These authors contributed equally to the manuscript as first author.
In acute stroke patients, plasma concentrations of direct oral anticoagulants (DOAC) at hospital admission only poorly mirror DOAC exposure or the coagulation status at the time of the event. Here, we evaluated whether DOAC exposure and DOAC plasma concentration at the time of transient ischemic attacks (TIA) and ischemic strokes correlate with their likelihood of occurrence.
Prospectively, consecutive DOAC patients with acute ischemic stroke or TIA were included. Admission DOAC plasma concentrations were measured by ultraperformance liquid chromatography– tandem mass spectrometry. Individual DOAC exposure (area under the curve) and DOAC concentrations at event onset were derived from population pharmacokinetic analyses.
DOAC exposure was successfully modeled in 211 patients (ischemic stroke 74.4%, TIA 25.6%). Compared to published values, 63.0% had relatively lower DOAC exposure and they more often received lower DOAC doses than recommended (odds ratio [OR], 2.125; 95% confidence interval [CI], 1.039 to 4.560;
Low DOAC exposure is strongly associated to ischemic stroke and its severity. By monitoring DOAC plasma concentrations, patients prone to ischemic stroke might be identified.
Increasing numbers of patients exposed to direct oral anticoagulants (DOAC) are admitted to emergency departments with ischemic stroke and transient ischemic attack (TIA) [
Finally, although plasma concentrations at the time of hospital admission can guide treatment decisions, these measurements do not mirror DOAC exposure or the coagulation status at onset of an ischemic cerebrovascular event, in particular when hospital admission is considerably delayed. Knowledge of actual DOAC plasma concentrations at onset of an ischemic cerebrovascular event would enable evaluating and establishing a concentration-effect relationship and help deciding whether DOAC exposure of affected patients is within the target range (signifying non-response to treatment) or whether patients are underdosed or non-adherent.
In the present study, we addressed these questions by measuring DOAC plasma exposure at admission and estimating concentrations at the onset of ischemic symptoms.
Consecutive patients aged >18 years, suspected to take a DOAC, and admitted to the neurological department of Heidelberg University Hospital due to symptoms of acute ischemic stroke or TIA between September 4, 2016 and June 12, 2018, were prospectively considered for inclusion into this observational study. Routine work-up for all patients encompassed a clinical examination by board-certified neurologists, brain imaging (computed tomography [CT] or magnetic resonance imaging [MRI]), and assessment of the National Institutes of Health Stroke Scale (NIHSS) for stroke severity. Occlusions of brain-supplying vessels were diagnosed by CT, MRI, or digital subtraction angiography. Occlusions of the distal internal carotid artery, the middle cerebral artery, the anterior cerebral artery, the posterior cerebral artery, or the basilar artery were defined as large vessel occlusion (LVO). Moreover, demographic variables, cardiovascular risk factors, time of symptom onset (if known), and time of hospital admission were recorded.
Nature and dose of DOAC and the time of the last DOAC intake were recorded. If the last intake was not reported or unknown (n=58/211; 27.5%), it was assumed that the DOAC was taken regularly and that the last ingestion occurred at 8:00 AM (once a day and twice a day regimens) and 8:00 PM (twice a day schedules). Physicians´ adherence to approved doses as recommended in the corresponding product characteristics (SmPCs) by the European Medicines Agency was evaluated by comparing the actual prescription scheme with the prescribing information of the respective DOAC in each patient. The degree of disability before stroke was assessed by the premorbid modified Rankin Scale (mRS). All patients with proven ischemic stroke or TIA, current DOAC prescription, and at least one immediate blood sampling at admission were considered for inclusion. Functional outcome after 3 months was assessed by the mRS during a standardized telephone interview.
As part of our standard of care, immediately after admission, standardized routine laboratory testing was performed. This included a full blood count, glucose, electrolytes, urea, creatinine, prothrombin time, activated partial thromboplastin time, international normalized ratio (INR), and DOAC plasma concentrations. DOAC plasma concentrations were measured from plasma samples drawn at admission (t1) and 6 hours later (t2) by UPLC-MS/MS (lower limit of quantification [LLOQ] of 1 ng/mL), developed and validated according to U.S. Food and Drug Administration and European Medicines Agency guidelines for bioanalytical method validation [
Estimation of individual pharmacokinetic parameters of our patients enabled us to estimate individual concentration-time profiles (for an example, see
As a measure of internal validity, we checked the agreement between model-based extrapolated concentrations and non-parametric extrapolations in a sample of patients with more than one measurement. In order to estimate individual elimination rate constants (λ), two DOAC UPLC-MS/MS measurements had to be available that were collected ≥6 hours apart within the same dosing interval, of which the first had to be drawn not earlier than 2 hours after the last drug intake, i.e., after expected peak concentrations. The slope of the line connecting the logarithms of the two measured concentrations over time was defined as λ [λ=(log C1–log C2)/(t2–t1)], where C1 is the concentration in the first-drawn admission sample, C2 the concentration in the sample collected ≥6 hours after C1 within the same elimination phase, and t2–t1 the numeric interval between the corresponding concentrations.
This slope (l) was used to back-extrapolate concentrations (Ce) expected at the time (te) of the ischemic event [log Ce=λ((e–t1)+log C1], provided that symptom onset occurred after drug absorption (i.e., >2 hours after the last drug intake). In 19 patients all measurements were below the analytical LLOQ; these values were set to zero and the patients were considered non-adherent.
The responsible independent Ethics Committee of the Medical Faculty of Heidelberg University approved this study, written informed consent was obtained from patients or their legal representatives.
To facilitate standardized comparisons across the four DOACs, we calculated fold changes from dividing our estimated values by the mean concentration and AUC at steady-state extracted from external reference populations (for apixaban [
Standard statistical methods were applied for univariate comparisons. Multivariate logistic and linear regression was performed to explore factors explaining differences between patients with TIA and ischemic stroke, stroke severity (NIHSS), the occurrence of LVO in ischemic stroke patients, and the severity of clinical outcome (mRS) after 3 months (dichotomized at the level of 2).
To determine whether overall exposure (AUC) or the estimated concentration at the time of the event had a higher explanatory value to predict the nature of events (ischemic stroke or TIA) or stroke severity (NIHSS), we compared subpopulations for which both measures were available. Therefore, separate models were fitted including either normalized AUC or normalized concentration values as independent variables (in addition to clinical covariates for confounding adjustment). A formal model comparison of these non-nested models was based on an appropriate likelihood ratio test assessing the working hypothesis that the AUC model fits better than the respective concentration model [
All tests were two-sided and a
The selection of the study population is illustrated in
The median time between reported last drug administration and admission was 582 minutes (IQR, 282 to 891). DOAC concentrations at admission for individual DOACs are listed in
Lower relative DOAC exposure (AUC) than expected was observed in almost two-thirds (63.0%) of our patients. Clinical and DOAC-specific variables in patients with relatively lower and higher DOAC exposure are given in
Multivariate logistic regression revealed a substantially higher risk for ischemic stroke when DOAC exposure was low (odds ratio [OR], 2.411; 95% confidence interval [CI], 1.254 to 4.638;
Information on the specific time of ischemic stroke or TIA was available in 179/211 patients thus allowing to extrapolate DOAC concentration at the time of the event (
Univariate comparisons between patients with relatively lower and higher DOAC concentrations are provided in
Sensitivity analyses with alternating event definitions revealed robust results for the influence of DOAC exposure and DOAC plasma concentration at the time of the event on the risk of ischemic stroke also when data were restricted to patients with AF or patients with cardioembolic ischemic strokes (
In ischemic stroke patients, DOAC exposure (AUC) better predicted the stroke severity than estimated DOAC concentration at the event (
Overall, in 199 patients of our cohort (94.3%), follow-up information after 3 months was available. In these patients, median functional outcome (mRS) was 3 (1 to 5) (
The main findings of our study are that (1) a large proportion of patients hospitalized with acute ischemic cerebrovascular events had lower than expected DOAC exposure; (2) these patients were more likely to have a stroke than a TIA and their strokes were more severe; and (3) low DOAC exposure was more likely when the prescribed dosage regimens contradicted approved standards. Finally (4) DOAC exposure had a higher explanatory value for stroke severity than single concentrations at the time of the event.
In contrast to vitamin K antagonists (VKAs), the anticoagulatory effect of all DOACs is rapid and clearly concentration-dependent [
Because of the importance of supporting acute treatment decisions, studies in DOAC-pretreated patients with acute cerebrovascular events have so far used the results of (faster) non-specific or specific coagulation tests as surrogates for DOAC activity at the time of hospital admission, which occurs often hours after event onset. However, such single activity testing of coagulation parameters represents an approximate snap-shot of the actual DOAC plasma concentration only, the quality of anticoagulation over time cannot be assessed and it gives no information on DOAC concentrations at the event time. To close this gap, we meticulously collected information on dose and time of individual drug intake, modeled individual concentration-time profiles, and correlated these data with the reported occurrence of stroke symptoms. This approach is independent of time of admission and considers the specifics of individual dosing regimens and drug intake. To the best of our knowledge, this is the first study designed to evaluate the significance of DOAC plasma concentrations at the event for the occurrence of TIA, ischemic strokes, and their severity.
Irrespective of the prescribed DOAC, exposure of our patients was lower than expected and in a substantial proportion of patients this was a result of physicians´ non-adherence to guidelines (underdosing: 24.2%) or non-adherence of patients (9%). Poor guideline adherence with a trend to lower doses has been reported repeatedly and is associated with less favorable outcomes [
Our study enabled to determine whether DOAC exposure over time (AUC) or the concentration at event onset better predicted ischemic stroke or its severity and found that AUC was superior to explain stroke severity than DOAC concentration at the time of the event. Our findings therefore suggest that lower DOAC exposure (and not the concentration at stroke onset) is more relevant for treatment efficacy. These results are in accordance to other reports, suggesting that AUC values might more closely reflect actual drug action than either peak [
When transferring the broad knowledge on treatment with VKA to DOAC patients, our observation that stroke severity was better predicted by DOAC exposure than by plasma concentration at the event is plausible. Exposure to VKA can be expressed by INR values and it is well known that INR values of ≥2.0 reduce the frequency of ischemic stroke and its severity as well as the risk of death from stroke in patients with AF [
Taken together, our findings have important clinical implications for the future management of patients using DOACs. By now, recommendations to perform regular controls of plasma concentrations in DOACs are absent. In contrast, our data suggest that monitoring these patients by thorough control of dosing schemes and long-term drug exposure might help identifying patients with inadequately low exposure and subsequent dose adaptions could considerably improve stroke prevention. Whether this strategy will help improving outcomes will now have to be tested in a prospective clinical trial.
An obvious strength of the present study is the prospective inclusion of a large number of anticoagulated acute ischemic stroke and TIA patients, irrespective of a prespecified DOAC treatment. Moreover, external standardization of DOAC plasma concentrations provided sound knowledge on associations between DOAC plasma concentrations and ischemic cerebrovascular events. However, modeled exposure in our study is based on the existent literature and limited to the last hours before stroke. Longitudinal exposure information was not available, the numbers of patients for single DOACs are limited and the single-center approach might restrict generalizing our results. It could be speculated that assuming a regular drug use in patients in whom the last drug intake was not reported or unknown may have generated bias. However, excluding these patients yielded even higher risks for stroke occurrence due to low DOAC plasma exposure (OR, 2.99, data not shown). This indicates that the main approach of approximating drug intake times in those patients can be considered as rather conservative as main results appeared to be biased towards the null, if at all. Due to the observational design, we did not perform brain imaging in a predefined structured manner and therefore cannot adequately report stroke volumes. Moreover, we did not consider details of recanalization therapies or changes in renal function when determining the functional outcome. Longitudinal information on exposure was not available, the number of patients with individual DOACs was small, as was the number of 1–2 observations per patient available for extrapolation of individual pharmacokinetics. The lack of a control group and of patients with intracerebral hemorrhages is a further limitation.
Our data reveal that low DOAC exposure is strongly associated to ischemic stroke and its severity. In consequence, monitoring plasma concentrations in DOAC patients on a regular basis might identify patients prone to ischemic stroke and subsequent dose adaptions could considerably improve preventing ischemic cerebrovascular events by achieving adequate DOAC exposure. Monitoring these patients longitudinally would also enable to examine associations between the impact of duration of suboptimal anticoagulation on the occurrence of cerebrovascular events. This should now be assessed in an adequately powered prospective trial.
Supplementary materials related to this article can be found online at
Demographic findings, cardiovascular risk factors, and DOAC-specific findings of all included patients (n=211)
Differences between low and high DOAC exposure (n=211)
Multivariate logistic regression between high and low DOAC exposure (n=211)
Multivariate logistic regression between patients with and without large vessel occlusions of all included patients and of patients with modeled DOAC concentration at the event
Differences between low and high DOAC concentrations at onset of the event (n=179)
Differences between favorable and unfavorable 3 months outcome in ischemic stroke patients (n=149)
Multivariate logistic regression between favorable and unfavorable 3 months outcome in ischemic stroke patients with follow-up information (n=149)
Diagnostic plots to explore deviations of predicted concentrations from observed measurements at the respective times of measurement. (A, C) Panels visualize the bivariate relationship between predicted concentrations und observed measurements with distinct pairs of values colour-coding individual direct oral anticoagulants (DOACs) or whether the indicator was derived from a pharmacokinetic profile estimated by one or two measurements per patient. Residual plots illustrate residuals over time after the last DOAC administration (B) or residuals stratified by their origin from pharmacokinetic profiles with one-point or two-point estimation (D).
Forest plot of effect estimates (expressed as odds ratios) of either low direct oral anticoagulant (DOAC) plasma exposure (A) or low DOAC plasma concentration at the time of the event (B) on the risk of ischemic stroke. Different outcome definitions are plotted on the discrete y-axis with the results from the main analysis, a restricted sample including only patients with atrial fibrillation (AF), and a sample including only cardioembolic ischemic strokes. Whiskers around the point estimates visualize 95% confidence intervals. AUC, area under the curve.
Substance-specific modulation of overall direct oral anticoagulant (DOAC) effects expressed as odds ratio for the probability of stroke occurrence (left side, A, C) or as a linear increase in the National Institutes of Health Stroke Scale (NIHSS) score for stroke severity (right side, B, D). The top row indicates substance-specific effects around the DOAC class effect (dashed vertical line) in terms of exposure (area under the curve [AUC]), while the bottom row indicated substance-specific effects in term of concentration at the time of the event. Whiskers visualize 95% confidence intervals of the respective estimates.
Timolaos Rizos received consulting honoraria, speakers’ honoraria and travel support from Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, Bayer HealthCare, Portola Pharmaceuticals and Daiichi Sankyo, outside of the present work; Jan Purrucker received consulting honoraria and travel support from Abbott, Akcea, Boehringer Ingelheim, Daiichi Sankyo and Pfizer, outside of the present work; David Czock received honoraria and travel support from Biogen GmbH, Chiesi GmbH and Daiichi Sankyo, outside of the present work; Peter A. Ringleb and Walter E. Haefeli received honoraria from Bayer, Boehringer Ingelheim, Daiichi Sankyo and Pfizer, outside of the present work.
Andreas D. Meid, Chris Dumschat, Andrea Huppertz, Kathrin I. Foerster, Jürgen Burhenne, and Ekkehart Jenetzky report no disclosures.
The work of Andreas D. Meid was supported by a grant from the Medical Faculty of Heidelberg University (Physician Scientist program).
Model-based concentration-time profile of an exemplary patient treated with apixaban (red line). Shaded areas (purple) visualize the typical range of 95% virtual patients as predicted from the underlying population pharmacokinetic model for apixaban while accounting for available covariates of the particular patient or assuming median values [
Selection of the study population. DOAC, direct oral anticoagulant; TIA, transient ischemic attack; AUC, area under the curve; NA, non-adherence.
Box plots of the ratio of modeled area under the curve (AUC) and published figures corresponding to the respective doses with superimposed individual AUC values of all included patients. The broken line indicates the threshold between relatively higher and lower direct oral anticoagulant (DOAC) exposure than the published expected average. Each boxplot contains the median (horizontal line in the box), the upper quartile (75th percentile, top of box), the lower quartile (25th percentile, bottom of box). The whiskers plot the minimal and maximal DOAC exposure. Solid circles: Dot plots of categorized individual AUC results of all included patients (lower limit of quantification for ultraperformance liquid chromatography–tandem mass spectrometry 1 ng/mL). Open circles: non-adherent patients (concentration <1 ng/mL; n=19).
Multivariate logistic regression between ischemic stroke and TIA patients in all included patients and in all patients with modeled DOAC concentration at the event
Variable | Ischemic stroke vs. TIA |
|||||
---|---|---|---|---|---|---|
All included patients (n=211) |
Patients with extrapolated DOAC concentration at the event (n=179) |
|||||
OR | 95% CI | OR | 95% CI | |||
Low DOAC exposure |
2.411 | 1.254–4.638 | 0.008 | - | - | - |
Low DOAC concentration at event |
- |
- | - | 4.123 | 1.834–9.268 | 0.001 |
Female sex | 0.610 | 0.294–1.270 | 0.187 | 0.528 | 0.244–1.145 | 0.106 |
Age | 0.961 | 0.917–1.008 | 0.100 | 0.983 | 0.935–1.034 | 0.506 |
Hypertension | 1.132 | 0.365–3.516 | 0.830 | 0.722 | 0.204–2.555 | 0.614 |
Diabetes mellitus | 0.487 | 0.235–1.008 | 0.053 | 0.340 | 0.149–0.774 | 0.010 |
Hypercholesterolemia | 0.657 | 0.320–1.347 | 0.251 | 0.726 | 0.324–1.624 | 0.435 |
Previous stroke/TIA | 1.066 | 0.531–2.142 | 0.857 | 0.956 | 0.440–2.078 | 0.956 |
Congestive heart failure | 1.428 | 0.576–3.540 | 0.442 | 1.436 | 0.534–3.857 | 0.473 |
Vascular disease | 0.940 | 0.445–1.989 | 0.872 | 1.047 | 0.460–2.385 | 0.912 |
Atrial fibrillation | 0.880 | 0.254–3.049 | 0.076 | 0.907 | 0.229–3.600 | 0.890 |
TIA, transient ischemic attack; DOAC, direct oral anticoagulant; OR, odds ratio; CI, confidence interval.
Derived from area under the curve (AUC) ratios normalized to reference populations;
No published data available for comparison.
Multivariate linear regression of stroke severity (NIHSS) in all included ischemic stroke patients and in all ischemic stroke patients with modeled DOAC concentration at the event
Variable | NIHSS |
|||||
---|---|---|---|---|---|---|
All included ischemic stroke patients (n=157) |
Ischemic stroke patients with extrapolated DOAC concentration at the event (n=131) |
|||||
Slope | 95% CI | Slope | 95% CI | |||
Low DOAC exposure |
3.161 | 0.741 to 5.581 | 0.011 | - | - | - |
Low DOAC concentration at event |
- |
- | - | 1.570 | –1.320 to 4.334 | 0.293 |
Female sex | –2.708 | –5.125 to –0.291 | 0.028 | –2.559 | –5.398 to 0.281 | 0.077 |
Age | 0.076 | –0.053 to 0.205 | 0.246 | 0.099 | –0.060 to 0.257 | 0.220 |
Hypertension | 0.103 | –3.717 to 3.924 | 0.957 | 0.379 | –3.875 to 4.633 | 0.860 |
Diabetes mellitus | 0.380 | –2.312 to 3.072 | 0.781 | 0.154 | –3.214 to 3.522 | 0.928 |
Hypercholesterolemia | –1.629 | –4.039 to 0.780 | 0.183 | –1.454 | –4.318 to 1.409 | 0.317 |
Previous stroke/TIA | 1.737 | –0.769 to 4.243 | 0.173 | 1.661 | –1.322 to 4.644 | 0.272 |
Congestive heart failure | 1.001 | –1.924 to 3.927 | 0.500 | 1.119 | –2.383 to 4.622 | 0.528 |
Vascular disease | 1.212 | –1.292 to 3.717 | 0.340 | 1.354 | –1.648 to 4.356 | 0.374 |
Large vessel occlusion | 7.773 | 5.449 to 10.098 | <0.001 | 7.597 | 4.796 to 10.397 | <0.001 |
Atrial fibrillation | 2.285 | –1.687 to 6.257 | 0.257 | 1.936 | –2.977 to 6.850 | 0.437 |
NIHSS, National Institutes of Health Stroke Scale; DOAC, direct oral anticoagulant; CI, confidence interval; TIA, transient ischemic attack.
Derived from ratios normalized to reference populations;
No published data available for comparison.