Download The SAMe-TT2R2 score and quality of anticoagulation in AF: Can

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Invited Editorial Focus
The SAMe-TT2R2 score and quality of anticoagulation in AF:
Can we predict which patient benefits from anticoagulation?
Laurent Fauchier1; Daniela Poli2; Brian Olshansky3
1Service
de Cardiologie, Pôle Coeur Thorax Vasculaire, Centre Hospitalier Universitaire Trousseau et Faculté de Médecine, Université François Rabelais, Tours, France; 2Department of
Heart and Vessels, Thrombosis Centre, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy; 3Division of Cardiology, Cardiac Electrophysiology Mercy Hospital – North Iowa,
Mason City, Iowa, USA
Anticoagulants effectively prevent stroke
and systemic thromboembolism in patients
with atrial fibrillation (AF) when used
properly. In many healthcare systems, vitamin K antagonists (VKA) remain the
most commonly used anticoagulant drugs
(1). For benefits to exceed risks with these
drugs, the international normalised ratio
(INR) must be maintained in a therapeutic
target range of 2.0–3.0, but maintaining
this range remains a challenge. In clinical
practice, the average time in therapeutic
range (TTR) of INRs can be suboptimal (2,
3), and if the TTR is < 65 %, expectation of
benefits from the VKA may be eliminated.
The TTR can be influenced by many patient clinical features, but sometimes guesswork or a ‘trial of warfarin’ was used to see
how the previously anticoagulation-naive
patient does after starting VKA.
In 2013, the SAMe-TT2R2 score (sex female, age < 60 years, medical history [> 2
comorbidities], treatment [interacting
drugs], tobacco use [doubled], race nonCaucasian [doubled]) was proposed to
identify patients likely to have a poor INR
control reflected by an average TTR < 65 %.
This simple score, based on easily measurable clinical features, appeared to identify
AF patients who could maintain a
TTR> 65 % (SAMe-TT2R2 score of 0–2) or
not (SAMe-TT2R2 score > 2) (4). However,
Correspondence to:
Prof. Laurent Fauchier
Service de Cardiologie et Laboratoire
d’Electrophysiologie Cardiaque
Centre Hospitalier Universitaire Trousseau
37044 Tours, France
Tel.: +33 2 47 47 46 50
E-mail: [email protected]
Received: June 26, 2015
Accepted: June 26, 2015
Epub ahead of print: August 6, 2015
http://dx.doi.org/10.1160/TH15-06-0518
Thromb Haemost 2015; 114: 657–659
this score, derived retrospectively from a
trial initiated 20 years ago, may not apply
now. Thus, independent modern ‘real
world’ AF cohorts were needed for validation.
In this issue of the journal, Ruiz-Ortiz et
al. (5) evaluated a nationwide population of
1,056 AF patients prescribed VKAs in 120
outpatient cardiology clinics throughout
Spain. Of those recruited, the mean TTR
was 64 ± 26 % with a progressive decline in
the mean TTR from a SAMe-TT2R2 score
of 0 (68 % ± 25 %) to ≥ 4 (53 ± 29 %). The
score discriminated good anticoagulation
control (TTR ≥ 65 %) with a C-statistic of
0.57 (p< 0.0005). SAMe-TT2R2 score of 0–1
was associated with a TTR ≥ 65 % (sensitivity, specificity, positive and negative predictive values of 64 %, 48 %, 58 % and 54 %, respectively). The odds ratio of having a
TTR< 65 % if the score was ≥ 2 was 1.64.
The Spanish study was meritorious in
measuring the TTR and validating the
main purpose of the SAMe-TT2R2 score,
i. e. identifying patients who will not do
well with VKA (8–10). These data support
the SAMe-TT2R2 score as a viable predictor
of poor (and good) quality of anticoagulation based on the TTR for patients taking
VKAs (6) but issues remain.
changes between consecutive INR
measurements are linear, but interpolation
of values not measured creates gaps in
credibility. There is variability during the
time not measured in practice and there
are other flaws in the calculation as well.
The Percent of Visits in Range looks at
how many visits had INRs in range and divides by the total number of visits. If the
patient had nine visits and six had readings
within their therapeutic range, then the patient is considered in range 66 % of the
time. This usually defines a Percentage of
INRs in therapeutic range (PINRR). The
PINNR is intuitive but is not the most
widely accepted. The TTR and PINNR are
not absolutely interchangeable even if they
correlate.
The percent of visits in range on a given
date, a cross-section method, considers a
specific date; all patients are evaluated on
the last reading to see if they were within
range. The number of patients in range on
their last reading is taken as a percentage of
the total patients on that date. This method
is not relevant for the individual management but is dedicated to evaluation of
populations in a trial or in a registry. It may
also reflect the quality of the global organisation in different healthcare systems.
The TTR methodology – there are
problems
Does the study validate
SAMe-TT2R2 for all?
A strong relationship between quality of
anticoagulation and clinical outcomes has
previously been demonstrated, thus supporting its use as a relevant outcome variable (7, 8). At least three different methods
are identified for quantifying quality of
anticoagulation (9). The TTR, or percent of
days with INRs of 2.0–3.0 used by RuizOrtiz and defined by Rosendaal is not as
simple as it may seem. The TTR is calculated by incorporating INR measurement
frequency and values, assuming that
The SAMe-TT2R2 score, initially built from
a secondary analysis of the AFFIRM trial
included patients with > 12 months of uninterrupted VKA treatment and > 8 INR
values (4). The initial report included additional external validation from a UK hospital using the TTR calculated via the Rosendaal method. Considering subsequent
Editorial Focus on ▶Ruiz-Ortiz et al. Thromb
Haemost 2015; 114: 695-701.
© Schattauer 2015
Thrombosis and Haemostasis 114.4/2015
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Invited Editorial Focus
work, in lieu of these data, the SAMeTT2R2 score appears convincingly validated in highly selected clinical-trial cohorts to real-world populations (4, 10, 12,
16) but does this real-world population
represent long-term anticoagulation in all
clinical practices?
The quality of anticoagulation is the result of a dynamic process with potential for
rapid and long-term variation within the
single patient in relation to compliance,
health status or intercurrent disease. An inherent problem of the SAMe-TT2R2 score
is the assumption that a fixed set of patient
characteristics predicts a lifetime course of
VKA treatment quality. Some contributing
factors (tobacco use and nonwhite race)
may be under- or over-represented depending on a particular setting potentially
limiting generalisability of the score. In the
original report (4), the external validation
cohort had a poor TTR (< 0.64) only for
scores ≥ 6 limiting the usefulness of the
score only to a very select subgroup. It is
known that a determinant of the quality of
anticoagulation is experience in managing
VKA.
Dlott et al. reported that the number of
patients tested per physician practice was
positively associated with TTR (13), reflecting volume-related drug familiarity
and/or better-organised VKA management. The need for an organised management of VKA treatment is one of Best Practices Statement indicated by ACCP Guidelines (2012) (14). Unfortunately, these aspects are not included in the SAMe-TT2R2
score and the effect of a good VKAs management may actually trump individual patient characteristics.
Intrinsically, measures of c-statistic obtained with SAMe-TT2R2 score still remain
relatively low (0.55–0.60) although statistically significant and broadly similar to other
clinical factor based scores (e.g. CHADS2 for
stroke risk stratification in AF). This means
that individual identification of a low TTR
remains problematic and improvement may
be warranted. The addition of alcohol abuse,
low eGFR, diabetes mellitus, heart failure
and history of malignancy, over SAMeTT2R2 may improve the score performance
for prediction of low TTR and were consistently identified in previous reports (6, 15).
However, additional parameters may offer
marginal improvement in predictive ability
at the cost of losing simplicity and everyday
practicality.
Figure 1: Choosing a strategy for oral anticoagulation in patients with non valvular AF using
the SAMe-TT2R2 score. 1Medical history defined as more than two of the following: hypertension, diabetes, coronary artery disease/myocardial infarction, peripheral arterial disease, congestive heart failure,
previous stroke, pulmonary disease, hepatic or renal disease. AF = atrial fibrillation; GFR = glomerular
filtration rate; NOAC = non-VKA oral anticoagulant; VKA = vitamin K antagonists; TTR = time in therapeutic range.
Other limitations of the study
Ruiz-Ortiz et al. (5) report observational
data and several factors of the design could
have led to a selection of a population of
rather well-controlled anticoagulation by
physicians in cardiology departments particularly involved in AF management. The
authors did not collect data about educational level, socioeconomic status and
distance from care providers which may
have an association with the overall quality
of anticoagulation. The authors were not
able to look at what happened to patients
with high SAMe-TT2R2 in terms of clinical
events which may be affected by INR out of
target. It has previously been found that
SAMe-TT2R2 has a good ability to capture
the risk of developing major bleeding,
thromboembolic complications, and/or
death (6, 11). Beyond labile INRs, the
SAMe-TT2R2 score predicts stroke, thromboembolic events, severe bleeding, major
bleeding and death among the patients taking VKAs but not for other patients (11).
What to do if SAMe-TT2R2 predicts
a low TTR
Non-valvular AF patients with high
CHA2DS2VASc scores benefit from doseadjusted VKAs or non-VKA oral anticoagulants (NOAC). The latter can be used
unless contraindicated, particularly when
there are difficulties in keeping the INR
within range with VKA (16, 17). A high
SAMe-TT2R2 score suggests that choosing
a NOAC instead is logical. However, benefits of such a strategy have not been demonstrated and are not yet proposed in current guidelines. A high SAMe-TT2R2 score
may be the marker of a low treatment adherence and/or compliance, which may affect the effectiveness of VKAs or NOACs. It
may also reveal a higher risk of pharmacological interaction, some of which are specific to VKAs, some other are also possible
with NOACs. Whether the SAMe-TT2R2
score identifies patients who would do
worse when treated with a NOAC is currently unknown and should be evaluated
now. Some caution is in order to assume
that a low TTR means that a NOAC will
perform better. Conversely, any error or
wide swings in anticoagulation will not be
Thrombosis and Haemostasis 114.4/2015
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Invited Editorial Focus
seen at all with the NOAC strategy since no
measure of anticoagulation efficacy is possible. This approach may be like sweeping
dirt under a rug where it is not seen.
Next steps
For now, the SAMe-TT2R2 score may help
clinicians to choose a relevant strategy to
anticoagulate patients with non-valvular
AF from medical and economic perspectives even though these outcome measures
have yet to be proven. Many are currently
unenthusiastic to use a NOAC as a firstline strategy for AF patients because of
cost. Also, VKAs may be as effective as
NOACs when the TTR is high (18). Use of
an additional score whose only purpose is
to predict another score makes little sense
unless actionable intervention improves
safety, efficacy, survival or costs for those at
risk, particularly, for those with lower
SAMe-TT2R2 scores. Clinicians may already be beyond score saturation.
However, given the mounting available
evidence, the SAMe-TT2R2 score may
avoid a crude “VKA strategy for everybody” (a ‘trial of warfarin’ advocated by
some physicians and wished by payers) or
“NOAC for everybody unless contraindicated’ (defended by evidence-based medicine but perhaps too expensive). Instead,
the SAMe-TT2R2 score may provide new
insights into how we can decide which approach makes most sense when considering the best strategy to prescribe oral anticoagulation for non-valvular AF patients.
Conflicts of interest
LF has served as a consultant for Bayer,
Boehringer Ingelheim, Medtronic, Novartis and Sanofi Aventis and has been on the
speaker’s bureau for Bayer, BMS/Pfizer,
Boehringer Ingelheim, Boston Scientific
and Daiichi Sankyo. DP: has received funding for conference travel and educational
symposia from Bayer, Boehringer Ingelheim, BMS/Pfizer and Daiichi Sankyo. BO
is a consultant for Medtronic, Boston
Scientific, Amarin, BioControl, Boehringer
Ingelheim, On-X, Biotronik, Daiichi Sankyo and Lundbeck. He has served on
DSMB for Amarin, Boston Scientific and
Sanofi-Aventis. He is the national coordinator for the GLORIA AF trial sponsored
by Boehringer Ingelheim.
This editorial reflects the view of its author(s) and is not representative of the view of
the Editorial Board or the Publishers.
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© Schattauer 2015
Thrombosis and Haemostasis 114.4/2015
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