European Heart Journal (2014) 35, 3328–3335 CURRENT OPINION

doi:10.1093/eurheartj/ehu352

What is ‘valvular’ atrial fibrillation? A reappraisal

Raffaele De Caterina 1 and A. John Camm 2*
1
Institute of Cardiology and Center of Excellence on Aging, G. D’Annunzio University – Chieti, and G. Monasterio Foundation, Pisa, Italy; and 2Division of Clinical Sciences, St George’s
University of London, London, UK

Received 22 April 2014; revised 18 July 2014; accepted 6 August 2014; online publish-ahead-of-print 29 September 2014

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Introduction Thrombo-embolic risk in various
Despite the same electrophysiological abnormality, the risk of forms of atrial fibrillation
stroke and systemic embolism in atrial fibrillation (AF) ranges
Patients with AF experience a widely variable risk of stroke/systemic
from ,1%/year to .20%/year and can be assessed by simple clin-
embolism. In the absence of anticoagulation thrombo-embolic risk
ical risk factors.1 This has led to the gradual adoption of vitamin K
ranges from ,1%/year—which is similar to the background risk of
antagonist (VKA) oral anticoagulation as a preventive strategy for
the age-matched population—to .20%/year.1
most patients with AF, unless clearly identifiable to be at very-low
Overall, valvular heart disease, independent of the underlying
risk.2,3 The recent availability of non-VKA oral anticoagulants
cardiac rhythm, is associated with a higher risk of thrombo-embolic
(NOACs) is likely to increase the number of AF patients treated
events. This risk is greatly amplified in the presence of AF. A
with these drugs for stroke prevention in the future. In some such
population-based historical cohort study in Olmsted County, Minne-
patients, atrial appendage occlusion devices are now also a viable
sota, with a first echocardiographic diagnosis of mitral stenosis (n ¼
alternative.3
19), mitral regurgitation (n ¼ 528), aortic stenosis (n ¼ 140), and
All the pivotal trials comparing VKAs with the NOACs in AF
aortic regurgitation (n ¼ 106) between 1985 and 1992, found,
have enrolled patients with so-called ‘non-valvular’ AF and
during 2694 person-years of follow-up, that 98 patients developed
excluded patients at particularly high risk of thrombo-embolism,
cerebrovascular events and 356 died. Compared with expected
such as those with AF accompanying mitral stenosis or patients
numbers, these observations are significantly higher, with standar-
with mechanical prosthetic valves.4 The reasons for not including
dized morbidity ratios of 3.2 (95% CI, 2.6 –3.8) and 2.5 (95% CI,
these patients in trials testing NOACs also included the possibility
2.2 –2.7) for a cerebro-vascular event and death, respectively. Con-
that the pathogenesis of thrombo-embolism may be substantially
versely, some types of AF, such as those accompanying rheumatic
different from other types of AF. The distinction between ‘valvular’
mitral stenosis and mechanical prosthetic valves, have always been
AF ‘non-valvular’ AF, however, still remains uncertain, with vari-
known for their high risk of thrombo-embolism.4 For this reason,
able definitions adopted in the NOAC trials. This has led to thera-
moderate/severe mitral stenosis and mechanical prosthetic valves
peutic confusion, well illustrated by a recent web-based survey
have been exclusion criteria in all AF trials with NOACs. There is a
among over 500 Italian physicians mainly involved in the prescrip-
wide uncertainty, however, as to the risk of thrombo-embolism in
tion of anticoagulants to AF patients. Here, only 57.1% of the car-
other forms of valvular disease, and specifically on how different
diologists and 67.9% of the internists agreed that the existing
such risk compares with AF patients without these specific valve
definitions of non-valvular AF (e.g. from Guidelines) were suffi-
problems.
ciently clear.5
Because of this, we have reviewed the literature related to the
thrombo-embolic risk in AF in the presence of the various types of Mitral stenosis
valvular heart diseases; definitions of the term in different trials In the pre-surgery and pre-anticoagulant therapy era, mitral stenosis
with NOACs; and the use of the term in current and recent guide- was estimated to be responsible of 25% of all deaths from systemic
lines. Specifically, we have addressed the risk of thrombo-embolism embolism.6 – 8 Up to 80% of patients with mitral stenosis and systemic
in AF with or without various forms of valvular heart disease; and embolism show AF on the ECG. One-third of embolic events occur
the qualitative type of thrombus forming in such conditions, as within 1 month of the onset of AF, and two-thirds occur within
both have implications for treatment. 1 year.9

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
* Corresponding author. Email: jcamm@sgul.ac.uk
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: journals.permissions@oup.com.
‘Valvular’ atrial fibrillation
Correlation between the occurrence of embolism and mitral
orifice dimensions or even the presence/absence of heart failure
symptoms is not strict,10 and embolism can be the first manifestation
of mitral stenosis,7 or it can occur in patients with mild mitral stenosis,
even before the development of dyspnoea.7,9 It is also controversial
whether patients with mitral stenosis but without AF or a previous
embolic event are at a higher risk for embolic events This has resulted
in low-grade recommendations for oral anticoagulants in recent
guidelines.11 – 13
At the other extreme, patients with mitral stenosis and AF who
have experienced an embolic event have recurrences at a rate of
15–40 events per 100 patient-months,14,15 which is the highest
rate of thrombo-embolism ever reported in AF. There are no rando-
mized trials examining the efficacy of anticoagulation in preventing
embolic events specifically in patients with mitral stenosis, and
current recommendations are only based on retrospective studies
showing a 4- to 15-fold decrease in the incidence of embolic events
with anticoagulation in these patients.16,17
Therefore, mitral stenosis, essentially on a rheumatic basis, is the
form of AF with native valves with the highest risk of thrombo-embolism,
probably related to the low-flow patterns occurring in the left atrium.
Such patients have never been randomized between alternative treat-
ments, but there are no reasons to suggest a differential response to various
anticoagulants.
Mitral regurgitation
Studies on the prevalence of thrombo-embolism in mitral regurgita-
tion have yielded contrasting results, most likely due to the multiple
mechanisms of mitral regurgitation. While some degree of mitral re-
gurgitation almost invariably accompanies rheumatic mitral stenosis,
which itself—when complicated by AF—substantially increases the
risk of thrombo-embolism, results may be very different in non-
rheumatic AF, including non-rheumatic disease of the leaflets [e.g.
mitral valve prolapse (MVP), endocarditis], chordal or papillary
muscle dysfunction, and enlargements of the annulus.
Several studies have reported a lower risk of thrombo-embolism in
mitral regurgitation accompanying mitral stenosis compared with
mitral stenosis without significant regurgitation,18 with higher risk
accompanying milder compared with more severe mitral regurgita-
tions.19 In a retrospective study, the incidence of thrombo-embolism
was significantly higher in the group with no mitral regurgitation.20
Few data are available concerning the effect of mild mitral regurgita-
tion on the occurrence of thrombo-embolic events. The presence
of mild mitral regurgitation in non-rheumatic AF was associated
with a higher prevalence of thrombo-embolic events.21 However,
in patients with non-rheumatic AF, age was an independent predictor
of an increased risk of stroke, and mitral regurgitation was found
to be protective against stroke, especially in patients with LA
enlargement.22
The idea that the occurrence of mitral regurgitation per se does not
entail an increased risk of stroke in AF and may actually be protective,
on the basis of higher flow patterns occurring in the atria, is also sup-
ported by studies on spontaneous echo-contrast on transoesopha-
geal echocardiography, considered to be a manifestation of a
hypercoagulable state due to red cell sludging at low shear rates, as
well as by studies in coagulation markers, such as D-dimer levels
(reviewed in detail in the Supplementary material online).
3329
Mitral valve prolapse
Mitral valve prolapse is a common, sometimes congenital, form of
valve disease occurring in 1–2.5% of the general population.12
Although early evidence from case series and control studies sug-
gested an association with stroke,23 – 29 Gilon et al.,30 and the Fra-
mingham Heart Study31 failed to replicate this.
Mitral valve prolapse may be complicated by AF, as there may be
LA dilatation and left ventricular enlargement depending on the pres-
ence and severity of mitral regurgitation,12 but it is unknown whether
the combination of MVP and AF increases the risk of stroke over and
beyond the risk conferred by AF alone.
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Other valve disease
Despite aortic stenosis, being the most common valvulopathy today,
frequently co-exists with AF, there is no report in the literature refer-
ring to a different risk of thrombo-embolism for AF accompanying
aortic stenosis and AF occurring in the absence of this valvular
heart disease. The same applies to aortic insufficiency.
While the onset of AF in the setting of chronic heart failure
increases both mitral and tricuspid regurgitation,32 there is no evi-
dence in the literature for a specific role of tricuspid insufficiency in
increasing the incidence of thrombo-embolism once AF has
occurred.
Therefore, with the notable exception of mitral stenosis all forms of
valvular heart disease accompanying AF do not appear to increase the
risk of thrombo-embolism beyond the level entailed by AF alone, and
do not apparently act as additional risk factors.
Hypertrophic cardiomyopathy
Although not a type of valvular heart disease, hypertrophic cardiomy-
opathy (HCM) enters in the differential diagnosis of valvular aortic
stenosis, and is sometimes lumped with valvular heart disease in
the setting of AF recommendations regarding anticoagulants. The as-
sociation of HCM with stroke in AF is reviewed in detail in the
Supplementary material online). The reported rate of thrombo-
embolism in HCM is higher than in a non-AF population, but
similar to what should be expected for non-anticoagulated
CHA2DS2-VASc ¼ 2 patients.
In summary, there are no compelling reasons, nor any evidence
from outcome data, to account for the exclusion of these patients
from trials with the NOACs and there is no reason to label them as
‘valvular’.
Prosthetic valves
Mechanical prostheses
Patients with a mechanical heart valve are at increased risk for
thrombo-embolism and require chronic anticoagulation with a
VKA33 even when normal sinus rhythm is present. Thrombo-embolic
risk can be further stratified by patient age, prosthetic valve type,
anatomic valve location and the number of valves, cardiomyopathy,
known intracardiac or prosthetic valve thrombus, and previous
stroke or other cardioembolic event.33 – 35 In addition, AF is a
well-known comorbidity, further enhancing the risk of thrombo-
embolism. There are multiple pathogenetic mechanisms for
thrombosis and thrombo-embolism in patients with a prosthetic
valve (especially a mechanical prosthesis) and AF. Thrombus may
3330
occur on the prosthesis (the ring, the struts, the leaflets), consisting of
an initial layer of platelets and a fibrin mesh; and in the left atrium,
largely in the left atrial appendage, due mostly to flow disturbances
caused by prosthesis, and largely consisting of a fibrin mesh trapping
blood components.62 It is very likely, that these two components are
differently responsive to current antithrombotic drugs, as shown by a
recent comparative trial of dabigatran etexilate and warfarin (see
below).
On average, the risk of thrombo-embolism is estimated to be
4.0%/year with no anticoagulation. Within this group, those with
mitral valve prostheses are at approximately twice the risk compared
with those with aortic valve prostheses.36 Systemic embolization
(predominantly cerebrovascular events) is reduced to a frequency
of 0.7 –1.0% per patient-year in patients with mechanical valves
who are treated with warfarin, and to 2.2% per patient-year with
aspirin.36 – 38
Patients with AF and a mechanical heart valve were systematically
excluded from all pivotal trials with the NOACs, on the assumption
of a need for a specific anticoagulation intensity in such patients and
the absence of experience. There were, however, strong hopes
that NOACs could be a valuable alternative to VKAs even in such
conditions.
On the basis of animal data, a phase II dose-validation study with
dabigatran etexilate was conducted in two populations of patients:
those who had undergone aortic- or mitral-valve replacement
within the past 7 days; and those who had had such a replacement
at least 3 months earlier.39 Patients were randomly assigned in a 2 :
1 ratio to receive either dabigatran or warfarin. The selection of
the initial dabigatran dose (150, 220, or 300 mg twice daily) was
based on kidney function. Doses were adjusted to obtain a trough
plasma level of at least 50 ng/mL. The warfarin dose was adjusted
to obtain an INR of 2 –3 or 2.5 –3.5 on the basis of thrombo-embolic
risk. The primary end-point was the trough plasma level of dabigatran.
Twenty-two and 26 patients had AF in the dabigatran and the warfarin
group, respectively. The trial was terminated prematurely after the
enrolment of 252 patients because of an excess of both thrombo-
embolic and bleeding events among patients in the dabigatran
group. In the as-treated analysis dose adjustment or discontinuation
of dabigatran was required in 52 of 162 patients (32%). Ischaemic or
unspecified stroke occurred in nine patients (5%) in the dabigatran
group and in no patients in the warfarin group; major bleeding
occurred in seven patients (4%) and two patients (2%), respectively.
All the patients with major bleeding had pericardial bleeding.39
Therefore, the use of dabigatran in patients with mechanical heart
valves was associated with increased rates of thrombo-embolic and
bleeding complications when compared with warfarin, showing no
benefit and an excess risk.
Differences in the mechanisms of action of dabigatran and warfarin
are likely to explain at least part of the findings. In patients with a
mechanical heart valve, coagulation activation, and thrombin gener-
ation induced by the release of tissue factor from damaged tissues
during surgery may partly explain the high risk of early thrombo-
embolic complications. In addition, thrombin generation can be trig-
gered by exposure of the blood to the artificial surface of the valve
leaflets, struts, and sewing ring, which induce activation of the
contact pathway of coagulation. It is thought that the sewing ring
becomes less thrombogenic once endothelial tissue has formed
R. De Caterina and A.J. Camm
around it. Vitamin K antagonists are here likely to be more effective
than dabigatran at suppressing coagulation activation because they
inhibit the activation of both tissue factor-induced coagulation (by
inhibiting the synthesis of coagulation factor VII) and contact
pathway-induced coagulation (by inhibiting the synthesis of factor
IX), as well as inhibiting the synthesis of factor X and thrombin in
the common pathway,9 whereas dabigatran exclusively inhibits
thrombin.40 If contact activation is intense, the resulting thrombin
generation may overwhelm local levels of dabigatran, which can
lead to thrombus formation on the surface of the valve and related
embolic complications.
This negative experience with dabigatran etexilate has temporarily
halted the development of other NOACs (FXa inhibitors) for such
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patients.
Therefore, at the present time, patients with AF and a mechanical heart
valve should only be treated with a VKA.
Bioprostheses
Bioprostheses are considered less thrombogenic than mechanical
valves, although the incidence of valve thrombosis in porcine valves
without anticoagulation approaches that of mechanical valves with
anticoagulation.41 Pericardial valves appear less susceptible to valve
thrombosis than porcine valves.41 In both types of bioprostheses,
the risk of valve thrombosis is increased by low cardiac output and
by structural valve deterioration, which creates an irregular, often cal-
cified surface.42,43
Although it is accepted that anticoagulation can be avoided in the
long-term in patients with bioprostheses and no additional risk
factors, controversy remains about antithrombotic management in
the first three post-operative months before superficial healing of
the sewing ring is complete.44 Despite lack of firm evidence and
lack of any long-term studies, current ACC/AHA guidelines recom-
mend only aspirin for patients with both aortic and mitral bioprosth-
eses and no other risk factors.12 In general, however, patients with a
bioprosthesis also having chronic AF and otherwise normal cardiac
function should always receive anticoagulation with a VKA, at a
target INR of 2.5 indefinitely.12,13,45
Transcatheter aortic valve implantation (TAVI), which is basically
the insertion of a bioprosthesis within an expandable stented struc-
ture, has been increasingly used over the past years as an alternative
to surgical aortic valve replacement. The optimal antithrombotic
treatment in this condition is still unknown. Despite the lack of evi-
dence, a combination of low-dose aspirin and a thienopyridine is
used early after TAVI, followed by aspirin or a thienopyridine
alone.13 In patients in AF and receiving a TAVI, a combination of a
VKA and aspirin or a thienopyridine is generally used, but should
be weighed against increased risk of bleeding.13 There are no data
in such patients from trials with the NOACs.
Whether thrombo-embolic risk accompanying bioprosthetic
valve implantation differs from common forms of AF is not ascer-
tained with certainty. Thrombo-embolism in patients with biopros-
thetic valves and AF presumably may relate to both the
bioprosthetic valve and to the AF.46 The incidence of thrombo-
embolism in these patients was reported to be as high as 16% at
31 –36 months,47,48 therefore in the range of 5–6%/year, not signifi-
cantly dissimilar from what found on an average age-matched AF
population with risk factors.
‘Valvular’ atrial fibrillation
Valve repair
Patients who had mitral valve repair have a small risk of thrombo-
embolic events,49 with the highest risk of thrombo-embolism occur-
ring during the first year after surgery, justifying the recommendation
for oral anticoagulation during the 3–6 post-operative months.11
However, only limited data are available concerning the efficacy of
warfarin therapy early after valve surgery, and the use of short-term
warfarin in patients with mitral valve annuloplasty is also controver-
sial.50 Age was the only predictor of thrombo-embolism. Atrial fibril-
lation did not increase the risk of thrombo-embolism by multivariable
analysis, but all patients in AF were on oral anticoagulant.
It is therefore not clear whether patients with a bioprosthetic heart
valve or valve repair and AF are sufficiently different from the purely ‘non-
valvular’ AF population to warrant special treatment or the avoidance of
NOACs.
Variable definitions of ‘valvular
atrial fibrillation’ in recent trials
of thromboprophylaxis in atrial
fibrillation
The issue of ‘valvular AF’ definition is of relevance because several
such patients were excluded from recent trials testing NOACs in
patients with AF. Reasons to exclude them were major uncertainties
on whether thrombogenesis in such patients is similar to that occur-
ring in the more common forms of ‘non-valvular’ AF, and, if that is the
case, what intensity of anticoagulation is needed. Criteria for exclud-
ing such patients were however quite variable (Table 1). For example,
restricting discussion to main phase III studies leading to the registra-
tion of NOACs, in the RE-LY trial testing two doses of dabigatran
etexilate vs warfarin, ‘history of heart valve disorders’ (i.e. prosthetic
valve or hemodynamically relevant valve disease) were exclusion cri-
teria,51,52 resulting in the exclusion, for example, of patients with AF
and severe mitral or aortic insufficiency or severe aortic stenosis.
Conversely, the ROCKET-AF trial, testing rivaroxaban against war-
farin, excluded only hemodynamically significant mitral valve stenosis,
and prosthetic heart valves, but permitted the inclusion of patients
with diseases in native valves other than the mitral valve, as well as
of patients treated with annuloplasty, commisurotomy or other
valvuloplasty’.
In the AVERROES trial, testing apixaban vs warfarin in patients con-
sidered ‘unsuitable’ to VKAs, the exclusion criterion was ‘valvular
disease requiring surgery’.53,54 Here, the ‘unsuitability’ to VKAs de
facto also excluded mechanical prosthetic valve patients. In ARIS-
TOTLE, testing apixaban vs warfarin, the study design55,56 only
excluded ‘clinically significant (moderate or severe) mitral stenosis’,
as well as ‘conditions other than AF that require chronic anticoagula-
tion (e.g. prosthetic mechanical heart valve)’, therefore allowing
inclusion of patients with native valvular heart disease other than
mitral stenosis and prosthetic heart valves.
Finally, in the ENGAGE-AF study, which tested two exposure
strategies of edoxaban vs warfarin, patients with ‘moderate or
severe mitral stenosis, unresected atrial myxoma, or a mechanical
heart valve’ were excluded and subjects with bioprosthetic heart
valves and/or valve repair were allowed.57,58
3331
After the publication of the main trial results,54,56,58 – 60 several
subanalyses are now addressing the fate of patients with some sort
of valvular heart disease included in the trials.
Thus, in a subgroup analysis of RE-LY in patients with symptomatic
heart failure, 1283 patients (26.2%) of the patients with heart failure
and 2661 patients (20.1%) without heart failure had some sort of
‘valvular heart disease’.61 Although overall the relative effects of dabi-
gatran vs warfarin on the occurrence of stroke or systemic embolism
and major bleeding were similar among those with and without heart
failure and those with low or preserved left ventricular ejection frac-
tion, no specific subgroup analysis of patients with ‘valvular heart
disease’ has been reported.
In an analysis of ROCKET AF,62 it has been reported that, of 14 171
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patients, 1992 (14.1%) had ‘significant’ valvular disease, often with
combined lesions (89.6% mitral regurgitation + aortic stenosis or
regurgitation). Combined efficacy end-points in patients (intention-
to-treat population) with and without valvular disease did not
show any significant differences in those treated with warfarin or
rivaroxaban. Bleeding outcomes (safety on-treatment population)
were not different in those without valvular disease, but were
more frequent on rivaroxaban than warfarin in valvular disease
patients (interaction P-value of valvular disease and treatment ¼
0.034 and 0.010 for major or non-major clinically relevant; and
major bleeding, respectively). Intracranial bleeding was significantly
reduced by rivaroxaban in those without valvular disease (HR:
0.59, 95% CI: 0.40– 0.86), and also reduced, albeit not significantly,
in valvular disease patients (interaction P-value ¼ 0.084). Overall,
these data suggest that the effects of warfarin and rivaroxaban on
thrombo-embolic and ischaemic cardiovascular outcomes are
similar among AF patients with and without ‘significant’ valvular
disease, whereas bleeding rates may differ.
Finally, in a subanalysis of ARISTOTLE,63 (A. Avezum et al., sub-
mitted) it has been reported that 4808 (26.4%) of the enrolled
patients had some ‘at least moderate’ heart valve disease, including
mitral or tricuspid insufficiency, and aortic stenosis or insufficiency,
and defined as having (i) a history of at least moderate valvular heart
disease; (ii) baseline echocardiographic evidence of at least moder-
ate valvular heart disease; or (iii) a history of prior valve surgery.
Some 251 patients had had valve surgery (not specified how many
of these were bioprosthetic implants or repair). The results of
this subanalysis were consistent with the results of the overall AR-
ISTOTLE trial (no significant interaction according to the presence
or absence of valvular heart disease for both stroke and systemic
embolism (P ¼ 0.378) and International Society on Thrombosis
and Haemostasis (ISTH) major bleeding (P ¼ 0.228), and demon-
strated that apixaban compared with warfarin reduced stroke or
systemic embolism, caused fewer major bleeding events, and
reduced all-cause mortality in ‘non-valvular AF atrial fibrillation
patients with or without valvular heart disease’.
In summary, although exclusion criteria for concomitant valve
disease varied in pivotal stroke prevention in AF trials with the
NOACs, there is reason to believe that stringent exclusion of most
valvular disease patients implemented in some studies was not justi-
fied by the comparative outcomes of warfarin vs NOACs in trials
where exclusion criteria were more lenient, in admitting patients
with non-rheumatic valvular disease, valve repair, or bioprostheses to
the studies.
 3332
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Table 1 Definitions of non-valvular atrial fibrillation as exclusion criteria in phase II and III trials with the new anticoagulants in atrial fibrillation

Study SPORTIF III SPORTIF V PETRO RE-LY ROCKET AF J-ROCKET AF

acronym/
name
.............................................................................................................................................................................................................................................
67,68 68 69 51,52 60 70
References
Study drug Ximelagatran Ximelagatran Dabigatran Dabigatran etexilate Rivaroxaban Rivaroxaban
etexilate
AF exclusion Mitral stenosis, previous Mitral stenosis, previous Mitral stenosis, History of heart valve disorder Haemodynamically significant mitral valve Haemodynamycally significant
criteria valvular heart surgery, valvular heart surgery, prosthetic (including haemodynamically stenosis, prosthetic heart valve mitral valve stenosis,
active infective active infective valves relevant valve disease and (annuloplasty with or without prosthetic prosthetic heart valve
endocarditis endocarditis prosthetic valve) ring, commisurotomy, valvuloplasty are
permitted)
.............................................................................................................................................................................................................................................
Study AVERROES ARISTOTLE ARISTOTLE-J EDOXABAN PHASE II STUDY ENGAGE AF-TIMI 48 EXPLORE-Xa
acronym/
name
53,54 55,56 71 72 57,58 73
References
Study drug Apisaban Apisaban Apisaban Edosaban Edosaban Betrixaban
AF exclusion Valvular disease Clinically significant Valvular heart Comorbid rheumatic valvular Moderate or severe mitral stenosis, unresected Conditions other than AF that
criteria requiring surgery (moderate or severe) disease disease, history of valvular atrial myxoma, mechanical heart valve required chronic
mitral stenosis surgery, infective endocarditis (bioprosthetic heart valve and valve repair anticoagulation
are permitted)

R. De Caterina and A.J. Camm

‘Valvular’ atrial fibrillation
Guidelines
In addition to the lack of justification reported above, the definitions
of ‘valvular’ and ‘non-valvular’ AF are also different according to dif-
ferent guidelines. The definition of non-valvular AF used by the
current AHA/ACC/HRS AF guidelines is the following: ‘the historical
term ‘nonvalvular AF’ is restricted to cases in which the rhythm dis-
turbance occurs in the absence of rheumatic mitral valve disease, a
prosthetic heart valve, or mitral valve repair’.64,65 The 2008 ACCP
Guidelines contemplate ad hoc recommendations for patients with
valvular heart disease and AF, including mitral stenosis and prosthetic
heart valves.34 No specific definition is given in the 2012 edition of the
same guidelines.46 The 2012 focused update of the ESC Guidelines on
AF3 acknowledges that it is ‘conventional’ to divide AF into cases
which are described as ‘valvular’ or ‘non-valvular’ and that no satisfac-
tory or uniform definition of these terms exists. In those guidelines,
the term ‘valvular AF’ is used to imply that AF is ‘related to rheumatic
valvular disease (predominantly mitral stenosis) or prosthetic heart
valves’.3
Proposal for alternative definitions
and conclusions
The term ‘valvular AF’ and its counterpart of ‘non-valvular AF’ cause
confusion, because they imply internally homogeneous categories
with similar pathogenesis of thrombo-embolism, similar thrombo-
embolic risk, and similar treatment needs. None of these criteria is
fulfilled, and such terms should be therefore either always defined
or abandoned for a more specific terminology.
Literature data indicate that
† the pathogenesis of thrombosis is most likely different for blood
coming into contact with the artificial surface of a mechanical pros-
thetic valve compared with what occurring in most common
forms of AF without concomitant valvular disease. In patients
with a mechanical prosthetic valve, even in the absence of AF,
the results of the only intervention trial so far performed with a
NOAC demonstrate that warfarin is more effective—and also
safer—than the relatively high doses of dabigatran etexilate that
were used;66
† the risk of thrombo-embolism is particularly high in AF accom-
panying moderate-to-severe mitral stenosis and mechanical
prosthetic valves. Since mitral stenosis, with or without other
associated valvular disease, is virtually always rheumatic, the
terms ‘AF with mitral stenosis’ and ‘rheumatic AF’ may be used
interchangeably. It is not clear, however, whether the patho-
genesis of thrombosis in AF accompanying mitral stenosis is
qualitatively different from those of most common forms of
‘non-valvular’ AF. This, together with the notion that—at
variance with most cases of AF in the presence of a mech-
anical heart valve—anticoagulation intensity with VKA can
be kept at the same target INR levels as in ‘non-valvular’ AF,
may justify properly conducted trials of NOACs in such a
condition;
† valvular heart diseases, such as mitral regurgitation, aortic stenosis,
or aortic insufficiency, do not result in conditions of low flow in the
left atrium, and do not apparently increase the risk of thrombo-
3333
embolism compared with that entailed by AF per se, and probably
do not make thrombo-embolic risk less responsive to NOACs
compared with most forms of ‘non-valvular’ AF;
† similarly, hypertrophic cardiomyopathy, even if possibly increasing
the risk of thrombo-embolism in AF, may not make thrombo-
embolic risk less susceptible to NOACs compared with most
forms of ‘non-valvular’ AF (but no data on this are available yet);
† AF in the presence of a bioprosthetic heart valve or after valve
repair appears to be at a risk of thrombo-embolism not substan-
tially different from more common forms of ‘non-valvular’ AF,
and in any case, on the basis of preliminary evidence accrued
from trials with NOACs there is no evidence of different efficacy
or safety compared with warfarin.
Downloaded from https://academic.oup.com/eurheartj/article/35/47/3328/2293144 by guest on 26 July 2021
We propose the term ‘mechanical and rheumatic mitral valvular AF’
(acronym: MARM-AF) as an accurate description of a disease entity
worthy of being kept separated from other forms of AF, but with possible
internal differences between the two conditions here encompassed.
Supplementary material
Supplementary material is available at European Heart Journal online.
Acknowledgements
We thank Dr Luca Sgarra, University of Bari, Italy, for help in
reviewing the pertinent literature; and Dr Claudio Cimminiello
and Dr Hernan Polo Friz for providing preliminary data from an
Italian survey on the cardiologists’ perception of the current
nomenclature.
Conflict of interest: R.D.C. receives consultant and speaker fees
from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi
Sankyo, and Lilly; and research grants from AstraZeneca and Boehrin-
ger Ingelheim. A.J.C. is a consultant/advisor to Daiichi, Bayer, Boeh-
ringer Ingelheim, Bristol Myers Squibb, Pfizer and Boston Scientific.
Research grants are held from Daiichi, Bayer and Pfizer/BMS. No spe-
cific funding was used for this manuscript.
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