Professional Documents
Culture Documents
doi: 10.1111/joim.12468
Content List – Read more articles from the symposium: Atrial fibrillation - from atrial extrasystoles to atrial
cardiomyopathy. What have we learned from basic science and interventional procedures
Abstract. Lip GYH, Potpara T, Boriani G, Blomstr€ om- ‘truly low-risk’ patients with AF, that is those
Lundqvist C (University of Birmingham Institute of patients with a CHA2DS2-VASc [congestive heart
Cardiovascular Sciences, Birmingham, UK; Aalborg failure, hypertension, age ≥75 years (two points),
University, Aalborg, Denmark; University of Belgrade, diabetes mellitus, stroke (two points), vascular
Belgrade, Serbia; University of Bologna, S.Orsola- disease, age 65–74 years, sex category] score of 0
Malpighi University Hospital, Bologna, Italy; Uppsala (male) or 1 (female), who do not need any
University, Uppsala, Sweden). A tailored treatment antithrombotic therapy. Subsequently, patients
strategy: a modern approach for stroke prevention in with ≥1 stroke risk factors can be offered effective
patients with atrial fibrillation. (Review Symposium). stroke prevention, that is oral anticoagulation. The
J Intern Med 2016; 279: 467–476. SAMe-TT2R2 [sex female, age <60 years, medical
history (>2 comorbidities), treatment (interacting
The main priority in atrial fibrillation (AF) manage- drugs), tobacco use (two points), race non-Cauca-
ment is stroke prevention, following which deci- sian (two points)] score can help physicians make
sions about rate or rhythm control are focused on informed decisions on those patients likely to do
the patient, being primarily for management of well on warfarin (SAMe-TT2R2 score 0–2) or those
symptoms. Given that AF is commonly associated who are likely to have a poor time in therapeutic
with various comorbidities, risk factors such as range (SAMe-TT2R2 score >2). A clinically focused
hypertension, heart failure, diabetes mellitus and tailored approach to assessment and stroke pre-
sleep apnoea should be actively looked for and vention in AF with the use of the CHA2DS2VASc,
managed in a holistic approach to AF management. HAS-BLED [hypertension, abnormal renal/liver
The objective of this review is to provide an function (one or two points), stroke, bleeding
overview of modern AF stroke prevention with a history or predisposition, labile international nor-
focus on tailored treatment strategies. Biomarkers malized ratio, elderly (>65 years) drugs/alcohol
and genetic factors have been proposed to help concomitantly (one or two points)] and SAMeTT2R2
identify ‘high-risk’ patients to be targeted for oral scores to evaluate stroke risk, bleeding risk and
anticoagulation, but ultimately their use must be likelihood of successful warfarin therapy, respec-
balanced against that of more simple and practical tively, is discussed.
considerations for everyday use. Current guideli-
nes have directed focus on initial identification of Keywords: atrial fibrillation, bleeding, stroke.
ª 2016 The Association for the Publication of the Journal of Internal Medicine 467
G. Y. H. Lip et al. Review Symposium: Tailored stroke prevention
Here, our objective was to provide an overview of In another community study, conducted by Eng-
modern AF stroke prevention with a focus on dahl et al. [7], all inhabitants in the municipality of
practical, tailored treatment strategies. Halmstad, Sweden aged 75–76 years were invited
to take part in a stepwise screening programme for
AF. As a first step, participants recorded a 12-lead
Rationale for opportunistic screening for AF
electrocardiogram (ECG) and reported their rele-
AF is very common and is present in 3–6% of acute vant medical history. In step 2, those in sinus
medical admissions. Given the missed opportuni- rhythm according to the 12-lead ECG, no history of
ties for stroke prevention, screening for AF has AF and ≥2 risk factors according to CHADS2
been proposed in recent guidelines [1]. [congestive heart failure, hypertension, age
≥75 years, diabetes mellitus, stroke (two points)]
Approximately a third of AF patients are asymp- score were invited to participate in a 2-week
tomatic, and such patients may have a poorer recording period using a hand-held ECG device.
prognosis compared with symptomatic patients [2]. Previously undiagnosed silent AF was found in 1%
Martinez et al. [3] reported the findings of a cohort of 848 individuals who recorded a 12-lead ECG,
study of 5555 patients with incidentally detected and 43% of the 81 patients with known AF were not
ambulatory AF where asymptomatic AF was sig- receiving OAC treatment. Amongst the 403 persons
nificantly associated with a high risk of stroke and with ≥2 risk factors for stroke, 7.4% were diag-
death. Importantly, there was reduction in the risk nosed with paroxysmal AF. Thus, a stepwise risk
of both stroke and death with oral anticoagulants factor-stratified AF screening programme in a
(OACs) but not with antiplatelet treatment. Even in population of 75-year-old individuals yields a large
the historical randomized trials, OACs reduced the proportion of high-risk AF patients eligible for OAC
risk of stroke/systemic embolism by 64% and all- treatment. Broadly similar findings were reported
cause mortality by 26%, compared with controls/ from the STOPSTROKE (Systematic ECG Screening
placebo [4]. for Atrial Fibrillation Among 75 Year Old Subjects
in the Region of Stockholm and Halland, Sweden)
Lowres et al. [5] conducted a systematic review of study [8], where of 7173 elderly participants (age
screening to identify unknown AF and concluded 75–76 years) in a screening programme, 3.0% were
that the prevalence of AF across all included found to have previously unknown AF. A prior
studies was 2.3% [95% confidence interval (CI) diagnosis of AF was found in 9.3%, and the total AF
2.2–2.4%], increasing to 4.4% (95% CI 4.1–4.6%) in prevalence in the screened population was 12.3%.
those aged ≥65 years. This is perhaps unsurprising Overall, 5.1% of the screened elderly population
given the increasing prevalence of AF with increas- had untreated AF [8].
ing age. Of note, the authors found that the overall
incidence of previously unknown AF was 1.0% Other results were reported from the SEARCH-AF
(95% CI 0.89–1.04%), increasing to 1.4% (95% CI study, in which community screening for unknown
1.2–1.6%) in those aged ≥65 years [5]. Of those AF was examined in pharmacies using an iPhone
with previously unknown AF, 67% were at high risk ECG (iECG) and cost-effectiveness was determined
of stroke, perhaps justifying how community AF [9]. In SEARCH-AF, pharmacists performed pulse
screening strategies in older age groups could palpation and iECG recordings in 1000 pharmacy
potentially provide stroke prevention opportunities customers aged ≥65 years (mean 76 7 years;
and reduce the overall health burden associated 44% male), with cardiologist iECG over-reading.
with AF-related stroke. Newly identified AF was reported in 1.5% of the
cohort and all patients had a CHA2DS2-VASc score
In the community setting, opportunistic or system- ≥2. Thus, AF prevalence was 6.7% and the auto-
atic screening for AF was tested in the Screening for mated iECG algorithm showed 98.5% sensitivity
AF in the Elderly (SAFE) trial [6]; the results for AF detection and 91.4% specificity. Such a
showed that opportunistic screening was the more community-based AF screening programme was
cost-effective strategy compared with systematic also found to be cost-effective.
screening. Given that common cardiovascular dis-
orders all contribute to AF and its complications, What about noncommunity settings? Even in
initial focus on screening for AF in such patients patients presenting with an ischaemic stroke, more
with associated comorbid risk factors allows better intense monitoring would allow a higher rate of
opportunity for detecting AF. detection of AF; that is, the harder one looks the
468 ª 2016 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2016, 279; 467–476
G. Y. H. Lip et al. Review Symposium: Tailored stroke prevention
more likely it is that AF will be found. In a high risk (score ≥2) [13]. A categorical approach to
systematic review, Sposato et al. [10] examined stroke risk stratification and treatment decisions
the proportion of patients diagnosed with post- artificially divides patients into low-, moderate-
stroke AF in four different phases: (i) phase 1 and high-risk strata, despite stroke risk being a
(emergency department) consisted of admission continuum. Also, many studies have shown that
ECG; (ii) phase 2 (in hospital) comprised serial high-risk patients were undertreated with warfarin
ECG, continuous inpatient ECG monitoring, con- and that those patients defined as ‘low risk’ using
tinuous inpatient cardiac telemetry and in-hospital the CHADS2 score were not low risk, with a stroke
Holter monitoring; (iii) phase 3 (first ambulatory rate as high as 3.2%/year [14].
period) consisted of ambulatory Holter; and phase
4 (second ambulatory period) consisted of mobile The availability of the non-VKA oral anticoagulants
cardiac outpatient telemetry, external loop record- [(NOACs) previously referred to as new or novel OACs
ing and implantable loop recording. The authors [15]] and the recognition of the need for high-quality
concluded that poststroke AF occurred in 7.7% of anticoagulation control with a VKA [with average time
patients (95% CI 5.0–10.8) in phase 1, 5.1% (3.8– in therapeutic range (TTR) >70% [16]] has changed
6.5) in phase 2, 10.7% (5.6–17.2) in phase 3 and the approach. The NOACs offer many advantages,
16.9% (13.0–21.2) in phase 4. The overall AF but some unanswered questions and gaps in trans-
detection yield after all phases of sequential car- lation to clinical practice remain [17, 18].
diac monitoring was 23.7% (95% CI 17.2–31.0)
[10]. Thus, by sequentially combining cardiac All the major guidelines [European, American and
monitoring methods, AF might be newly detected National Institute for Health and Care Excellence
in nearly a quarter of patients presenting with (NICE)] now recommend use of the CHA2DS2-VASc
stroke or transient ischaemic attack. Accordingly, score for stroke risk stratification [19–21]. The
more stroke recurrences could be prevented in this CHA2DS2-VASc score extends the earlier CHADS2
high-risk population. score by including ‘non-CHADS2’ risk factors such
as age 65–74 years, vascular disease and female
Even in patients considered to have cryptogenic sex [22] (Table 1). The CHA2DS2-VASc score out-
stroke (more recently referred to as ‘embolic stroke performs the CHADS2 score in being able to
of uncertain source’ [11]), mobile cardiac outpa- discriminate ‘low-risk’ patients, who would not
tient telemetry detects AF in a substantial propor- derive any benefit from antithrombotic therapy
tion [12]. In a study by Favilla et al. [12], for [23].
example, age >60 years and radiographic evidence
of prior cortical or cerebellar infarction were good With the use of antithrombotic therapy, bleeding
indicators of occult AF. With improving technology risks as part of tailored therapy and decision-
for detecting AF, the diagnosis of cryptogenic making also have to be considered. Stroke and
stroke may become less easy to justify. bleeding risks track each other, but it would be
important to assess the patient’s potential risk of
bleeding at clinical review and follow-up [24]. The
Are efficacy and safety of anticoagulation improved if tailored to the
HAS-BLED score has been recommended as an
patient’s profile? The role of genes and biomarkers
easy, validated bleeding risk assessment tool [25]
Whilst AF increases the risk of stroke five-fold (Table 1 for definition). The HAS-BLED score has
overall, this risk is not homogeneous and is been shown to be as good as, and possibly better
dependent upon the presence of various stroke than, other bleeding risk scores in predicting
risk factors. In earlier guidelines, the initial focus clinically relevant bleeding events [26, 27]. A high
was to identify patients at high risk of stroke, to be HAS-BLED score is not a reason to withhold OAC
targeted for OAC therapy, given that until recently treatment but to ‘flag up’ patients potentially at
the only OACs available were the vitamin K antag- risk of bleeding for more careful review and follow-
onists [(VKAs) e.g. warfarin]. up and, importantly, to help identify and correct
potentially reversible risk factors for bleeding, such
Risk factors for stroke in AF have been used to as uncontrolled hypertension (the H in HAS-
formulate stroke risk stratification schemes. For BLED), labile international normalized ratios
example, the CHADS2 score was proposed for [(INRs) if a warfarin user; the L in HAS-BLED],
stroke risk assessment, categorizing patients as alcohol excess or concomitant antiplatelet use in
low risk (score = 0), moderate risk (score = 1) and an anticoagulated patient.
ª 2016 The Association for the Publication of the Journal of Internal Medicine 469
Journal of Internal Medicine, 2016, 279; 467–476
G. Y. H. Lip et al. Review Symposium: Tailored stroke prevention
Table 1 Stroke and bleeding risk stratification with the CHA2DS2-VASc and HAS-BLED schemas
BP, blood pressure; LV, left ventricular; MI, myocardial infarction; NSAID, nonsteroidal anti-inflammatory drug; PAD,
pulmonary artery disease; TE, thromboembolism; TIA, transient ischaemic attack; INR, international normalized ratio.
A tailored approach to stroke prevention is shown in AF patients with a single additional stroke risk
in Fig. 1, with the use of the various clinical scores factor [i.e. CHA2DS2-VASc score of 1 (male) or 2
to evaluate stroke risk, bleeding risk and likelihood (female); adjusted hazard ratio 0.59, 95% CI 0.40–
of successful warfarin therapy, respectively [28, 0.86, P = 0.007] [35].
29]. The initial focus is on identification of ‘truly
low-risk’ patients with AF (step 1), that is those A positive net clinical benefit (NCB) of OAC versus
patients who with a CHA2DS2-VASc score of 0 No treatment, or OAC versus aspirin, was clearly
(male) or 1 (female), who do not need any evident in patients with a single stroke risk factor
antithrombotic therapy. Subsequently (step 2), [i.e. CHA2DS2-VASc score of 1 (male) or 2 (female)];
patients with AF and ≥1 stroke risk factors can be by contrast, the NCB of aspirin versus no treat-
offered effective stroke prevention, that is oral ment was neutral/negative, indicating no benefit
anticoagulation. Oral anticoagulation is given of aspirin even with a single stroke risk factor
either as a NOAC or a VKA (e.g. warfarin) with [36, 37].
good anticoagulation control as reflected by a TTR
of >70%. This is the approach used in the Euro- Thus, clinicians would need to ask themselves
pean [19] and NICE [21] guidelines. whether it is worth taking the risk of exposing
patients to fatal and disabling strokes. Impor-
Recently, whether a single risk factor [i.e. tantly, AF patients are also not ‘static’ in relation
CHA2DS2-VASc score of 1 (male) or 2 (female)] to their risk profile, given that the patient popula-
merits oral anticoagulation has been discussed tion is often elderly and having multiple comor-
[30, 31]. The results of a recent Swedish study [32] bidities.
suggested that ischaemic stroke rates in this
category may be too low to warrant anticoagula- Some European healthcare systems also manage
tion, but methodological issues were a concern anticoagulation control with warfarin very well,
given that all patients who were started on OAC and thus, a common question is how can we
therapy at any time were excluded from the study, identify those patients likely to do well on warfarin,
thus ‘conditioning on the future’ and resulting in rather than using a blanket ‘NOAC for everyone’
bias towards artificially lower event rates [30, 31]. policy or a ‘trial of warfarin’ approach which leaves
In addition, the Swedish results are at variance patients with suboptimal anticoagulation control
with other data from Asia and Europe [33, 34] for the initial few months prior to a decision being
showing ischaemic stroke rates of 1.5–2.5%/year taken about whether a NOAC can be prescribed.
with a single stroke risk factor. Indeed, in the Loire The SAMe-TT2R2 score [38] has recently been
Valley AF study it was found that OAC use was introduced to help physicians make informed
independently associated with a better prognosis decisions on those patients likely to do well on
470 ª 2016 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2016, 279; 467–476
G. Y. H. Lip et al. Review Symposium: Tailored stroke prevention
Fig. 1 A tailored approach to assessment and stroke prevention in atrial fibrillation (AF) with the use of the CHA2DS2VASc,
HAS-BLED and SAMeTT2R2 scores to evaluate stroke risk, bleeding risk and likelihood of successful warfarin therapy,
respectively. Non-vitamin K antagonist oral anticoagulants (NOACs) may be considered where the SAMeTT2R2 score
predicts poor control of anticoagulation with warfarin. VKA, vitamin K antagonist; INR, international normalized ratio;
NSAID, nonsteroidal anti-inflammatory drug; OAC, oral anticoagulant; and TTR, time in therapeutic range. Reproduced from
Shields and Lip, with permission [29].
warfarin (SAMe-TT2R2 score 0–2) or those who are patients have a higher risk of intracranial
likely to have a poor TTR (SAMe-TT2R2 score >2) haemorrhage (ICH) and, even on warfarin, have
(Table 2 for definition). The latter group would higher risks of stroke/systemic embolism and
benefit from more intense counselling, education major bleeding, compared with non-Asians with
and follow-up [39] or, preferentially, a NOAC [40, AF; however, Asian patients show impressive
41]. The SAMe-TT2R2 score has been validated in reductions in ICH related to the use of NOACs
multiple independent cohorts [42, 43], and a high [47]. Whilst on warfarin, a poor average TTR
score has been related to labile INRs, and the amongst Asians is common, and may contribute
associated sequelae of thromboembolism, serious to the high event rates. Many reasons for the poor
bleeding and mortality [44, 45]. TTR have been discussed but include the tendency
for physicians to aim towards a lower INR range,
What aspects of the patient profile should be use of herbal medicines and poor compliance.
considered? Numerous patient factors can be con-
sidered. For example, Asian patients with AF Renal function is also an important consideration,
present some additional issues with regard to as illustrated by a recent consensus document
stroke prevention [46, 47]. Specifically, Asian from the European Heart Rhythm Association
ª 2016 The Association for the Publication of the Journal of Internal Medicine 471
Journal of Internal Medicine, 2016, 279; 467–476
G. Y. H. Lip et al. Review Symposium: Tailored stroke prevention
Table 2 The SAMe-TT2R2 score for assisting with decision- should be on the initial identification of low-risk
making for use of oral anticoagulants patients, following which effective stroke preven-
tion can be offered to those with ≥1 additional
Acronym Definitions Points
stroke risk factors.
S Sex (female) 1
A Age (less than 60 years) 1 What about genetic factors? Warfarin metabolism
M Medical historya 1 genotypes have been proposed to overcome the
e interpatient variability in responsiveness and min-
T Treatment (interacting drugs 1 imize the requirement for INR dose adjustment.
Results from randomized trials of genotype-guided
e.g. amiodarone for rhythm control)
warfarin dosing have been disappointing [54, 55]. A
T Tobacco use (within 2 years) 2 substudy of the Effective Anticoagulation With
R Race (non-Caucasian) 2 Factor Xa Next Generation in Atrial Fibrillation
Maximum points 8 (ENGAGE – AF TIMI – 48) trial found that CYP2C9
and VKORC1 genotypes identified patients who
a
Two of the following: hypertension, diabetes mellitus, were more likely to experience early bleeding with
coronary artery disease/myocardial infarction, pul- warfarin and who derived a greater early safety
monary artery disease, cardiac heart failure, previous benefit from edoxaban compared with warfarin for
stroke, pulmonary disease, hepatic or renal disease.
stroke prevention [56].
472 ª 2016 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2016, 279; 467–476
G. Y. H. Lip et al. Review Symposium: Tailored stroke prevention
ª 2016 The Association for the Publication of the Journal of Internal Medicine 473
Journal of Internal Medicine, 2016, 279; 467–476
G. Y. H. Lip et al. Review Symposium: Tailored stroke prevention
A clinically focused tailored approach to assessment 7 Engdahl J, Andersson L, Mirskaya M, Rosenqvist M. Stepwise
and stroke prevention in AF with the use of the screening of atrial fibrillation in a 75-year-old population:
implications for stroke prevention. Circulation 2013; 127:
CHA2DS2VASc, HAS-BLED and SAMeTT2R2 scores
930–7.
to evaluate stroke risk, bleeding risk and likelihood 8 Svennberg E, Engdahl J, Al-Khalili F, Friberg L, Frykman V,
of successful warfarin therapy, respectively, is Rosenqvist M. Mass screening for untreated atrial fibrillation:
advocated. Finally, patient values and preferences the STROKESTOP study. Circulation 2015; 131: 2176–84.
should be considered, as advocated in a recent 9 Lowres N, Neubeck L, Salkeld G et al. Feasibility and cost-
consensus document from the EHRA [66]. Manage- effectiveness of stroke prevention through community screen-
ing for atrial fibrillation using iPhone ECG in pharmacies. The
ment of the patient with AF can only improve.
SEARCH-AF study. Thromb Haemost 2014; 111: 1167–76.
10 Sposato LA, Cipriano LE, Saposnik G, Vargas ER, Riccio PM,
Conflict of interest statement Hachinski V. Diagnosis of atrial fibrillation after stroke and
transient ischaemic attack: a systematic review and meta-
Prof GYH Lip has been a member of various analysis. Lancet Neurol 2015; 14: 377–87.
committees/reviewing bodies for guidelines and 11 Hart RG, Diener HC, Coutts SB et al. Embolic strokes of
position statements from European Society of undetermined source: the case for a new clinical construct.
Lancet Neurol 2014; 13: 429–38.
Cardiology, EHRA, NICE, and others; a member
12 Favilla CG, Ingala E, Jara J et al. Predictors of finding occult
of steering committees for various Phase II and III atrial fibrillation after cryptogenic stroke. Stroke 2015; 46:
studies, and health economics and outcomes 1210–5.
research; an investigator in various clinical trials 13 Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW,
of cardiovascular disease, including antithrom- Radford MJ. Validation of clinical classification schemes for
botic therapies in AF, ACS, lipid disorders, and predicting stroke: results from the National Registry of Atrial
Fibrillation. JAMA 2001; 285: 2864–70.
others; a consultant for Bayer/Jensen J&J, Astel-
14 Olesen JB, Torp-Pedersen C, Hansen ML, Lip GY. The value of
las, Merck, Sanofi, BMS/Pfizer, Biotronik, Medtro- the CHA2DS2-VASc score for refining stroke risk stratifica-
nic, Portola, Boehringer Ingelheim, Microlife and tion in patients with atrial fibrillation with a CHADS2 score 0–
Daiichi-Sankyo; and a speaker for Bayer, BMS/ 1: a nationwide cohort study. Thromb Haemost 2012; 107:
Pfizer, Medtronic, Boehringer Ingelheim, Microlife, 1172–9.
Roche and Daiichi-Sankyo. Prof G Boriani received 15 Husted S, de Caterina R, Andreotti F et al. Non-vitamin K
antagonist oral anticoagulants (NOACs): no longer new or
speaker fees from Boehringer, Boston, Medtronic,
novel. Thromb Haemost 2014; 111: 781–2.
St. Jude. 16 De Caterina R, Husted S, Wallentin L et al. Vitamin K
antagonists in heart disease: current status and perspectives
(Section III). Position paper of the ESC Working Group on
Thrombosis-Task Force on Anticoagulants in Heart Disease.
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61 Nagarakanti R, Ezekowitz MD, Oldgren J et al. Dabigatran UK.
versus warfarin in patients with atrial fibrillation: an analysis (fax: +44 121 5075503; e-mail: g.y.h.lip@bham.ac.uk).
476 ª 2016 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2016, 279; 467–476