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Coagulation Testing in Acute Ischemic Stroke Patients Taking Non-Vitamin K
Antagonist Oral Anticoagulants
Jan C. Purrucker, MD; Kirsten Haas, PhD; Timolaos Rizos, MD; Shujah Khan, Sven Poli,
MD; Peter Kraft, MD; Christoph Kleinschnitz, MD; Rainer Dziewas, MD; A. Binder, MD;
Frederick Palm, MD; Sebastian Jander, MD; Hassan Soda, MD; Peter U. Heuschmann, MD;
and Roland Veltkamp, MD, for the RASUNOA investigators
Cover Title: Coagulation tests in ischemic stroke on NOACs
Affiliations:
Departments of Neurology, University Hospitals, Heidelberg (JCP, TR, SK, RV), Tübingen
(SP), Würzburg (PK, CK), Essen (CK), Münster (RD), Kiel (AB), Ludwigshafen (FP),
Duesseldorf (SJ), Bad Neustadt (HS), Institute of Clinical Epidemiology and Biometry,
University Würzburg, Würzburg (KH, PUH), the Comprehensive Heart Failure Center, and
Clinical Trial Center, University Hospital Würzburg, Würzburg (PUH), Germany; and the
Department of Stroke Medicine, Imperial College London, London, United Kingdom (RV).
Correspondence:
Roland Veltkamp, M.D.
Department of Stroke Medicine
Imperial College London
Charing Cross Campus
Fulham Palace Road
London, W6 8RF
United Kingdom
Phone: 44-20-33130133
E-mail: [email protected]
Keywords: anticoagulants, coagulation testing, stroke
Subject terms: ischemic stroke, anticoagulants
Counts: Tables 3 (+ III online suppl.), Figures 2, word-count: 4611
Abstract
Background and Purpose—In patients who present with acute ischemic stroke (AIS) while
on treatment with non-vitamin K antagonist oral anticoagulants (NOACs), coagulation testing
is necessary to confirm the eligibility for thrombolytic therapy. We evaluated the current use
of coagulation testing in routine clinical practice in patients who were on NOAC treatment at
the time of AIS.
Methods—Prospective multi-center observational RASUNOA registry (February 2012 to
2015). Results of locally performed nonspecific (international normalized ratio [INR],
activated partial thromboplastin time [aPTT], thrombin time [TT]) and specific (anti-factor Xa
tests, hemoclot assay) coagulation tests were documented. The implications of test results for
thrombolysis decision-making, were explored.
Results—In the 290 patients enrolled, nonspecific coagulation tests were performed in ≥ 95%
and specific coagulation tests in 26.9% of patients. Normal values of aPTT and INR did not
reliably rule out peak drug levels at the time of the diagnostic tests (false-negative rates 11 to
44% [95% CI, 1–69%]). 12% of patients apparently failed to take the prescribed NOAC prior
to the acute event. Only 5.7% (9/159) of patients in the 4.5 hour time-window received
thrombolysis, and NOAC treatment was documented as main reason for not administering
thrombolysis in 52.7% (79/150) of patients.
Conclusions—NOAC treatment currently poses a significant barrier to thrombolysis in
ischemic stroke. Because nonspecific coagulation test results within normal range have a high
false-negative rate for detection of relevant drug-concentrations, rapid drug-specific tests for
thrombolysis decision-making should be established.
Clinical Trial Registration Information—http://www.clinicaltrials.gov. Unique identifier:
NCT01850797.
Page 3
Introduction
Patients on oral anticoagulation treatment at the time of acute ischemic stroke (AIS) pose a
frequent challenge as thrombolysis is contraindicated in those who are effectively
anticoagulated.1-3 Patients on vitamin K antagonists who present with an International
Normalized Ratio (INR) ≤ 1.7 can be thrombolysed without a significant increase in the risk
of hemorrhagic complications.4, 5 Point-of-care INR testing allows for rapid decision-making
with regards to the decision to proceed with thrombolytic therapy.6 In contrast, the decisions
around thrombolysis treatment in patients on non-vitamin K antagonist oral anticoagulants
(NOAC) are an unresolved issue. Current American Heart Association/American Stroke
Association guidelines recommend that thrombolysis can be administered if there is evidence
that the patient failed to take the anticoagulant, or if there is evidence that excludes significant
anticoagulatory activity as measured by sensitive coagulation tests.7, 8
Drug specific coagulation tests are currently not available at the bedside, but are usually
performed in central laboratories which leads to delays in obtaining the necessary results.
Furthermore, these tests are frequently not available out of hours.9 Calibrated chromogenic
anti Xa assays allow for the quantitative assessment of drug-specific concentrations in the
case of the factor Xa inhibitors rivaroxaban and apixaban.10 For dabigatran, modified versions
of the diluted thrombin time test are available. Mass spectrometry can provide reliable drug
level estimates but are usually unavailable in the emergency setting.11 Importantly, although
guidance for the interpretation of coagulation test results allowing safe thrombolysis in
patients on NOAC treatment have been proposed,12, 13 data supporting their validity is
limited.11, 14 The impact of time-consuming NOAC-specific coagulation testing in acute stroke
management is currently unclear, and the actual use of these tests in clinical practice is
unknown.
We report on the current use of standard and specific coagulation tests in assessing NOAC-
related anticoagulant activity in routine clinical care among acute ischemic stroke patients
Page 4
enrolled into the prospective multi-center Registry of Acute Stroke under New Oral
Anticoagulants (RASUNOA-pilot).
Methods
Study design, setting and patients
RASUNOA was an investigator-initiated, multi-center, prospective, observational cohort
study without commercial funding (ClinicalTrials.gov, NCT01850797). 38 Departments of
Neurology, with certified stroke units across Germany, participated in the registry. Patients
with acute ischemic stroke were prospectively enrolled into the RASUNOA study between
February 2012 and February 2015. The inclusion criteria were age over 18 years old and
current therapy with a NOAC (i.e. apixaban, dabigatran or rivaroxaban) at the time of stroke
onset. Approval was obtained from the ethics committee of the Medical Faculty of
Heidelberg, Germany, as well as from the ethics committees of each participating center.
Data acquisition
Due to the observational nature of the study, all diagnostic and treatment decisions were left
to the discretion of the treating physicians. Participation in RASUNOA had no influence on
local standard operating procedures with regards to the use of specific or nonspecific
coagulation tests. Routine laboratory results of nonspecific coagulation tests (aPTT, ecarin
clotting time [ECT], thrombin time [TT] or INR), drug-specific coagulation tests (anti Factor
Xa- or hemoclot assay), platelet count, and renal function (creatinine, and glomerular
filtration rate [GFR]) obtained at admission, were collected using a pre-specified case report
form. Reference ranges for laboratory values are provided in the expanded methods section in
the online supplement (including dose-specific concentration ranges, supplementary Table I).
Information about medical history, stroke severity and clinical course, as well as the time of
Page 5
stroke onset (or “last seen well” in case of unknown onset), and the time of last drug intake,
were documented.
Decision-making based on coagulation tests
The impact of coagulation test results on the decision to administer thrombolytic treatment to
patients with ischemic stroke on NOAC treatment, was explored by applying two previously
published protocols.12, 13 The exploratory analysis was limited to patients presenting within a
4.5 hour time window.7 The upper ranges of normal values of nonspecific coagulation tests as
well as peak and trough levels of NOACs, are summarized in the online supplementary
methods section. In the protocol by Steiner et al.,12 in the absence of a generally accepted
upper range of normal (URN) of the ECT, we set the URN to 64 s, as this value most closely
correlated with the proposed dabigatran-concentration threshold of 50 ng/ml (data not shown).
We used the 5% percentile of the lowest trough range as the URN for anti-Xa levels of
rivaroxaban (12 ng/ml) and apixaban (34 ng/ml).12, 15, 16 Following the protocol by Kepplinger
et al., we used the INR-threshold of < 1.4 and performed a sensitivity analysis using an INR-
threshold of < 1.2 to account for different thromboplastin reagents with different
sensitivities.13, 17
Statistical analysis
Continuous variables are presented with means and standard deviations (SD). Categorical
variables are presented with medians and interquartile-ranges (IQR), and absolute and relative
frequencies are reported. To assess the correlation between specific and nonspecific
coagulation test values and the performance of specific tests, the Spearman’s non-parametric
correlation is calculated. We calculated test characteristics for the detection of peak range
drug concentration levels for the nonspecific tests aPTT, INR and TT, by cross tabulation of
dichotomized nonspecific tests (tests within normal range vs. elevated tests values) and drug
Page 6
concentrations (below lower peak range level vs. within or above peak range). The false-
negative rate was calculated as 1-sensitivity. All statistical tests were two-sided, and p values
of < 0.05 were considered statistically significant. If not indicated otherwise, analyses were
conducted using IBM SPSS Statistics, version 23.0.0.2 (IBM SPSS, Armonk, NY, USA).
Results
Patient cohort
A total of 290 ischemic stroke patients treated with NOACs at the time of stroke, were
enrolled into the prospective multi-center registry. Baseline characteristics are summarized in
Table 1 (mean age 77.1 [SD 9.2] years, 48.3% women). The majority of patients were mildly
to moderately affected (NIHSS at admission 4 [IQR 1–8]).
Availability and results of routine coagulation testing
Table 2 summarizes the availability of nonspecific and specific coagulation tests. Standard
coagulation parameters such as platelet count, INR and aPTT, were available in almost all
patients. Thrombin time was measured in less than half of patients on dabigatran (44.7%).
On admission, 60.2% of patients anticoagulated with rivaroxaban (100/166), and only 21.3%
of those on apixaban (10/47), had an elevated INR (Fig. 1C,D). Slightly elevated INR levels
were also observed in 56.2% of the 73 patients treated with dabigatran (Fig. 1A,B; online
Supplementary Table II). In contrast, the TT was above the upper limit of normal (> 24 s) in
94% of the dabigatran treated patients but only in 14% of patients taking factor-Xa inhibitors
(Supplementary Table II). As expected, the aPTT was also more frequently prolonged in
dabigatran (65%), compared to rivaroxaban (32%) and apixaban-treated patients (13%;
p < 0.001; Supplementary Table II).
Normal values of the aPTT and INR did not reliably rule out peak drug levels as determined
by calibrated tests (false-negative rates 11 to 44% [95% CI, 1–69%], irrespective of the
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NOAC used (test characteristics are summarized in the online Supplementary Table III).
Figure 1 further illustrates the high false negative rate of the nonspecific parameters, aPTT
and INR (Fig 1. A,C,D), in both factor Xa and direct thrombin inhibitors, and TT in factor Xa
inhibitors, respectively (Fig 1. C,D).
Availability and use of specific coagulation tests
Specific coagulation tests for NOAC treatment were performed in less than half of patients.
Anti-factor-Xa activity tests specific for NOACs were more frequently performed in patients
on rivaroxaban (42.5%) compared to apixaban (17.0%; Table 2). Longer ‘time from symptom
onset to admission’ was associated with a less frequent performance of specific coagulation
testing (Spearman’s rho = -0.146 [95% CI -0.28 – -0.1], p=0.04).
NOAC concentration levels were highly variable at admission (Fig. 2A-C) even when similar
intervals since last intake were compared. In 69 patients with atrial fibrillation taking
approved doses of NOACs for the prevention of ischemic stroke, quantitative NOAC
concentration measurements were available. Of these, 58% had drug levels within the
expected dose-specific trough and peak level ranges. In contrast, 25% had drug levels below
the trough level. Interestingly, 17% experienced a stroke although drug levels exceeded the
peak range. Based on specific coagulation tests, or normal TT in the case of dabigatran, 12 %
(6/50) of patients had apparently failed to take the prescribed NOAC.
Potential eligibility for thrombolysis and anticoagulation testing
In RASUNOA, only nine of all AIS patients presenting in the 4.5 h time window, received
intravenous thrombolysis (9/159, 5.7%). Suspected or proven NOAC treatment was
documented as the main reason for not administering thrombolysis in 52.7% (79/150).
Different models have been proposed to aid thrombolysis decision-making in patients who are
anticoagulated with NOACs. Table 3 summarizes the consequences if the suggested
Page 8
thresholds 12, 13 had been applied for off-label thrombolysis in patients presenting within a
4.5 h time window in RASUNOA. The number of patients theoretically eligible for
intravenous thrombolysis based on coagulation parameters alone, heavily depended on the
decision-protocol. For example, in rivaroxaban treated patients, if the decision to thrombolyse
had been based on normal anti-Xa levels, only 12% of patients would have been eligible for
thrombolysis. In contrast, basing eligibility for thrombolysis on normal aPTT and PT values,
the number of eligible patients (24%) would have doubled. This highlights that the sensitivity
of aPTT and PT/INR for the detection of low or even peak drug concentrations of
rivaroxaban, is low.
Discussion
Our study has yielded five new findings with regards to the use of coagulation testing in acute
ischemic stroke patients treated with NOACs: (1) Standard coagulation tests are not reliable in
predicting actual NOAC drug levels; (2) Specific coagulation tests are performed in less than
half of acute stroke patients in the emergency setting; (3) Ischemic stroke occurs despite
NOAC drug concentrations within the peak range at the time of the stroke; (4) Decision-
making for off-label thrombolysis in NOAC-anticoagulated patients based on currently
proposed protocols yields inconsistent conclusions depending on whether nonspecific or
specific coagulation tests are used; and (5) Treatment with NOACs is currently a barrier for
thrombolysis in acute ischemic stroke.
Although most stroke centers participating in our multi-center study were large and
experienced, drug-specific coagulation testing was performed in less than half of patients.
This is suprising given that our observational data demonstrates that nonspecific coagulation
tests do not provide reliable information on the current anticoagulation status of NOAC-
treated patients. Nonspecific coagulation tests may only be of value if highly sensitive
reagents are used, and locally determined reagent-specific cut-offs are established for each
Page 9
test and each NOAC.11, 18 As a consequence, current available guidance on the use of
nonspecific coagulation tests in the decision-making process for thrombolysis administration
may have to be revised.7, 8
The thrombin-inhibitor dabigatran has different effects on standard coagulation parameters
when compared to factor Xa-inhibitors.19 In our study, the aPTT was more often prolonged in
patients on dabigatran, whereas the INR was elevated in the majority of patients receiving
rivaroxaban or dabigatran, but not in patients taking apixaban. Use of a less sensitive factor
Xa-inhibitor recombinant thromboplastin in some centers, may explain this finding.
Therefore, clinicians should be aware of the thromboplastin time reagent used in their local
laboratory. For example, some reagents are very sensitive to rivaroxaban (e.g. Neoplastin
Plus® or HemosIL RecombiPlasTin 2G®) whereas others barely react (e.g. Innovin®).17
Importantly, a particularly low sensitivity for apixaban is observed with all current reagents
used for prothrombin time testing. Therefore, their use is not recommended with apixaban.10
The occurrence of a stroke in a patient on a NOAC, is frequently attributed to failure of
anticoagulant intake just prior to the stroke (e.g. due to a missed dose).20 This has been of
particular concern for NOACs with once-daily dosing regimens where a single-missed dose
may result in critically low concentrations.21 Notably, results of coagulation tests in our study
suggest that failure to take a NOAC immediately before the stroke may not be associated with
a substantially increased stroke risk. Only 12% of patients with available specific coagulation-
tests had no NOAC-activity. Instead, concentrations a few hours after symptom onset
suggested that drug levels were in the peak range at the time of the stroke or even exceeded
established peak range levels. A potential explanation for this finding might be that the
patients experienced strokes of other etiologies rather than cardio-embolism. Although
hypercoagulable states are rare, we cannot rule out the presence of these conditions in
individual cases.
Page 10
Based on the experience with VKAs, effective anticoagulation with NOACs is a
contraindication to thrombolysis because of a potentially increased risk of symptomatic
intracranial hemorrhage (sICH).1 A recent study aggregating data from several centers found
no increased risk of sICH in patients on NOAC treatment who underwent thrombolysis
compared to patients not on anticoagulation treatment.14 However, drug concentrations were
not available in the majority of patients and the median time interval since last NOAC intake
was 13 hours.
Two protocols have been proposed which incorporate laboratory-based nonspecific and
specific coagulation test results in decision-making for thrombolysis.12, 13 Notably, both
protocols lack prospective validation of their safety. Post-hoc application of these protocols to
our cohort of NOAC-treated acute ischemic stroke patients showed large inter- and intra-
protocol differences. In the model proposed by Steiner et al.12, the number of patients treated
with rivaroxaban deemed eligible for thrombolysis was nearly doubled when only aPTT and
PT were used (n=12/32 vs. n=22/82, Table 3). The number of patients theoretically eligible
for thrombolysis was even higher13 when the INR-based threshold alone, as proposed by
Kepplinger and colleagues, was used (n=42/83; at INR < 1.2). Our data suggests that reliance
on aPTT and INR may result in potentially dangerous under-estimation of the actual
anticoagulatory effect of NOACs. The use of the thrombin time should be limited to patients
taking dabigatran and this can only be used to exclude any dabigatran usage.19 In our series,
patients with low dabigatran concentrations still show a markedly prolonged thrombin time
(Fig. 1).
Pre-existing oral anticoagulation treatment in patients presenting with an acute ischemic
stroke is a challenge for thrombolysis decision-making. However, the current impact of
anticoagulation treatment with NOACs on thrombolysis rates in acute stroke is largely
unknown. In our study, only 6% of patients on NOAC treatment at the time of AIS received
thrombolytic treatment. In 53% of patients, treatment with a NOAC was the reported reason
Page 11
for withholding thrombolysis. This contrasts with a reported thrombolysis rate of 50% to 64%
of ischemic stroke patients presenting within 4.5h after symptom onset in a nation-wide
quality report.22 This discrepancy highlights that NOAC treatment at the time of a stroke
represents a significant barrier for thrombolysis. Establishment and wide spread availability of
drug-specific point-of-care coagulation devices for NOACs, as well as prospective registry
data, may help to refine parameters allowing safe thrombolysis despite treatment with a
NOAC.
Our study has some limitations. We relied on information provided by patients and caregivers
with regards to the time of last drug ingestion, and this information may not always have been
accurate. Furthermore, delays in blood sampling may have resulted in lower drug-
concentrations than actually present at the exact time of admission. RASUNOA was
performed in a single-country in selected centers only, and current practices may have been
different in other settings. With regards to the administration of thrombolysis, the local
physician’s decision may have been influenced by the relatively mild to moderate deficits of
the patients.
In conclusion, our multi-center observational study indicates that drug-specific coagulation
testing is not yet part of clinical routine in the majority of major German stroke centers, and
standard coagulation tests often do not reflect the anticoagulatory activity of NOACs
adequately. More evidence is needed to establish solid reference ranges of coagulation test
results, including point-of-care devices, for safe and rapid thrombolysis in acute stroke.
Sources of Funding: Investigator-initiated, without commercial funding.
Conflicts of Interest: Personal fees, speakers, consulting honoraria, research support were
received from Pfizer (JP, TR, SP, CK, FP, HS), BMS (TR, SP, PK, CK, FP), Boehringer
Page 12
Ingelheim (JP, TR, SP, PK, CK, FP, HS), Bayer (TR, SP, PK, CK, RV), Daiichi Sankyo (TR,
SP, PK, CK, FP, HS, RV), CSL Behring (RV), outside of present work. PUH: grants from
German Federal Ministry of Education and Research, European Union, Charité, Berlin
Chamber of Physicians, German Parkinson Society, University Hospital Würzburg, Robert-
Koch-Institute, Charité–Universitätsmedizin Berlin (within MonDAFIS, supported by
unrestricted research grant to Charité from Bayer), University Göttingen (within FIND-AF,
supported by an unrestricted research grant from Boehringer Ingelheim), University Hospital
Heidelberg (RASUNOA-prime, supported by unrestricted research grant from Bayer, BMS,
Boehringer Ingelheim, Daiichi Sankyo), outside of the present work. All other authors declare
no conflicts of interest.
Appendix
We thank all principal investigators of the RASUNOA study and participating hospitals who
enrolled at least one ischemic stroke patient (A-Z). A. Binder (Kiel), M. Dichgans (München),
R. Dziewas (Münster), K. Gröschel (Mainz), M. Eicke (Idar-Oberstein), M. Ertl
(Regensburg), MG. Hennerici (Mannheim), C. Hobohm (Leipzig), T. Höhle (Herne), S.
Jander (Düsseldorf), E. Jüttler (Ulm), A. Khaw (Greifswald), C. Kleinschnitz (Würzburg), A.
Kraft (Halle), M. Köhrmann (Erlangen), F. Meisel (Karlsruhe), T. Neumann-Haefelin (Fulda),
C. Opherk (Heilbronn), F. Palm (Ludwigshafen), S. Poli (Tübingen), J. Röther (Hamburg), E.
Schmid (Stuttgart), G. Seidel (Hamburg), H. Soda (Bad Neustadt), C. Tanislav (Gießen), G.
Thomalla (Hamburg), R. Veltkamp (Heidelberg), K. Wartenberg (Halle-Wittenberg), C.
Weimar (Essen).
Page 13
Table 1. Patient Characteristics
Variable Patients
N 290
Age, years; mean (SD) 77.1 (9.2)
Women; n (%) 140 (48.3)
NOAC; n (%)
Apixaban 47 (16.2)
Dabigatran 76 (26.2)
Rivaroxaban 167 (57.6)
Indication for oral anticoagulation; n (%)
Atrial fibrillation 267 (92.1)
Venous thromboembolism 13 (4.5)
Other 10 (3.4)
Concomitant antiplatelet therapy; n (%) 31 (10.7)
Renal function at admission
GFR; median (IQR) 60 (52–78)
GFR < 60 ml/min; n (%) 103/259 (39.8)
Time since last intake NOAC until
admission, hours; median (IQR)
9 (4.5 – 16.9)
Admission < 4.5 h time window 141 (48.6)
NIHSS at admission; median (IQR) 4 (1–8)
Pre-stroke modified Rankin Scale score;
median (IQR)
1 (0–2)
NOAC, non-vitamin K antagonist oral anticoagulant; GFR, glomerular filtration rate
(electronic GFR); NIHSS, National Institute of Health Stroke Scale.
Page 14
Table 2. Availability of Key Coagulation Laboratory Parameters in Clinical Routine
According to Non-vitamin K Antagonist Oral Anticoagulant
Variable All Dabigatran Rivaroxaban Apixaban
N (Patients) 290 76 167 47
Nonspecific tests
Platelet; n (%) 285
(98.3)
74 (97.4 164 (98.2 47 (100)
INR; n (%) 286
(98.6)
73 (96.1) 166 (99.4) 47 (100)
aPTT; n (%) 280
(96.6)
72 (94.7) 161 (96.4) 47 (100)
TT; n (%) 120
(41.4)
34 (44.7) 64 (38.3) 22 (46.8)
ECT; n (%) - 7 (9.2) - -
Specific tests
Anti-Xa; n (%) - - 71 (42.5) 8 (17.0)
calibrated (drug-specific); n (%) - - 54 (32.3) 6 (12.8)
Dabigatran concentration (hemoclot
assay); n (%)
- 18 (23.7) - -
INR, international normalized ration; aPTT, activated partial thromboplastin time; TT,
thrombintime; ECT, ecarin clotting time.
Page 15
Table 3. Thrombolysis* Decision Protocols and Number of Patients Theoretically Eligible
According to the Protocol
NOAC Model 1
(Steiner et al.)
Patients
considered
eligible n/N
(%)
Model 2
(Kepplinger et al.)
Patients
considered
eligible n/N
(%)
Dabigatran
TT, ECT or
Hemoclot (< 50
ng/ml)
6/22 (27) TT ≤ 21 s 0/18 (0)
TT < 96 s or
ECT (< 2*URN)
or Hemoclot (<
50 ng/ml)
12/22 (55) TT > 21 s + CDabigatran
< 31 ng/ml
2/6 (33)
Missing
parameters +
normal aPTT
3/40 (8) TT > 21 s + CDabigatran
< 62 ng/ml + aPTT <
36 s
4/6 (67)
Rivaroxaban
Anti-Xa normal 5/36 (14) INR < 1.4 73/93 (78)
INR < 1.2 49/93 (53)
Anti-Xa <
2*URN or < 100
ng/ml
16/36 (44) INR ≥ 1.4 + CRivaroxaban
< 20 ng/ml
0/36 (0)
Page 16
INR ≥ 1.2 + CRivaroxaban
< 20 ng/ml
0/36 (0)
aPTT and PT
normal
26/92 (28) INR ≥ 1.4 + CRivaroxaban
< 91 ng/ml
0/36 (0)
INR ≥ 1.2 + CRivaroxaban
< 91 ng/ml
2/36 (6)
Apixaban
Anti-Xa normal 1/4 (25) INR < 1.4 22/24 (92)
INR < 1.2 20/24 (83)
Anti-Xa <
2*URN or < 10
ng/ml
0/4 (0) INR ≥ 1.4 + CApixaban
< 21 ng/ml
1/4 (25)
INR ≥ 1.2 + CApixaban
< 21 ng/ml
1/4 (25)
aPTT and PT
normal
13/24 (54) INR ≥ 1.4 + CApixaban
< 40 ng/ml
1/4 (25)
INR ≥ 1.2 + CApixaban
< 40 ng/ml
1/4 (25)
NOAC, non-vitamin K antagonist oral anticoagulant; INR, international normalized ration;
aPTT, activated partial thromboplastintime; TT, thrombintime; ECT, ecarin clotting time.
Patients administered < 4.5 h time window only (n=159).
*Thrombolysis after individual risk-benefit estimation.
Page 17
Figure 1. (A,C,D) Correlation of routine coagulation tests with NOAC concentrations at
admission (A-B, dabigatran, C, rivaroxaban, D, apixaban). (B) Correlation of the dabigatran
sensitive thrombin time (TT) with activated partial thromboplastin time (aPTT) and
international normalized ratio (INR). Note that although significantly positive correlated,
rivaroxaban concentrations were widely related to normal aPTT and INR values even at peak
Page 18
range values (online supplementary Table I). Dotted lines represent the upper range of
normal. Rho indicates Spearman’s rho.
Page 19
Figure 2. Observed non-vitamin K antagonist oral anticoagulant (NOAC)-specific
concentrations at admission according to the time after last drug administration
(UNK=unknown). x mg indicates NOAC-dose, OD=omne in die, BID=bis in die.
Page 20
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