN ablation exists.101,102 Whether AF ablation might be non-inferior
longer history of AF may develop atrial structural remodelling and of- (or even superior) to a ‘pace and ablate’ strategy has only been assessed
ten evolve to forms of AF with worse response to drugs and abla- in very small retrospective settings.103–106 Furthermore, little evidence
tion.86 It is unclear whether early intervention using catheter ablation exists as to which device (model, vendor etc.) and which functionality
is beneficial and stops and prevents the progression to therapy-resis- (sensor,107–110 programming features algorithms,111,112 diagnostic pos-
tant substrates. Clinical trials investigating the role of AF ablation tim- sibilities,113,114 etc.) works best in AF patients, especially using modern
ing are currently under way (e.g. EAST). However, further devices. This may be of importance as a ‘class effect’ of devices is
longitudinal follow-up studies with advanced imaging technologies unclear and in fact unlikely to be the case, both regarding quality of life
such as MRI are needed. Moreover, structured trials evaluating indica- and, possible, hard clinical endpoints.115
tions for re-ablation after AF-recurrence also comparing different His-bundle pacing (HBP) is being increasingly adopted as an alter-
treatment strategies are warranted. native to right or biventricular pacing. Little is known if HBP is supe-
Pulmonary vein isolation is the present cornerstone of AF abla- rior in terms of clinical outcome. A randomized trial with His/paraHis
tion.86 Different technologies [point-by-point radiofrequency (RF) pacing in 16 patients has been published.116 Furthermore, AVN abla-
ablation, cryo-ablation, and other balloon-based ablation technolo- tion in this setting may be challenging due to the proximity of the ab-
gies] have been reported to achieve this goal. In patients with parox- lation target site and the pacing lead. The largest series includes 42117
ysmal AF no differences in arrhythmia recurrence after ablation have and 37 patients.118 An early case series,119 and a case report,120 have
been found between point-by-point RF ablation and cryo-balloon ab- been published.
lation.92 However, generally accepted data are not available for non- Sudden death due to ventricular arrhythmias shortly following
paroxysmal AF. AVN ablation has prompted pacing at a higher baseline rate (90
Multiple studies have evaluated the role of extra-PV ablation strat- b.p.m.) for the first weeks, to mitigate repolarization abnormalities as-
egies especially in patients with non-paroxysmal AF (linear lines, abla- sociated with a sudden drop in heart rate. There are only two non-
tion of complex fractionated electrograms, low-voltage area ablation, randomized studies (with 255 and 69 patients) supporting this
LAAO isolation, debulking of the posterior wall). Most strategies strategy.121,122
failed to prove benefits in the frame of prospective randomized tri- The mode of delivery of anti-tachycardia pacing (ATP) at the atrial
als.93 This may be at least partially due to lack of definition for and sys- level showed an evolution in recent years (resulting in so called ‘reac-
tematic application of solid ablation endpoints. tive ATP’),123–131 so that delivery of atrial ATP during more regular
Various novel software and hardware tools have been introduced atrial tachyarrhythmias may result in arrhythmia termination and pre-
to improve ablation safety and outcome. While observational data in- vention of its evolution to a persistent/permanent form.128–133 While
dicate benefits of such innovations randomized trials failed to show reactive atrial ATP has been validated in patients with bradyarrhyth-
such benefits.94 mias with a randomized clinical trial (MINERVA trial),128–133 there is
The use of anticoagulation before and during the ablation proce- lack of controlled evaluation in patients with a dual-chamber implant-
dure is supported by various clinical trials and presently well stan- able cardioverter-defibrillator (ICD) or with cardiac resynchroniza-
dardized and established.95 Less is known about the need for and tion therapy (CRT) devices (Table 6).134,135 Data derived from a large
duration of oral anticoagulation following the procedure. dataset of remote monitoring, analysed through propensity score, ap-
Observational studies indicate reduced risk of stroke after ablation, pear to confirm a clinical benefit, but no RCT is currently planned in
however, such data need validation in randomized trials.88 these settings.136
The mechanism and prevention of some severe complications, ‘Out of the box’ programming of pacemakers, ICDs and CRT devi-
such as atrio-oesophageal fistula, need to be established. In addition, ces can be proposed for an average patient but may not be optimal in
the long-term consequences of radiation and subclinical cerebral specific cases.115 The perspective of a ‘tailored’ use of devices can in-
lesions following AF ablation are poorly understood. Long-term con- clude a specific ‘individual programming’, ‘disease specific’ program-
sequences of subclinical stroke need to be established and compared ming, or a programming according to predefined specific
with cognitive decline at long term in non-ablated AF patients. characteristics. Although some recommendations on device
EHRA White Paper: knowledge gaps in arrhythmia management 994g

Table 6 Knowledge gaps in AF device therapy

Knowledge gaps Less than More than Limited knowledge (small Resolution of gap Upcoming trials in
10 case 11 case trials or registries, but no (in principle) the field (Clinical
reports reports RCT) feasible Trial.gov)
.........................................................................................................................................................................................................................
Timing of AVN ablation and PM Yes Yes None
implantation
His bundle pacing and AVN Yes Yes None
Pacing rate after AVN ablation Yes Yes None
AF ablation vs. ‘Ablate and Pace’ Only PABA-CHF trial with small Yes None

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sample size and no hard
endpoints
Comparison of single-chamber pacemakers Yes Yes Partly
in patients with AF (incl. features, sensor
etc.)
Hard outcome data on atrial ATP out of the Yes Yes AT-PATCH:
setting of sinus node disease NCT03209583
Optimal device programming Yes Yes No acronyms:
NCT03422705
NCT03627585
NCT02964650
NCT03556189
NCT03338374

AF, atrial fibrillation; AVN, atrioventricular node; PM, pacemaker; RCT, randomized controlled trial.

programming have been published,137–140 they are not fully validated been observed, with AF being the most frequent type.153 Finally, iso-
by solid data, collected and validated in randomized trials. Disease- lated cases of AF have been reported in patients with Wegener’s dis-
specific and patient-tailored approaches to device programming need ease and Fabry disease, with resolution of the arrhythmia after
to be more precisely defined and validated in prospective studies,141 treatment of the underlying disease.154,155
as done for detection intervals or detection time in ICDs.142–147 Regarding hereditary arrhythmogenic disorders, the prevalence of
atrial arrhythmias has been shown to be variable.25 In patients youn-
Atrial fibrillation in orphan diseases ger than 50 years with genetically demonstrated long QT syndrome
Frequent comorbidities such as arterial hypertension or diabetes (LQTS) the prevalence of AF is approximately 2%, being significantly
mellitus induce atrial remodelling that favours ectopia and intraatrial higher in men than in women and more frequent in Type 1 than in 2
conduction delays, conditioning the development, and perpetuation and 3.156 Kirchhof et al.157 reported that both prolonged atrial action
of AF.25 Infrequent diseases such as hereditary arrhythmogenic disor- potential and refractory periods in LQTS induce polymorphic atrial
ders148 or infiltrative cardiovascular diseases also can be associated tachycardias that can degenerate into AF. These patients have a rela-
with disorders of atrial rhythm.149 In the case of infiltrative heart dis- tive risk of 18 to present with AF before 50 years of age.156 In short
ease, the accumulation of deposits in the myocyte or in the interstitial QT syndrome (SQTS), AF incidence ranges between 26% and 70%,
space produces an increase in myocardial thickness, with develop- being more frequent in Type 2 SQTS. In these patients, shortening of
ment of ventricular diastolic dysfunction and, subsequently, the ap- the QT leads to a transmural dispersion of the refractory period,
pearance of atrial remodelling.50,149 This is especially true in cardiac which causes atrial re-entry leading to AF.148 In the Brugada syn-
amyloidosis where diverse proteins can give rise to amyloid deposits drome (BrS), spontaneous atrial arrhythmias have been described in
in the heart, with different evolution, diagnosis and treatment accord- 6–38% of patients. The prevalence of latent BrS in patients who un-
ing to the subtype: cardiac amyloidosis due to senile transthyretin dergo pharmacological cardioversion with flecainide is 5.8% in
(ATTRwt) presents with AF in 43–67% of the cases, whereas heredi- patients with AF.158 The increased duration of intraatrial conduction
tary transthyretin (ATTRm) is found in 10%. In these patients, fre- observed in these patients could contribute to the development of
quently a stroke is the first manifestation of the disease.50,150 On the AF.159 Finally, catecholaminergic ventricular tachycardia (VT) has
other hand, recent studies show that AF does not have a negative im- been associated with AF in approximately 40% of cases.25 Atrial
pact on the survival of patients with ATTRwt.151 Other infiltrative arrhythmias in this group of patients can trigger late post-potentials
cardiomyopathies related to the appearance of AF are Danon’s dis- and induce ventricular arrhythmias due to triggered activity,160 and
ease and Emery-Dreifuss cardiomyopathy,87 associated with a high also cause inappropriate discharges in patients with ICD.148
premature thromboembolic risk,152 and sarcoidosis with cardiac in- In conclusion, AF can be the initial manifestation of rare diseases in
volvement, in which up to 32% of supraventricular arrhythmias have the general population, and, in addition to the usual therapeutic arsenal,
994h A. Goette et al.

Table 7 Knowledge gaps in risk prediction of ventricular arrhythmias and SCD

Knowledge gaps Available evidence Feasibility Ongoing trials

of study
......................................................................................................................................................................................................................
Personalized risk prediction The selection of best candidates to ICD therapy is usually Intermediate None
based on the inclusion criteria of main primary preven-
tion trials
Temporal changes of the individual Not definite role for evolution of heart disease, type of High Long-term follow-up in previous
risk for SCD therapy, electrical and anatomical remodelling published trials (MADIT-II, SCD-
HeFT, etc.)

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Use of cardiac MRI in risk Role of LGE for SCD risk High Several observational studies
stratification
Information on large population Data on several ICD registries High Several observational studies
Electrical storm management Information obtained from single-centre registry High None

ICD, implantable cardioverter-defibrillator; LGE, late gadolinium enhancement; MRI, magnetic resonance imaging; SCD, sudden cardiac death.

treatment of the underlying disease could contribute to the resolution main interest would probably be the identification of patients with
of arrhythmia. In hereditary channelopathies, pharmacological treat- low individual risk for SCD that would not need the ICD.
ment of AF is difficult due to proarrhythmic ventricular effects of most (2) A personalized risk prediction for patients with ischaemic or non-
AADs, and therefore, AF ablation is recommended in many patients.161 ischaemic cardiomyopathy and only moderately reduced or pre-
served ejection fraction is also not available. In this field, we do not
Thus, important knowledge gaps remain in this field: (i) Biomarker
know exactly which patients may have a substantial risk for SCD,
panels/imaging modalities to identify or predict the presence of atrial car-
and therefore, require protection with an ICD.
diomyopathy in orphan diseases? (ii) Time course of AF development in
(3) Another conceptual gap is to understand if a certain risk prediction
certain orphan diseases? (iii) Impact of orphan diseases on atrial throm- would remain stable over time. Are there temporal changes of the
bogenesis in the absence of AF? (iv) Different subcohorts of orphan dis- individual risk for SCD depending on age, favourable ventricular re-
ease patients with paroxysmal or persistent AF? (v) Factors leading to verse remodelling, alternative therapies for underlying heart dis-
progression from paroxysmal AF to persistent AF? (vi) Effects of certain ease? Is it necessary to reassess periodically the individual risk?
diseases specific therapies (immunosuppressive drugs, antibody therapy, (4) A systematic use of cardiac MRI in risk stratification of patients with
etc.) on AF? Due to the low prevalence/incidence of the orphan dis- ischaemic or non-ischaemic cardiomyopathy needs a large prospec-
eases, however, several knowledge gaps will never be solved. tive assessment. In particular, can we properly identify and charac-
terize the value of the vulnerable scars? Can we use the degree of
inhomogeneity and physical characteristics of the scar as a marker
for future arrhythmia development? It is known that late gadolinium
Ventricular arrhythmia and enhancement (LGE) is a powerful predictor of ventricular arrhyth-
sudden death mic risk in patients with ventricular dysfunction, irrespective of
Risk prediction ischaemic and non-ischaemic cardiomyopathy aetiology, but the
prognostic power of LGE in patients with mild reduction of ejection
Without any doubt ventricular arrhythmias and sudden death have
fraction needs to be confirmed to improve patient selection for
been one of the fields of major development in cardiology over the
ICD implantation.166
last decades.162–169
(5) We also lack information on large populations, trying to understand
From the knowledge of ventricular arrhythmias and sudden death the true risk for SCD in subpopulations not identified by present
pathophysiology, cardiological community has advanced in the recog- ICD eligibility criteria and not well represented in the main published
nition of patients at risk and also in the management of these patients. trials. Moreover, the best approach to patients who need ICD re-
Basically, we have some tools to recognize large populations at risk, placement, but who may not be at persistent risk of SCD due to im-
and we have some means to treat and prevent sudden death, but we provement in LVEF, should be prospectively evaluated.167,169
are still having a large number of gaps in our knowledge including the (6) Finally, we lack complete information on patients who experienced
impact of the autonomic nervous system. Major gaps in this field in- electrical storms trying to understand the main causes, the underly-
clude (see also Table 7): ing electrical and anatomical substrates, the short- and long-term
effects, and the optimal type of management, etc. The best strategy
(1) A personalized risk prediction for sudden cardiac death (SCD) appears to reduce ICD shock should be individualized to ensure that
fundamental for selection of patients that might receive or might not patients receiving ICD therapy experience the maximal benefit,
receive ICD for primary prevention of SCD. Personalized risk pre- while minimizing the adverse consequences.162–166
diction for patients with ischaemic or non-ischaemic cardiomyopathy
and severe reduction of LVEF (<35%) is lacking, because in clinical A survey at the various European countries could be useful to
practice the selection of best candidates to ICD therapy is usually identify a future and universal strategy of properly selection and
based on the inclusion criteria of main primary prevention trials. The treatment of patients without clear and well defined indication to
EHRA White Paper: knowledge gaps in arrhythmia management 994i

Table 8 Knowledge gaps in pharmacological therapies for VT/SCD

Knowledge gaps Available evidence Feasibility of study Ongoing trials

....................................................................................................................................................................................................................
Role of combination of potassium and sodium channel Observational Moderate None
blockers (amiodarone þ propafenone/flecainid) in
patients with ICD and frequent adequate interventions/
arrhythmic storm
Safety of Class IC in combination with beta-blockers in Observational Feasible None
patients with ICD and frequent adequate interventions/
arrhythmic storm

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Azimilide in patients with ICD and frequent adequate inter- RCT SHIELD, SHIELD-2 Likely None
ventions/arrhythmic storm Underpowered
Use of AAD during resuscitation for refractory VF/VT Underpowered trials Moderate None
Role of ranolazine (inhibitor of late INa) in preveng non- MERLIN-TIMI 36, post hoc Moderate RAID trial (NCT
sustained VT and SCD in patients post-ACS analysis NCT01215253)
Targeted therapy with AAD for treatment of frequent ven- Observational Likely None
tricular ectopy
Targeted AAD therapy for cardiac channelopathies Observational Moderate None
Role of late sodium current blockers (mexiletine, lidocaine) Healthy volunteers Likely None
in preventing TdP by reducing drug-induced QTc
prolongation

AAD, antiarrhythmic drug; ACS, acute coronary syndrome; ICD, implantable cardioverter-defibrillator; SCD, sudden cardiac death; VF, ventricular fibrillation; VT, ventricular
tachycardia.

appropriate therapy, such as ICD implantation, in order to reduce arrhythmia mechanism crucial for the individual patient. It has
the still high burden of SCD.167 been demonstrated experimentally that several such mechanisms
exhibit targetable selective chamber occurrence and/or up-
Pharmacological therapies regulation in various syndromes and posses potentially modifiable
Antiarrhythmic drugs were until the end of the eighties the cor- properties, e.g. atrial-specific Kþ-currents (IKur, TASK-1 I NaL),
nerstone of therapy for ventricular tachyarrhythmias. Their use RyR2, SK channel.171
was based on their efficacy in experimental settings which, how- With the widespread use of ICDs a new clinical scenario
ever, did not demonstrate any clear impact on mortality in clinical emerged: ICD is a palliative therapy and patients continue to have
trials. The armamentarium of arrhythmia therapy was revolution- ventricular arrhythmias frequently cumulated into arrhythmic
ized with the introduction of interventional approaches: catheter storms which trigger ICD discharges. Suppressing their occur-
ablation and ICD. In fact, rapid progress of interventional therapy rence is a very important unmet clinical need. Currently, two
of arrhythmias has been driven also by the demonstration of in- drugs have some promising potential in this indication—ranola-
creased mortality in the CAST trial with Class IC AAD highlighting zine and azimilide. Ranolazine, a late sodium current inhibitor, has
the hitherto underestimated proarrhythmic potential of AAD. shown promising antiarrhythmic potential in post hoc analyses of
The development of Class I and Class III drugs for the treatment of the MERLIN TIMI-36 trial and is currently tested in a RCT
ventricular arrhythmias and prevention of SCD almost completely (RAID—Ranolazine And the Implantable DefibrillaTor). Azimilide
ceased thereafter.167 (an iKr and IKs repolarizing current inhibitor) showed in the pre-
Until present no convincing evidence is available for reducing ar- maturely terminated SHIELD-2 trial promise as a safe and effective
rhythmic mortality by specific AADs (Table 8). The only drug used in drug in reducing all-cause shocks, unplanned hospitalizations, and
patients with high risk of SCD due to malignant ventricular arrhyth- emergency interventions in ICD patients.172
mia is amiodarone. This is mainly due to neutral mortality impact of In spite of the enormous progress of interventional therapy for
amiodarone in patients with heart failure with reduced LVEF in the ventricular arrhythmias it is clear that localized destruction of myo-
SCD-HEFT trial.170 Thus, trials with AAD were not able to reduce cardial tissue achieved by catheter ablation in diseased myocardium is
arrhythmic mortality in neither secondary nor primary preventative largely a palliative therapy. Complete elimination of arrhythmogenic
indication. substrate in diseased hearts is rarely possible. Antiarrhythmic drugs
Most of the currently available AAD affect multiple electro- will be needed in the future to precisely target the arrhythmogenic
physiological targets in various tissues of the heart and are used mechanism on the cellular membrane level in individual patients.
empirically for a wide spectrum of arrhythmias. This is the main Genetic testing allows for identifying such targets and allows for
reason of their adverse proarrhythmic potential. There is an choosing the appropriate drug: therapeutic use of mexiletine in Type
unmet need for highly selective AAD targeting precisely the 3 LQTS is an example. In this condition genetically mediated gain of
994j A. Goette et al.

Table 9 Knowledge gaps in device therapies for VT/SCD

Knowledge gaps Less than 10 More than 11 Limited knowl- Resolution of gap Upcoming trials in
case reports case reports edge (small trials (in principle) the field (Clinical
or registries, but feasible Trial.gov)
no RCT)
....................................................................................................................................................................................................................
Impact of modern medical treatment on One RCT (DANISH Conduction of large EU-CERT-ICD
the utility of ICD therapy trial) RCT feasible but (NCT02064192,
with significant prospective
difficulties observational)

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Device therapies for protection of None Personalized risk pre- PRESERVE-EF
patients with LVEF >35% but high in- diction needed, but (NCT02124018)
dividual risk for SCD in principle feasible SMART-MI
(NCT02594488)
Role of subcutaneous ICD compared Registries RCT already being PRAETORIAN
with the transvenous systems (EFFORTLESS and conducted (NCT01296022)
others)

ICD, implantable cardioverter-defibrillator; LVEF, left ventricular ejection fraction; RCT, randomized controlled trial; SCD, sudden cardiac death; VT, ventricular tachycardia.

function of the slow Na current prolongs of action potential and QT reduced LVEF, they are much more numerous as a result of modern
interval. This can be counteracted by inhibiting the delayed Na cur- successful therapy for heart failure. Therefore, in absolute terms the
rent by several AAD, however, the ideal one with ‘pure’ properties majority of SCD cases finally occur in exactly this low-risk population
targeting uniquely this current is still missing. Nevertheless, this ap- that is left unprotected with current treatment strategies.182 Our
proach shows considerable promise for the future of AAD for treat- knowledge regarding personalized risk stratification in these patients
ing ventricular arrhythmias.173 with the aim to identify the high-risk subgroup within this low-risk
group and protect it by ICD implantation is very limited.
A further knowledge gap (Table 9) is the impact of modern medical
Device therapies to prevent ventricular
treatment on the utility of the ICD. Modern optimal heart failure
tachycardia/sudden cardiac death and treatment reduces not only total mortality but also SCD.183,184 The
lead management impact of the advances of the last decades on the need for device
Device therapies have been a major breakthrough in treatment of therapies is completely unknown. Recently, the DANISH trial indi-
ventricular arrhythmias and prevention of SCD.174 The ICD can ef- cated a reduced utility of ICD therapy under modern treatment,185
fectively terminate life-threatening arrhythmias and prevent and these results have already had an effect on clinical practice.186
SCD.170,175 Impaired LVEF with a cut-off mostly set at 35% is a major Technical developments such as the subcutaneous defibrillator187–189
risk factor for SCD in patients with structural heart disease176 and may change benefit and risk of device therapies for prevention of
current European Society of Cardiology (ESC) guidelines recom- SCD compared with transvenous systems. More data are expected
mend ICD implantation for primary prevention of SCD in patients in this field in the near future. Finally, the need for ICD implantation
with ischaemic or non-ischaemic cardiomyopathy and LVEF after catheter ablation of VT, particularly in patients with preserved
<_35%.167 Despite the success and the wide implementation of this or only moderately reduced ejection fraction, is currently unknown.
therapy,177 several knowledge gaps remain or have emerged. As de- There are numerous gaps in evidence in the topic of lead manage-
scribed in the preceding chapters, one major gap is the correct identi- ment, which have recently been outlined in a recent EHRA consensus
fication of patients that are truly at increased risk. Although a document.190 Some of the gaps (see also Table 10) are listed below.
reduced LVEF is a major risk factor, several other factors may influ- (i) Data on extraction tools: It is well accepted that a variety of extrac-
ence the individual risk and have an impact on the need for ICD ther- tion tools is necessary to maximize patient safety as well as proce-
apy such as clinical characteristics,178 fibrosis of the left ventricle as dural success. Comparison of safety and efficacy of the different tools
assessed by modern imaging techniques,179 autonomic dysregula- is problematic, as some devices (e.g. snares) may be used as backup
tion180 etc. Personalized risk stratification guiding ICD implantation is solutions for difficult cases. Nevertheless, multicentre studies are
definitely needed, but currently no established method for such a necessary for acquiring data, especially with the introduction of new
personalized approach exists (Table 9). In addition, the role of a wear- tools for which sparse data exist (e.g. occlusion balloons191). (ii) Risk
able defibrillator is not clearly established. stratification: There are a number of risk factors associated with lead
The need for personalized application of ICD therapy is underlined extraction procedures. Further research may provide scores for risk-
by the fact that the majority of SCD cases occur in patients with only stratification which may help with management strategies. (iii)
moderately reduced or preserved LVEF.181 Although these patients Management of infected leads: Although in case of infected devices a
have a lower SCD risk in relative terms than patients with severely complete removal is recommended, the following points need to be
EHRA White Paper: knowledge gaps in arrhythmia management 994k

Table 10 Knowledge gaps in lead management

Knowledge gaps Less than More than Limited knowledge Resolution of gap (in Upcoming trials in
10 case 11 case (small trials or regis- principle) feasible the field (Clinical
reports reports tries, but no RCT) Trial.gov)
....................................................................................................................................................................................................................
Data on extraction tools Yes Yes RELEASE
(NCT03688412)
Risk stratification for lead extraction Yes Yes None
Management of infected leads Yes Yes None
Management of abandoned leads Yes Yes None
Special patient populations No Yes None

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RCT, randomized controlled trial.

further evaluated: (a) Defining the role of additional diagnostic tools catheter ablation in patients with non-ischaemic cardiomyopathy,
(e.g. positron emission tomography-computed tomography) in which is of particular interest as these patients are often younger
patients with occult infections. (b) Clinical effectiveness of different with more preserved cardiac function and less comorbidity. In addi-
antibiotic therapies and their cost-effectiveness. (c) Determine the tion, although two small randomized trials (Smash VT, VTACH) sug-
safety of 1-stage contralateral device replacement compared with gested a potential benefit of ‘prophylactic’ ablation after a first
delayed device replacement as a management scheme in local and episode of VT in selected patients with post-myocardial infarction
systemic infection. (iv) Management of abandoned and recalled leads: VT, the optimal timing of VT ablation remains unknown for the ma-
Abandoned or recalled pacemaker and ICD leads create a challenging jority of the patients. In patients with ischaemic cardiomyopathy,
decision-making process. The main issues are around clearly defining: substrate-based ablation has been demonstrated to be superior to
(a) the risk associated with lead abandonment and (b) whether the limited ablation of the clinically documented stable VT only.198
potential benefit of lead extraction outweighs the risk of the proce- However, the most appropriate substrate-based ablation strategy
dure. There are few data on the lead burden that results in venous ac- remains unknown since the efficacy of different substrate-based abla-
cess issues and superior vena cava syndrome, and consensus tion techniques has never been directly compared. Finally, although
documents192,193 are based on expert opinion as to the numbers of some observational studies have suggested that systematic use of
abandoned leads that justify extraction. For leads under advisory or multipolar mapping catheters and image integration might improve
recall, surveillance and data collection are essential to aid with clinical post-myocardial infarction VT ablation outcome,199,200 data arising
decision making.194 (v) Special patient populations: There exists a from multicentre randomized study confirming these findings is lack-
strong need to generate a scientific basis for future, evidence-based ing. Another gap in evidence in the field of VT ablation is the need for
lead extraction recommendations in special patient populations. ICD implantation in patients with preserved left ventricular systolic
Such special patient populations consist of but are not restricted to function and tolerated monomorphic VT that undergo apparently
paediatric patients, grown-up congenital heart disease (GUCH) successful VT ablation. Currently, the overwhelming majority of
patients. Common to all these special patient populations is the fact these patients undergo ICD implantation even if successfully ablated.
that the numbers of such patients in single institutional series, even in However, there are no data that demonstrate either the necessity or
high-volume centres, are too small to create statistically solid data. the lack of necessity for ICD implantation (see Tables 11–13).
Therefore, it is of utmost importance to perform future studies based
on a data pooling of multiple centres, either in the form of multi-
centre studies or registries.
Heart failure
Pharmacological therapies
Catheter ablation Pharmacological therapy of arrhythmia in the present of heart failure
Catheter ablation is increasingly used for the treatment of recurrent is difficult, since the only currently approved AADs in this clinical indi-
VT in a wide spectrum of patients with structural heart disease of dif- cation is amiodarone. Furthermore, the effect of modern heart failure
ferent aetiologies. In general, VT ablation is considered to be a symp- medication an arrhythmia occurrence is limited. The enclosed table
tomatic therapy with no clear impact on mortality. However, summarizes the current knowledge gaps in the field (Table 14).
information on the indication and timing of the procedure, ablation
techniques and outcomes are mainly derived from post-infarct New monitoring devices/technologies
patients and often extrapolated to the highly heterogeneous non- Pacemakers and defibrillators have various diagnostic capabilities that
ischaemic patient population. Of importance, the currently available offer a promising tool to guide heart failure treatment and to prevent
RCTs comparing the efficacy of VT ablation with ICD implantation adverse clinical events by providing early warning of clinical deteriora-
vs. ICD implantation only and vs. anti-arrhythmic drugs have been tion.201 In addition, remote monitoring has become standard of care
conducted in post-myocardial infarction patients (Smash VT, in the follow-up of such patients, thus improving the ability to contin-
VTACH, Vanish).195–197 There are no data comparing AADs and uously monitor parameters relevant to the course of heart failure.
994l A. Goette et al.

Table 11 Knowledge gaps in catheter ablation in post-MI ventricular tachycardia

Knowledge gaps Available evidence Feasibility of study Ongoing trials

....................................................................................................................................................................................................................
Effect on survival Pooled data from observa- Moderate BERLIN VT (NCT02501005)
tional studies (7, 8) VANISH 2 trial (NCT02830360)
Timing of ablation in patients with ICDs Observational (9) Yes PARTITA trial (NCT01547208)
BERLIN VT (NCT02501005)
VANISH 2 trial (NCT02830360)
Indication for primary endo-epicardial ablation Observational, one RCT (10) Moderate EPILOGUE trial (NCT02358746)
approach

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Comparison between different substrate abla- Moderate None
tion techniques on outcome
Impact of image integration (CT/MRI) on Observational (5) Yes None
outcome
Comparison between multipolar/single tip cath- Small RCT, observational Yes None
eters on outcome, safety, procedural dura- (5, 6)
tion, and costs

CT, computed tomography; ICD, implantable cardioverter-defibrillator; MI, myocardial infarction; MRI, magnetic resonance imaging; RCT, randomized controlled trial.

Table 12 Knowledge gaps in catheter ablation of ventricular tachycardia in DCM

Knowledge gaps Available evidence Feasibility of study Ongoing trials

....................................................................................................................................................................................................................
Comparison between effect of anti-arrhythmic drugs/catheter ablation on outcome None Yes None
Timing of ablation None Yes None
Relevance of underlying aetiology on ablation indication and timing None Moderate None

DCM, dilated cardiomyopathy.

Table 13 Knowledge gaps in catheter ablation of ventricular tachycardia in ARVC

Knowledge gap Available evidence Feasibility of study Ongoing trials

....................................................................................................................................................................................................................
Comparison between primary endo-epicardial ablation approach Observational study Yes None
vs. patient-tailored approach (epicardial after endocardial
failure)

ARVC, arrhythmogenic right ventricular cardiomyopathy.

However, despite considerable research into device based heart fail- into better outcomes (Table 14). A crucial element to achieve this
ure monitoring, only one study using ICD-based multiparameter aim is further progress in the different technological aspects of moni-
monitoring202 has been able to demonstrate an improvement in clini- toring.209–212 It needs to be clarified which sensors or which multi-
cal outcomes, whereas others have provided different results show- parameter combinations of sensors are particularly useful to direct
ing no benefit from remote monitoring. Thus, currently the potential heart failure management. The possibility of a combined use of infor-
of remote monitoring to improve clinical outcome is still debated. In mation from implantable and external sensors needs to be further
addition, monitoring of pulmonary artery pressures using a wireless explored. The technical set-up of remote device monitoring may
sensor203 has been shown to improve clinical outcomes and these have an important impact and it has been suggested that a higher level
two approaches are cited with a Class IIb recommendation in current of connectivity with more frequent data transmission is linked to bet-
heart failure guidelines.204 ter outcomes.213 Solutions including automatic intelligence systems
Therefore, there is a clear clinical need to better understand how may help to facilitate data processing and automatic analysis of large
implantable heart failure monitoring can be improved to translate amounts of diagnostic information. Furthermore, more effective
Table 14 Knowledge gaps in pharmacological therapies in heart failure

Knowledge gaps Less than More than 11 case Limited knowledge (small trials or Resolution of gap (in princi- Upcoming trials in the field (Clinical
10 case reports registries, but no RCT) ple) feasible Trial.gov)
reports
................................................................................................................................................................................................................................................................................................
Effect of digitalis in patients in No RCT on effects of digoxin on morbidity Feasible: to show that digoxin DECISION trial
HF patients suffering from AF and mortality in AF, added to standard reduces repeated HF hospitali- https://www.zonmw.nl/nl/onderzoek-resul
therapy. Destructive meta-analyses have zation and death taten/doelmatigheidsonderzoek/program
incriminated digoxin, whilst prescription mas/project-detail/goed-gebruik-genees
bias and confounding by indication hamper middelen/digoxin-evaluation-in-chronic-
proper evaluation; also clinical impression heart-failure-investigational-study-in-out
and randomized data in SR show reduced patients-in-the-netherlands/
HF hospitalization
Beta-blocker therapy not effec- Post hoc analyses suggest that beta-blockers Feasible: 1st do a mechanistic None
tive in reducing mortality in are not effective in reducing mortality in study to dissect beneficial from
AF and HF AF and HF (individual patient data analysis deleterious effects of BB in AF;
from randomized studies.205 BB may in- 2nd perform RCT
crease BNP in permanent AF.206
EHRA White Paper: knowledge gaps in arrhythmia management

Effects of ARNI on sudden death MRA reduce inci- Predefined analysis of PARADIGM trial: Feasible; post hoc results suggest None
and incidence of AF and dence of AF in Sacubitril’s effect on incidence of AF un- no effect on incidence of AF
whether prevention of AF is HFrEF, however, no known as is potentially related effect on
beneficial effect on mortality survival
(EMPHASIS)
HFpEF and AF: morbidity and Management of AF in HFpEF uncertain since To show that a comprehensive None
mortality multiple mechanisms play a role mechanism driven treatment
Separate effects of drugs (MRA, drugs acting improves survival and
on actin-myosin binding), AF ablation, morbidity
and rehabilitation are unknown
HFpEF and persistent AF, role of Yes Difficult to separate HF from AF symptoms None
diagnostic cardioversion in in HFpEF complicated by AF or vice versa
work-up towards chronic
rhythm control is uncertain
SCD is suggested as the most Yes Limited data from HFPEF studies IPRESERVE, To show mechanisms of sudden VIP-HF (NCT01989299)
common mode of death in CHARM-Preserved, and TIME-CHF: most demise (arrhythmic, non-ar-
HFPEF. An ILR may reveal in- deaths in HFPEF are cardiovascular death rhythmic) and identify treat-
cidence of sustained VT and (60–70% of all deaths), sudden cardiac ment schemes including drugs
facilitate ICD implantation death is most common mode of death and ICD
(26–28%), followed by HF death (14–
21%)
Continued
994m

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 994n

Table 14 Continued

Knowledge gaps Less than More than 11 case Limited knowledge (small trials or Resolution of gap (in princi- Upcoming trials in the field (Clinical
10 case reports registries, but no RCT) ple) feasible Trial.gov)
reports
................................................................................................................................................................................................................................................................................................
Reduction of ventricular arrhyth- Preliminary data suggest efficacy of ranola- Ranolazine to reduce VAs in peo- RAID study (NCT01215253)
mias in HF/ICD patients using zine. It may have antiarrhythmic and antii- ple with ICD on top of stan-
late sodium channel blockade schemic effects dard therapy
(ranolazine)
Is digoxin beneficial in acute Observational data on Management of AHF syndromes is challeng- Feasible: short-term digoxin may DIG-START-AHF (NCT02544815)
management of acute decom- nitroprusside, ing and most previous drugs failed to de- appear beneficial
pensated heart failure dobutamine, and crease post-discharge mortality and
(ADHF) diuretics readmission rates
Is there a role for sacubitril/val- Effects unknown in patients hospitalized with PIONEER-HF
sartan in acute decompen- ADHF. After PIONEER-HF we have one ClinicalTrials.gov Identifier: NCT02554890
sated HF in patients with large RCT showing reduction HF hospitali- Velazquez et al.207
HFrEF? zation and reduced BNP
Safety and efficacy of istaroxime It will provide mecha- Effects of Istaroxime in ADHF unknown. NCT02617446
in treatment of ADHF? nistic data, no HF/ New drug with lusitropic and inotropic
arrhythmia effects
endpoints
Prospective assessment of pre- Observational data in Frequent PVCs have shown to induce a re- Feasible: to show that AAD PAPS (NCT03228823)
mature ventricular contrac- 10’s of patients versible cardiomyopathy (amiodarone) or VPB ablation CAT-PVC (NCT02924285)
tions suppression in improve CMP
cardiomyopathy
Treatment of inflammatory HF/ ARAMIS is a 120 IL-1b blocker anakinra in acute myocarditis Feasible ARAMIS (NCT03018834)
acute myocarditis using IL-1 patients study
blocker
Treatment of inflammatory HF/ CANTOS Subanalysis (NCT01327846)
CMP using IL-1 blocker Canakinumab reduces HF hospitalizations
Canakinumab among responders (patients who reach
CRP <2); small effect of hospitalization
with highest dose:
Everett et al.208

Continued
A. Goette et al.

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Table 14 Continued

Knowledge gaps Less than More than 11 case Limited knowledge (small trials or Resolution of gap (in princi- Upcoming trials in the field (Clinical
10 case reports registries, but no RCT) ple) feasible Trial.gov)
reports
................................................................................................................................................................................................................................................................................................
Can drugs be withdrawn in re- TRED-HF—this trial was designed to test Shows that withdrawal is associ- TRED-HF: do not withdraw HF drugs in re-
covered DCM? the safety and feasibility of heart failure ated with recurrence of HF covered DCM. Future studies needed to
therapy withdrawal in patients with recov- distinguish patients at risk of recurrence
ered DCM from those who are not; needs detailed
analysis of cause of HF in DCM patients
Low dose NOAC to reduce Low-dose rivaroxaban use in HF significantly COMMANDER-HF (NCT01877915)
stroke in severe HFrEF? reduced the risk for thromboembolic
events in the COMMANDER HF trial
population
................................................................................................................................................................................................................................................................................................
Studies on interventions other than pharmacological, or drugs not directly affecting SCD or arrhythmias
................................................................................................................................................................................................................................................................................................
Stem cell therapy for heart 55 patients in a Phase Feasible TAC-HFT-II (NCT02503280)
failure I/II, Placebo-
EHRA White Paper: knowledge gaps in arrhythmia management

Controlled RCT
Stem cell therapy for heart 66 patients; Feasible REMEDIUM
failure (DCM) Completen 2017 Repetitive intramyocardial CD34þ cell
therapy in dilated cardiomyopathy
(REMEDIUM)
Stem cell therapy for heart 9 patients included; Feasible PROMETHEUS (NCT00587990)
failure completion of study
2011
Anti-diabetic drugs to reduce EMPA-HEART, SGLT2 inhibitors to reduce CV endpoints in- Feasible DECLARE-TIMI-58 (NCT01730534)
HF hospitalization in high-risk ClinicalTrials.gov cluding HF hospitalization in T2DM; pre-
patients Identifier: liminary data from
NCT02998970—
effects of SGLT2 in-
hibitor
Empagliflozin on LV
reversed remodel-
ling (less LVH etc.)
in 97 patients with
T2DM and CVD
Renal sympathetic modifica- Renal denervation decreases sympathetic To show renal sympathetic modi- NCT01402726
tion in patients with heart nerves activity. RD may improve cardiac fication reduces MACCE in HF
failure patients
Continued
994o

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994p A. Goette et al.

clinical response mechanisms to device mediated alerts are needed

AF, atrial fibrillation; ADHF, acute decompensated heart failure (ADHF); BB, beta-blockers; BNP, brain natriuretic peptide; CVD, cardiovascular diseases; DCM, dilated cardiomyopathy; HF, heart failure; HFrEF, heart failure with reduced
ejection fraction; HFpEF, heart failure with preserved ejection fraction; ICD, implantable cardioverter-defibrillator; LV, left ventricular; LVH, left ventricular hypertrophy; MACCE, major adverse cardiac and cerebrovascular events; RCT,
................................................................................................................................................................................................................................................................................................
in order to incorporate the information from monitoring into mean-

Soon to be announced in ClinicalTrials.gov

Upcoming trials in the field (Clinical

ingful action. As the importance of person entered medicine is in-

creasingly recognized, the feasibility of integrating patients into the
information loop of remote monitoring thereby enabling self-
directed treatment adjustments needs to be further explored.214
Subcutaneously implanted loop recorders are today used to monitor
rhythm abnormalities, but this information and other sensors incor-
porated into these devices may also be helpful for the purpose of
heart failure monitoring. Other implantable technology, in particular
Trial.gov)

the use of central pressure sensors needs to be further explored.

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RACE-8

None
Finally, the selection criteria of patient groups most suitable for spe-
cific monitoring approaches need to be established. Given that im-
plantable heart failure monitoring can be further improved by
ablation using robust cryobal-

mortality and morbidity in AF

Resolution of gap (in princi-

To show that effective catheter

research addressing the above issues, the impact on mortality and

loon technology decreases

patients suffering from HF

morbidity needs to be re-established (see Table 15).

Pacing technologies and cardiac

ple) feasible

resynchronization therapy
Cardiac resynchronization therapy has been clinically introduced
more than two decades ago, and its use in the selected population of
Yes

heart failure patients has been well consolidated by the recommenda-

randomized controlled trial; SCD, sudden cardiac death; T2DM, type 2 diabetes mellitus; VA, ventricular arrhythmia; VT, ventricular tachycardia.

tions of different international societies of cardiology.185,215–220 As

ablation may reduce mortality and HF hos-
Data from CASTLE-AF suggest that catheter

CAVE: catheter ablation vs. medical therapy

function and reduce CV events including

AF, NCT02686749) stopped in 2018 for

in congested hearts with AF (CATCH-

shown in Table 16, there are still a significant number of questions

Limited knowledge (small trials or

about the use of CRT in some patient cohorts that have not been sys-
pitalization. Further data needed.

tematically addressed by RCTs. Although the benefit of CRT is depen-

dent upon QRS duration and morphology, there is recent evidence
registries, but no RCT)

that PR interval may play a key role in response to CRT; however,

prospective evidence is missing.221–223 One of the most clinically rele-
lack of enrolment

vant issues is, whether the risk for SCD progressively declines over
time after CRT or whether death due to competing risks may signifi-
arrhythmias

cantly reduce the protective benefit of an ICD particularly in non-

ischaemic cardiomyopathy.185 Of similar clinical relevance is the bene-
fit of CRT in patients with AF, and whether ablation of AV node shall
be systematically performed, has been studied only in (large) regis-
More than 11 case

tries.90,91,144 Multiple prospectively designed registries have shown

that a large proportion of patients is referred to CRT for upgrade
from implantable pulse generator or ICD; outcome of small studies
and registries is inconsistent.216,219,220 In an attempt to improve re-
reports

sponse rate to CRT, endocardial pacing has been proposed as a more

physiological way of resynchronizing the heart.224–227 The initial evi-
dence from a single RCT and small observational studies indicates the
feasibility and symptomatic benefit, which however is counterbalanced
Less than

reports
10 case

by an increased risk of lead failure and thromboembolic events. The

incremental benefit on prognosis and reduction in symptoms of endo-
Yes

cardial pacing over conventional pacing is also unknown.224–227

Additional gaps in knowledge have been identified in the device type
mal medical therapy including

Oncological heart failure and

patients with HFrEF on opti-

selection in patients with conventional indication to pacing (regardless

Table 14 Continued

Effect of AF ablation in

of ejection fraction); indeed, it is unknown whether HBP, or CRT have

an equal benefit in terms of reverse remodelling, survival, device lon-
Knowledge gaps

gevity, and complications (Table 16).228–234

Apart from the missing evidence in the patient populations listed in
Table 16, there is a number of emerging indications to CRT or HBP
MRA

SCD

that may need future consideration including patients who develop a

left bundle branch block or complete atrioventricular block after trans-
cutaneous aortic valve implantation, or patients who have a
EHRA White Paper: knowledge gaps in arrhythmia management 994q

Table 15 Knowledge gaps in monitoring technologies in heart failure

Knowledge gaps Available evidence Feasibility of study Ongoing trials

....................................................................................................................................................................................................................
Need for defibrillator therapy in patients receiving a CRT de- Conflicting observational data, no Moderate RESET-CRT
vice for heart failure data from RCT (NCT03494933)
Predictors of heart failure reversibility by eliminating/reducing Observational, CASTLE-AF? Moderate None
(tachy-) arrhythmia burden
Factors associated with PVC induced LV systolic dysfunction Observational Moderate None
(cardiomyopathy)
Aetiological role of left bundle branch block induced dyssyn- Observational Low None

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chrony in dilated cardiomyopathy
Prediction of RV pacing-induced LV/RV dysfunction and/or Observational Moderate None
AV-valvular regurgitation
Discrimination between arrhythmia induced HF and HF in- Observational Moderate None
duced arrhythmias
Arrhythmia attributable factors in initiation and progression of Observational Low None
heart failure

CRT, cardiac resynchronization therapy; HF, heart failure; LV, left ventricle; PVC, premature ventricular complex; RV, right ventricle; RCT, randomized controlled trial.

Table 16 Knowledge gaps in pacing and CRT therapy in heart failure

Knowledge gaps Less than More Limited; no RCT Resolution gap feasible Upcoming trials in the field
10 case than 11 (clinical trial.gov)
reports case
reports
....................................................................................................................................................................................................................
Device type selection Subanalyses of COMPANION, A properly powered prospec- RESET-ICD (primary prevention;
(CRT-D or CRT- DANISH trials show no significant tively designed RCT is CRT-D vs. CRT-P; DCM and
P) in de novo difference in outcome between missing. Data from ICM); planned, n = 2030 and
patients CRT-D and CRT-P; meta-analysis DANISH trial provides ex- 361 events; tested is non-inferi-
using Bayesian approach shows cellent data for power ority of CRT-P vs. CRT-D (all-
1.5% absolute risk reduction by analysis of a new trial cause mortality). Anticipated
CRT-D vs. ICD or CRT-P endstudy completion date: May
2021 (www.clinicaltrials.gov:
NCT03494933)
Downgrading in CRT Single arm cohort study (DECODE): Needed is a randomized study None
patients without 7% of patients without ICD indica- investigating non-inferiority
past ICD interven- tion had event. A meta-analysis of downgrading from CRT-
tions (from CRT- showed reduced anti-arrhythmic D to CRT-P in patients who
D to CRT-P) therapy in CRT responders and showed good response to
very low absolute arrhythmic risk CRT and need ‘box change’.
in patients who increase their EF Outcome may be combina-
>45% tion of all-cause mortality
and quality of life
Device upgrade from Upgrade to CRT device in patients A prospective RCTs compar- Budapest trial and Cardia-MRI
ICD or IPG to with pacing-induced cardiomyopa- ing upgrade vs. no upgrade upgrade trial (USA)
CRT-P/D thy seems logical and has been in patients with pacing-in-
tested in small randomized trials duced cardiomyopathy
or registries. Large prospective needs to be designed.
RCTs are not available. Change in LVEF may be
Furthermore, there are controver- used as surrogate endpoint
sial recommendations between the of morbidity and mortality
ESC 2013 guidelines for cardiac to avoid a large trial assess-
pacing (Class IB) and the 2016 ESC ing morbidity and mortality
guidelines for the management of
heart failure (Class IIb B)
Continued
994r A. Goette et al.

Table 16 Continued

Knowledge gaps Less than More Limited; no RCT Resolution gap feasible Upcoming trials in the field
10 case than 11 (clinical trial.gov)
reports case
reports
....................................................................................................................................................................................................................
HBP vs. BiV pacing in There are multiple cases reports, and A controlled randomized trial There are several planned or on-
patients with CRT several single centre prospectively comparing CRT vs. His going studies comparing direct
indication designed studies assessing the ben- pacing is needed to assess His-pacing as an alternative to
efit of HBP in patients with CRT the efficacy but also the biventricular pacing in symp-

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indications. One recently published safety and long-term feasi- tomatic HFrEF Patients with
study showed impressive left ven- bility of His pacing when true LBBB. Chronic pacing
tricular reverse remodelling results compared with CRT threshold, narrowing of the
at 3 year follow-up QRS, decrease in LV end-sys-
tolic volume >15%, and re-
duction in hospitalization are
some of the endpoints
Device type selection Only one large randomized trial There are limited data avail- HOPE-HF trial enrolling for
(IPG, CRT-P, or (Block-HF trial) showed a benefit able in this group of brady and CRT
HB pacing) in (composite endpoint including patients
HFrEF patients mortality, heart failure decompen-
with standard indi- sation, or increase in left ventricu-
cation to lar end-systolic volume >15%) of
pacemaker CRT over RVA pacing in patients
with LVEF < 50%. In contrast to
this study, a subanlysis of the
BIOPACE trial did not show a ben-
efit of CRT over RVA pacing in
patients with LVEF <50%
Device type selection The randomized BIOPACE and RCT in patients with Class I
(IPG, CRT-P, or BLOCK-HF trials addressed the indication for pacemaker
HB pacing) in potential benefit of BiV vs. RV pac- implantation for advanced
patients with stan- ing in patients with high degree/ or complete AV block.
dard indication to complete AV block. BIOPACE has Three arms design: stan-
pacemaker never been published; results pre- dard RV, HBP, or BiV pac-
sented at a major international ing. Outcome shall be on
congress contradicted the finding soft and hard endpoints in-
of BLOCK-HF study. Recently, cluding atrial fibrillation
multiple single-centre studies recurrence
reported the feasibility and excel-
lent outcome of HBP in patients
with standard indication to pacing
CRT in patients with CASTLE-AF included a small propor- RCT on treatment strategy—
atrial fibrillation tion of patients with CRT and par- pulmonary vein isolation
oxysmal and persistent AF. Beside first and then CRT-P/CRT-
small observational studies, there D vs. PVI alone. Also RCT
is no evidence for the value of pul- comparing early AV ablation
monary vein isolation performed in CRT patients with perma-
before CRT implantation. The nent atrial fibrillation vs. de-
same holds for systematic use of vice based algorithm for
His-bundle ablation increasing the percentage of
pacing or pharmacological
therapy. Study outcome
shall consider both hard and
soft endpoints

Continued
EHRA White Paper: knowledge gaps in arrhythmia management 994s

Table 16 Continued

Knowledge gaps Less than More Limited; no RCT Resolution gap feasible Upcoming trials in the field
10 case than 11 (clinical trial.gov)
reports case
reports
....................................................................................................................................................................................................................
Endocardial vs. con- Small studies showed the haemody- A prospective study testing
ventional CRT namic benefit of endocardial vs. comparing conventional
conventional epicardial CRT. The biventricular pacing to en-
long-term ALSYNC, WISE-CRT, docardial CRT is highly de-

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and SELECT-LV studies showed sirable. However, technical
good CRT benefits of endocardial issues of each of the alter-
CRT systems, but also complica- native approaches repre-
tions. Finally, a novel pacing ap- sent a major challenge to
proach with pacing the conduct a randomized con-
interventricular septum has been trolled study
proposed
CRT in non-LBBB Substudies in randomized RethinQ Required would be a random-
patients with first (narrow QRS) and MADIT-CRT ized study in patients with
degree AV block (non-LBBB patients) show CRT long PR: no-pace/ICD vs.
and QRS duration benefit in patients with PR >230 CRT-P/CRT-D; endpoints:
120–150 ms ms echo and combined clinical
endpoint

CRT, cardiac resynchronization therapy; DCM, dilated cardiomyopathy; HBP, His-bundle pacing; HFrEF, heart failure with reduced ejection fraction; ICD, implantable cardi-
overter-defibrillator; ICM, ischaemic cardiomyopathy; LBBB, left bundle branch block; LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging; PVI, pulmonary
vein isolation; RCT, randomized controlled trial.

Table 17 Knowledge gaps in assist devices in heart failure

Scientific question Available evidence Feasibility of study Ongoing trials

....................................................................................................................................................................................................................
Benefit from ICD in VAD Meta-analysis Yes None
Benefit of VAD in VT/VF ablation Multicentre observational Yes None
Rhythm vs. rate AF management in VAD Observational Moderate None
VAD to assist cardiac arrest management Observational Likely None
Use of VAD to suppress incessant VA Small observational Likely None
Catheter ablation of VA in VAD patients Observational Likely None

AF, atrial fibrillation; ICD, implantable cardioverter-defibrillator; VAD, ventricular assist device; VF, ventricular fibrillation; VT, ventricular tachycardia.

hypertrophic cardiomyopathy, or presents with functional severe mi- challenging and study patients are difficult to recruit in this setting. As
tral regurgitation. Of future interest is the role of personalized compu- such there is a paucity of good quality data describing the optimal
tational models in prediction of SCD, reverse remodelling (CRT/HBP management strategy associated with the use of these devices.
responder), and heart failure hospitalization. Although all these latter Table 17 summarizes knowledge gaps, based on the importance in
groups of patients or approaches are of interest, we still need more ev- terms of potential cost benefit and feasibility of studies being able to
idence from large prospective single-centre studies before embarking provide clinically useful evidence. There are no data describing when,
on large RCTs. For these reasons, they are not included in Table 16. if and what the role of VAD are in managing refractory sustained ven-
tricular arrhythmia (VA). This is important because it is well recog-
nized that off-loading the failing heart may reduce arrhythmia
Assist devices burden235 and that VA are more common after left ventricular assist
While they are increasing in their use around the world, ventricular as- device (LVAD) implantation (see Table 17). Therefore, it is unclear
sist devices (VAD) remain a relatively rarely deployed therapy in a whether LVAD reduces VA in the longer term or whether patients
complex and sick population. Randomized studies are both ethically with refractory VA who are going to undergo LVAD should have
994t A. Goette et al.

catheter ablation first. At present there is however no evidence that Novartis. G.Y.H.L.: Consultant for Bayer/Janssen, BMS/Pfizer,
LVAD is an appropriate therapy for patients with intractable VA. Medtronic, Boehringer Ingelheim, Novartis, Verseon and Daiichi-
Whether this means that VAD is not a useful therapy for cardiac ar- Sankyo. Speaker for Bayer, BMS/Pfizer, Medtronic, Boehringer
rest victims and in whom it should be deployed is unclear. There are a Ingelheim, and Daiichi-Sankyo. No fees are directly received
few reports of use of circulatory support for ablation of sustained VT personally. Information for authors and reviewers are available in
in vulnerable patients, e.g. GUCH, but there is no evidence describing Supplementary Material online.
its value compared with conventional approaches or how often it is
required.236 Some observational studies suggest that VAD are associ- References
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