Medical treatment of venous thromboembolism (VTE) is undergoing a paradigm shift.[1] Before 2009, vitamin K antagonists (VKAs) such as warfarin were the only widely
available oral anticoagulants (OACs) for the acute and long-term treatment of VTE.
In the decade since, four direct OACs (DOACs) have become the first-line therapy for
many patients with VTE given their efficacy, favourable safety profile and ease of
use.[2] The same can be said for stroke prevention in patients with atrial fibrillation
(AF), where DOACs have also become the first-line therapy.[3]
However, with more therapeutic choices comes the challenge of selecting the best therapy
for each individual patient. For some patients, the choice is easy (e.g. VKA for patients
with mechanical heart valves). However, for many patients, a variety of clinical and
non-clinical factors may influence the decision process. It stands to reason that
predicting the quality of VKA therapy may be useful when selecting between VKA and
DOAC therapy. This is particularly important given the VKAs remain very widely used
globally.
Initially developed in 2013 for warfarin-treated patients with AF, the SAMe-TT2R2
score incorporates many clinical and demographics factors into a risk score for good
or poor warfarin control.[4] Using data from the Atrial Fibrillation Follow-up Investigation of Rhythm Management
trial, the authors who initially developed the SAMe-TT2R2 score described good discriminatory
ability (c-index of 0.70–0.72) for identifying which patients would experience extremely poor
VKA control (time in the therapeutic range [TTR] of 30–35%). However, the discriminatory
ability was less robust (c-index of 0.58) for a more clinically relevant TTR threshold of 50 to 55%. Similar
results were seen in other validation studies of VKA-treated patients with AF ([Table 1]).[5]
[6] Nonetheless, use of the SAME-TT2R2 score has been recommended as a possible guide
for OAC decision-making for patients with AF. Specifically, patients with a score
of > 2 are less likely to achieve a good TTR. Therefore, they are recommended to receive
early review, more frequent international normalized ratio checks and education or
counselling to ensure safe and effective warfarin therapy.[7] Otherwise, these patients can be considered for DOAC therapy instead of warfarin.
Table 1
Performance of the SAME-TTR score in AF and VTE studies
|
Study population
|
Study size
|
Study type
|
Outcome measure
|
c-Index (95% CI)
|
|
Atrial fibrillation (derivation study)[4]
|
1,019
|
Randomized trial
|
TTR < 31%
|
0.72
(0.64–0.79)
|
|
TTR < 50%
|
0.58
(0.53–0.62)
|
|
Atrial fibrillation[5]
|
911
|
Practice-based, observational
|
PINRR ≤70%
|
0.56
(0.52–0.60)
|
|
PINRR ≤60%
|
0.53
(0.49–0.57)
|
|
Atrial fibrillation[6]
|
1,524
|
Practice-based, observational
|
TTR < 65%
|
0.56
(0.53–0.59)
|
|
Venous thromboembolism[8]
|
3,874
|
Randomized trial
|
TTR < 66%
|
0.58
(0.56–0.60)
|
|
Venous thromboembolism[9]
|
1,943
|
Practice-based, observational
|
TTR < 65%
|
0.65[a]
|
|
Venous thromboembolism[10]
|
1,308
|
Practice-based, observational
|
TTR < 65%
|
0.52
(0.48–0.55)
|
Abbreviations: AF, atrial fibrillation; CI, confidence interval; PINRR, per cent of
international normalized ratio results; TTR, time in the therapeutic range; VTE, venous
thromboembolism.
a 95% confidence interval not provided.
The study by Barco et al in this issue of Thrombosis and Haemostasis explores the predictive ability of the SAMe-TT2R2 score for VKA control in patients
with VTE.[8] This is a reasonable question given that many of the SAMe-TT2R2 elements apply to
patients with AF and VTE (e.g. age, gender, race, tobacco use, co-morbidities). In
their analysis of 3,874 patients with VTE treated with warfarin in the control arm
of a randomized clinical trial, those with a low SAMe-TT2R2 score (0–1) represented
a minority of patients in the cohort (24%) and had a lower TTR than patients with
a SAMe-TT2R2 score of ≥ 2 (64.7% vs. 70.7%, p < 0.001). However, they found that low negative (0.59) and positive predictive ability
(0.52) and discriminatory characteristics (c-index 0.58) for a TTR cut-off of 66%. These findings broadly mirror those from prior
validation studies in VTE populations ([Table 1]).[9]
[10] Of note, many risk scores based on clinical factors have c-indexes near or under 0.6.
This is contrast to the practice-based observational study by Kataruka et al of 1,943
patients with newly diagnosed VTE being initiated on warfarin.[8] In that study, patients with higher SAMe-TT2R2 scores had lower mean TTR (57 ± 21%
vs. 50 ± 23% for SAMe-TT2R2 or 0–1 vs. > 3). The discriminatory ability to predict
a TTR of 65% was 0.65, moderately higher than in the Barco et al study. This may reflect
the overall lower quality of warfarin control in the practice-based cohort from Kataruka
et al than the randomized trial cohort reported by Barco et al.
Certain factors may have influenced the utility of the SAMe-TT2R2 score in this analysis
by Barco et al. First, they used a post hoc analysis of the Hokusai-VTE study, where
patients with acute VTE were randomized to warfarin or edoxaban therapy following
a 5- to 10-day parenteral lead in period. Using a highly selected randomized controlled
trial population with specific inclusion and exclusion criteria may introduce selection
bias in favour of patients who are healthier, more compliant with medical therapy
and often have closer health system monitoring than unselected practice-based patients.
Second, anytime a risk score is used in a different population than it was initially
derived (e.g. use in VTE while developed in AF), it may need adaptation to improve
its discriminatory and predictive properties. Perhaps other elements are needed to
predict VKA management quality that may be more specific to the VTE population.
Nevertheless, it is not clear that testing a summative risk score to predict good
versus poor quality VKA therapy is the most useful clinical question. For many patients,
DOAC therapy is the first line when clinically appropriate. However, for others, use
of VKA is preferable due to drug cost, availability or concerns about readily available
reversal agents. For these patients, identifying modifiable characteristics that may
improve the quality of VKA therapy is a worthwhile clinical and research endeavour.
Some of these characteristics are likely to be included in the SAMe-TT2R2 score, such
as tobacco use and concurrent use of medications with drug–drug interactions. However,
other elements of the SAMe-TT2R2 score (e.g. age, race, sex) are not modifiable. And
a direct connection between individual SAMe-TT2R2 score elements and VKA control is
not always apparent. For instance, it follows logically that removing an interacting
drug may improve the quality of VKA therapy. However, it is not clear how much tobacco
use itself influences VKA control or if tobacco use is a marker for some other patient
characteristic that influences VKA control.
Future studies aiming to improve anticoagulation care for patients with VTE are needed,
including:
-
How can risk scores be incorporated into decision aids that promote shared decision
making for patients with AF and/or VTE?
-
Which modifiable clinical factors associate with good/poor VKA therapy? Which of these
factors are specific to patients with AF and VTE?
-
What interventions can be targeted at these modifiable clinical factors and how much
improvement in the quality of VKA therapy can be expected?
-
How can these interventions be bundled and implemented for utilization?
-
Will the effectiveness of these assessments and interventions differ when performed
by nurses, pharmacists or physicians?
Answers to these and other important questions have the potential to greatly impact
care for patients with VTE. In the meantime, clinicians and patients searching for
guidance when selecting OACs in both AF and VTE treatment must look beyond the SAMe-TT2R2
score.
