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Administering Thrombolysis for Acute Ischemic Stroke in Patients Taking Direct Oral Anticoagulants: To Treat or How to Treat

March 2021
JAMA Neurology 78(1)

March 2021
78(1)

DOI:10.1001/jamaneurol.2021.0287

Authors:

David Seiffge

Inselspital, Universitätsspital Bern

Duncan Wilson

University College London

Teddy Wu

Canterbury District Health Board

Direct oral anticoagulants (DOAC), the factor Xa inhibitors rivaroxaban, apixaban, edoxaban, and the direct thrombin inhibitor dabigatran, are emerging as anticoagulant treatment of choice for stroke prevention in patients with nonvalvular atrial fibrillation. Acute ischemic stroke occurs in 1% to 2% of DOAC-treated patients per year, and many would present within the standard therapeutic time window for intravenous thrombolysis and endovascular thrombectomy. This poses a significant clinical conundrum; it is likely that most patients with ischemic stroke taking DOACs are compliant with therapy, rendering the very medications used to prevent stroke the reason for withholding therapy. Current American Heart Association/American Stroke Association guidelines give a class III recommendation that thrombolysis might be harmful within 48 hours after last intake and should not be administered. Epidemiologic data published in 2021¹ suggest this may affect up to 18% of patients with atrial fibrillation who present with stroke¹ who would be otherwise eligible for thrombolysis.

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Administering Thrombolysis for Acute Ischemic Stroke

in Patients Taking Direct Oral Anticoagulants

To Treat or How to Treat

Direct Oral Anticoagulants

and Acute Ischemic Stroke

Direct oral anticoagulants (DOAC), the factor Xa inhibi-

tors rivaroxaban, apixaban, edoxaban, and the direct

thrombin inhibitor dabigatran, are emerging as antico-

agulant treatment of choice for stroke prevention in

patients with nonvalvular atrial fibrillation. Acute ische-

mic stroke occurs in 1% to 2% of DOAC-treated patients

per year, and many would present within the standard

therapeutic time window for intravenous thrombolysis

and endovascular thrombectomy. This poses a signifi-

cant clinical conundrum; it is likely that most patients

with ischemic stroke taking DOACs are compliant with

therapy, rendering the very medications used to pre-

vent stroke the reason for withholding therapy. Current

American Heart Association/American Stroke Associa-

tion guidelines give a class III recommendation that

thrombolysis might be harmful within 48 hours after

last intake and should not be administered. Epidemio-

logic data published in 2021

suggest this may affect up

to 18% of patients with atrial fibrillation who present

with stroke

who would be otherwise eligible for

thrombolysis.

We strongly disagree with this generalized recom-

mendation. We all follow the oath of Hippocrates, “pri-

mum non nocere.” However, withholding effective re-

canalization treatments from patients with stroke may

actually harm the patient. Available data

2-5

show that

carefully selected patients taking prior DOAC therapy

have similar bleeding risks to patients not taking DOAC

after intravenous thrombolysis.

The therapeutic dilemma facing stroke and emer-

gency physicians is determining how to select patients

for thrombolysis. Unfortunately, American Heart Asso-

ciation/American Stroke Association guidelines pro-

vide only vague (eg, activated partial thromboplastin

time, INR, and normal platelet count) and imprecise (“are

normal”) guidance.

There is emerging evidence that we should not

categorically exclude patients who previously received

DOAC treatment from recanalization therapies. To

compound clinical decision-making, 2 often-suggested,

easy-to-use approaches are unsuitable: (1) traditional

routine coagulation profiles do not correlate well

with therapeutic efficacy of DOACs,

and (2) anticoagu-

lant activity of DOACs has substantial interindividual

heterogeneity likely related to different factors (eg,

kidney function, age, concomitant medication, and

dosage), making time since last intake a rather unreli-

able surrogate.

Thanks to a growing body of evi-

dence, there are several promising approaches that we

discuss here.

Selection for Thrombolysis Based on

Drug-Specific Assays

Drug-specific coagulation assays (eg, calibrated anti-Xa

activity; “DOAC drug levels”) can measure DOAC levels

and have been used to select patients at low anticoagu-

lant activity.This approach seems reasonably safe, with

approximately 2% rates of symptomatic hemorrhagic

transformation, although prior reports are restricted

to tertiary academic centers

2,7

while specific clotting

assays are not widely available. Thromboelastography

(TEG)

is a relatively novel tool that measures viscoel

astic properties of clotting blood. It provides highly sen-

sitive and specific point-of-care laboratory values cor-

relate with serum DOAC levels in healthy volunteers.

Although promising, selection for thrombolysis using

TEG has yet to be reported. Several details warrant fur-

ther research including the exact threshold to be safe for

thrombolysis (<30 ng/mL, <50 ng/mL, or <100 ng/mL

or even higher?) and important imperatives to make

these assays more broadly and rapidly available. At least

measuring calibrated anti-Xa activity seems feasible,

as demonstrated by many centers at reasonable costs

(approximately $50 per test). If blood is sampled imme-

diately on presentation, first results can be obtained

within 30 minutes without causing major delays in the

door-to-needle times.

Anticoagulant Reversal Before Thrombolysis

The development of effective and rapid reversal agents

for DOACs has opened a totally new, alternative win-

dow of opportunity for intravenous thrombolysis in

patients pretreated with DOAC. This approach involves

administration of a rapid and reliable DOAC reversal

agent, either concurrently or prior to intravenous throm-

bolysis. Idarucizumab provides a rapid and permanent

reversal of dabigatran anticoagulation and is adminis-

tered prior to intravenous thrombolysis. It would seem

intuitive that these patients should be approached as

nonanticoagulated patients with standard thromboly-

sis indications and contraindications. However, the

experience in managing patients taking dabigatran in

this manner is limited to select registry data and case

series,

4,5

likely owing to general reluctance to treat in the

absence of randomized controlled data and/or best-

practice guideline recommendations in addition to lack

of access to idarucizumab. Andexanet alpha provides re-

versal of anticoagulant effect of factor Xa inhibitors but

requires a continuous infusion. Although commercially

available, it is not widely accessible and is costly. Expe-

rience with intravenous thrombolysis following rever-

sal with andexanet alpha is currently limited to a single

case report.

VIEWPOINT

David J. Seiffge

Department of

Neurology, Inselspital

Bern, University

Hospital Bern,

University of Bern,

Switzerland.

Duncan Wilson, PhD

Department of

Neurology,

Christchurch Hospital,

Christchurch,

New Zealand; and

New Zealand Brain

Research Institute,

Christchurch,

New Zealand.

TeddyYuan-Hao Wu,

MD, PhD

Department of

Neurology,

Christchurch Hospital,

Christchurch,

New Zealand; and

New Zealand Brain

Research Institute,

Christchurch,

New Zealand.

Viewpoint

Corresponding

Author: David J.

Seiffge, PD, Drmed,

Department of

Neurology and Stroke

Center, Inselspital,

University Hospital of

Bern, Freiburgstrasse,

CH-3010 Bern,

Switzerland (david.

seiffge@insel.ch).

Opinion

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Patients Taking DOAC With Proven Large-Vessel Occlusion

and Endovascular Thrombectomy

Patients with large-vessel occlusive ischemic stroke pose another

therapeutic dilemma, particularly in patients presenting within the

standard window for intravenousthrombolysis. Endovascular throm-

bectomy appears safe and technically feasible in patients taking

DOACs without any specific precaution. The clinical conundrum in

these patients is whether to offer bridging thrombolysis before en-

dovascular thrombectomy. Bridging thrombolysis is to administer

thrombolysis prior to endovascular thrombectomy because throm-

bolysis may facilitate early recanalization in a subset of patients prior

to endovascular therapy. However, the potential effect of bridging

thrombolysis may be offset by an increased risk of symptomatic hem-

orrhagic transformation. In our opinion, the decision to offer bridg-

ing thrombolysis before thrombectomy should depend on several

clinical factors including rapid access to an endovascular center and

the type of DOAC the patient is taking. In patients presenting di-

rectly to an endovascular center, direct endovascular thrombec-

tomy without bridging thrombolysis should be preferred given early

recanalization is limited. Although observational data and a random-

ized clinical trial

(albeit in nonanticoagulated patients) suggest no

significant differences in outcomes with or without alteplase bridg-

ing, the trial data are based on relatively small patient numbers. On-

going randomized clinical trials (DIRECT-SAFE,NCT03494920; SWIFT

DIRECT, NCT03192332; and MR CLEAN-NO IV, ISRCTN80619088)

will provide further guidance in this practice. Where there may be a

delay in offering thrombectomy or where thrombectomy is not avail-

able, thrombolysis may be considered where last known ingestion

is more than 48 hours or drug specific levels suggest low levels of

circulating drug or in dabigatran patients with rapid access to idaru-

cizumab, as discussed in previous paragraphs.

Conclusions

The authors of this Viewpoint acknowledge that we advocate much

in favor for treatment of selected patients despite few data. How-

ever, it is unlikely that an appropriately powered randomized clini-

cal trial assessing DOAC reversal strategies prior to intravenous

thrombolysis would ever be feasible. Therefore, it is important that

international collaborations are made to further consolidate the

knowledge and experience in reperfusion therapy in this group

of patients and to provide opportunities for appropriate cost-

effective analysis of the different approaches discussed in this

Viewpoint. Given the complexity and potential risks associated with

intravenous thrombolysis in DOAC patients with acute ischemic

stroke, decision to treat should be made in consultation with stroke

specialists familiar in this subject. In conclusion, we recommend

a tailored approach to select patients taking DOAC with acute is-

chemic stroke for thrombolysis by combining clinical and imaging

information with anticoagulant activity and use of specific reversal

agents only if necessary.

ARTICLE INFORMATION

Published Online: March 15, 2021.

doi:10.1001/jamaneurol.2021.0287

Conflict of Interest Disclosures: Dr Seiffge

reported serving on the advisory board for Bayer

and Pfizer; personal fees from Portola; and grants

from Swiss National Science Foundation,

Bangerter-Rhyner-Foundation, Swiss Society of

Neurology, and BayerFoundation outside the

submitted work. No other disclosures were

reported.

Additional Contributions: We thank Jan Purrucker,

MD (Department of Neurology, University Hospital

Heidelberg, Germany), Thomas Meinel, MD, and

Urs Fischer, MD (Department of Neurology,

University Hospital Inselspital Bern, Switzerland),

and Johannes Kaesmacher, MD (Department of

Neuroradiology, UniversityHospital Inselspital

Bern, Switzerland), for insightful discussion on

the topic of this article.

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Opinion Viewpoint

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Too risky, too large, too late, or too mild—Reasons for not treating ischemic stroke patients and the related outcomes

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Background Despite effective treatments, many patients are still not offered reperfusion therapy for acute ischemic stroke. Methods We present a single-center observational study on acute ischemic stroke patients, who presented as candidates for reperfusion therapy but were deemed ineligible after work-up. Reasons for non-treatment were obtained by studying patient files and subsequently grouped into “too risky” (e.g., anticoagulant use, comorbidities), “too large” (large infarct), “too late” (late presentation of stroke and wake-up strokes), or “too mild” (clinically mild/remitting symptoms). Modified Rankin scale (mRS) score was prospectively collected in all patients by a structured telephone interview. All non-treated patients with a National Institute of Health Stroke Scale (NIHSS) score of 0–5 were compared with a similar cohort that was treated. Results Of 529 patients with acute ischemic stroke arriving as reperfusion therapy candidates, 198 (37.4%) were not treated. The majority (42%) were not treated due to admission outside the treatment window (too late) and 24% had absolute contraindications (too risky). Only 8% was excluded because their infarct was too large [median Alberta Stroke Program Early CT score 3 (2–4)]. In the “too mild” group (14%) the percentage of patients not being independent at 90 days was 30%. The adjusted odds ratio for a better outcome (lower mRS) among treated patients with NIHSS 0–5 compared with non-treated was 1.93 (95% confidence interval 1.15–3.23). Conclusion Presenting outside the treatment window is still the most common reason for not receiving therapy. Our study suggests a benefit of thrombolysis for patients with mild symptoms.

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Introduction Based on demographical trends and the expected worldwide increase in the number of individuals with atrial fibrillation, the rate of patients who are on oral anticoagulation therapy for secondary prevention of stroke rises continuously. Despite correct drug intake and good adherence to the respective medication, recurrent ischemic stroke still occurs in ~ 3% of patients. The question how to deal with such patients with regard to intravenous thrombolysis with rt-PA within the 4.5 h time window is of great relevance for daily clinical routine. However, international guidelines can be considered heterogenous or do even lack recommendations on this topic especially in light of available reversal agents. Therefore, we provide this SOP. Comments Beyond the identification of acute stroke patients on oral anticoagulation therapy, the type of medication, time since last intake, renal function and laboratory exams as well as the availability of reversal agents have to be considered before rt-PA application and potential endovascular therapy. Treatment on a Stroke Unit or Neuro-ICU is certainly recommended in any of those patients. Conclusions This standardized operating procedure was designed to guide stroke physicians through questions on eligibility for rt-PA treatment in patients with acute ischemic stroke who are on approved oral anticoagulation therapy thereby increasing the number of patients benefitting from thrombolysis and minimizing door-to-needle times.

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David Seiffge

Prior Anticoagulation in Patients with Ischemic Stroke and Atrial Fibrillation

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Full-text available

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OBJECTIVE The aim was to evaluate, in patients with atrial fibrillation (AF) and acute ischemic stroke, the association of prior anticoagulation with vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) with stroke severity, utilization of intravenous thrombolysis (IVT), safety of IVT, and 3-month outcomes. METHODS This was a cohort study of consecutive patients (2014-2019) on anticoagulation versus those without (controls) with regard to stroke severity, rates of IVT/mechanical thrombectomy, symptomatic intracranial hemorrhage (sICH), and favorable outcome (modified Rankin Scale score 0-2) at 3 months. RESULTS Of 8,179 patients (mean [SD] age, 79.8 [9.6] years; 49% women), 1,486 (18%) were on VKA treatment, 1,634 (20%) on DOAC treatment at stroke onset, and 5,059 controls. Stroke severity was lower in patients on DOACs (median National Institutes of Health Stroke Scale 4, [interquartile range 2-11]) compared with VKA (6, [2-14]) and controls (7, [3-15], p < 0.001; quantile regression: β -2.1, 95% confidence interval [CI] -2.6 to -1.7). The IVT rate in potentially eligible patients was significantly lower in patients on VKA (156 of 247 [63%]; adjusted odds ratio [aOR] 0.67; 95% CI 0.50-0.90) and particularly in patients on DOACs (69 of 464 [15%]; aOR 0.06; 95% CI 0.05-0.08) compared with controls (1,544 of 2,504 [74%]). sICH after IVT occurred in 3.6% (2.6-4.7%) of controls, 9 of 195 (4.6%; 1.9-9.2%; aOR 0.93; 95% CI 0.46-1.90) patients on VKA and 2 of 65 (3.1%; 0.4-10.8%, aOR 0.56; 95% CI 0.28-1.12) of those on DOACs. After adjustments for prognostic confounders, DOAC pretreatment was associated with a favorable 3-month outcome (aOR 1.24; 1.01-1.51). INTERPRETATION Prior DOAC therapy in patients with AF was associated with decreased admission stroke severity at onset and a remarkably low rate of IVT. Overall, patients on DOAC might have better functional outcome at 3 months. Further research is needed to overcome potential restrictions for IVT in patients taking DOACs. ANN NEUROL 2020.

Fully automated thromboelastograph TEG 6s to measure anticoagulant effects of direct oral anticoagulants in healthy male volunteers

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May 2019

Background The ability to assess the hemostatic effect of the direct oral anticoagulant (DOACs) may be valuable in clinical situations such as bleeding or thrombosis, before urgent surgery, or reversal of anticoagulation. We sought to assess the anticoagulant effect of DOACs with the new‐generation fully automated thrombelastograph TEG 6s using resonance‐frequency viscoelasticity measurements and disposable multichannel microfluidic cartridges. Methods A single dose of oral dabigatran 150 mg, rivaroxaban 20 mg, or apixaban 5 mg was given to 9 healthy males. Phlebotomy was performed at 0, 1, and 3 hours after administration of DOAC. TEG parameters were measured using TEG_6s. Concentrations of DOACs were measured using chromogenic assays. The TEG parameters were correlated to the DOAC concentrations. Results The reaction time (R) demonstrated the strongest response to DOAC intake. There were no correlations between other TEG parameters and DOAC concentrations. Using the direct thrombin inhibitor (DTI) channel, R was significantly correlated with dabigatran levels (r = 0.94, P < 0.0001). Using the anti–factor Xa (AFXa) channel, R was significantly correlated with rivaroxaban and apixaban levels (r = 0.93 and r = 0.83, respectively; P < 0.0001 for both). R >2.5 minutes for dabigatran (DTI channel), >2.5 minutes for apixaban, and >1.8 minutes for rivaroxaban (AFXa channel) were associated with 100% sensitivity and ≥ 90% specificity to detect DOAC levels of ≥ 50 ng/mL. Conclusion We have demonstrated that TEG_6s R has significant correlation with DOAC blood concentrations and has potential for monitoring the DOAC's effect on hemostasis with reasonable sensitivity in the small sample analyzed. This novel technology is easy to use on a small volume of whole blood without requiring a specialized laboratory. Further study is warranted to correlate R with clinical outcomes.

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Full-text available

Sep 2017

Background and Purpose Standard operating procedures (SOP) incorporating plasma levels of rivaroxaban might be helpful in selecting patients with acute ischemic stroke taking rivaroxaban suitable for IVthrombolysis (IVT) or endovascular treatment (EVT). Methods This was a single-center explorative analysis using data from the Novel-Oral-Anticoagulants-in-Stroke-Patients-registry (clinicaltrials.gov:NCT02353585) including acute stroke patients taking rivaroxaban (September 2012 to November 2016). The SOP included recommendation, consideration, and avoidance of IVT if rivaroxaban plasma levels were 100 ng/mL, respectively, measured with a calibrated anti-factor Xa assay. Patients with intracranial artery occlusion were recommended IVT+EVT or EVT alone if plasma levels were ≤100 ng/mL or >100 ng/mL, respectively. We evaluated the frequency of IVT/EVT, door-to-needle-time (DNT), and symptomatic intracranial or major extracranial hemorrhage. Results Among 114 acute stroke patients taking rivaroxaban, 68 were otherwise eligible for IVT/EVT of whom 63 had plasma levels measured (median age 81 years, median baseline National Institutes of Health Stroke Scale 6). Median rivaroxaban plasma level was 96 ng/mL (inter quartile range [IQR] 18‒259 ng/mL) and time since last intake 11 hours (IQR 4.5‒18.5 hours). Twenty-two patients (35%) received IVT/EVT (IVT n=15, IVT+EVT n=3, EVT n=4) based on SOP. Median DNT was 37 (IQR 30‒60) minutes. None of the 31 patients with plasma levels >100 ng/mL received IVT. Among 14 patients with plasma levels ≤100 ng/mL, the main reason to withhold IVT was minor stroke (n=10). No symptomatic intracranial or major extracranial bleeding occurred after treatment. Conclusions Determination of rivaroxaban plasma levels enabled IVT or EVT in one-third of patients taking rivaroxaban who would otherwise be ineligible for acute treatment. The absence of major bleeding in our pilot series justifies future studies of this approach.

Determination of non-Vitamin K oral anticoagulant (NOAC) effects using a new-generation thrombelastography TEG 6s system

Article

Full-text available

May 2017
J THROMB THROMBOLYS

Non vitamin K oral anticoagulants (NOACs) do not require regular monitoring but information about their pharmacodynamic effect may be importantin situations like trauma, stroke oremergent surgery. Currently, no standardized point-of-care test is available to evaluate the anticoagulant effects of NOACs. We evaluated the anticoagulant effect of NOACs with the next generation point-of-care TEG assay (TEG® 6S) based on a fully-automated thrombelastography system. We used two TEG® 6S assays, the DTI assay and Anti-Factor Xa (AFXa) assay, to detect anticoagulant effects and classify NOACs. Blood from healthy volunteers (n = 26) was used to obtain a baseline reference range. Data derived from patients on factor Xa inhibitors (FXi) (rivaroxaban and apixaban) (n = 39), and direct thrombin inhibitors (DTIs) (dabigatran) (n = 25) were compared against the reference range for detection of drug effect and drug classification. TEG®6s R-time highly correlated to each NOAC. Presence of NOACs caused elongation of R-time on the AFXa assay compared to the reference range (4.3 ± 1.7 vs. 1.3 ± 0.3 min. for FXi, p < 0.001 and 3.5 ± 1.2 vs. 1.3 ± 0.3 min. for DTI, p < 0.001). R-time on the DTI assay was elongated only in presence of a DTI (3.4 ± 1.0 vs. 1.5 ± 0.2 min, p < 0.001). The cutoff for detection of a DTI effect was an R time of 1.9 min and for anti-Xa effect was 1.95 min. For detection of NOAC therapy, there was ≥92% sensitivity and ≥95% specificity. The automated TEG®6s NOAC assay may be an effective tool to identify an anticoagulant effect from NOAC therapy and facilitate care of patients with bleeding or at risk of bleeding in the event of needing emergency surgery.

Endovascular Thrombectomy with or without Intravenous Alteplase in Acute Stroke

Article

May 2020

Background In acute ischemic stroke, there is uncertainty regarding the benefit and risk of administering intravenous alteplase before endovascular thrombectomy. Methods We conducted a trial at 41 academic tertiary care centers in China to evaluate endovascular thrombectomy with or without intravenous alteplase in patients with acute ischemic stroke. Patients with acute ischemic stroke from large-vessel occlusion in the anterior circulation were randomly assigned in a 1:1 ratio to undergo endovascular thrombectomy alone (thrombectomy-alone group) or endovascular thrombectomy preceded by intravenous alteplase, at a dose of 0.9 mg per kilogram of body weight, administered within 4.5 hours after symptom onset (combination-therapy group). The primary analysis for noninferiority assessed the between-group difference in the distribution of the modified Rankin scale scores (range, 0 [no symptoms] to 6 [death]) at 90 days on the basis of a lower boundary of the 95% confidence interval of the adjusted common odds ratio equal to or larger than 0.8. We assessed various secondary outcomes, including death and reperfusion of the ischemic area. Results Of 1586 patients screened, 656 were enrolled, with 327 patients assigned to the thrombectomy-alone group and 329 assigned to the combination-therapy group. Endovascular thrombectomy alone was noninferior to combined intravenous alteplase and endovascular thrombectomy with regard to the primary outcome (adjusted common odds ratio, 1.07; 95% confidence interval, 0.81 to 1.40; P=0.04 for noninferiority) but was associated with lower percentages of patients with successful reperfusion before thrombectomy (2.4% vs. 7.0%) and overall successful reperfusion (79.4% vs. 84.5%). Mortality at 90 days was 17.7% in the thrombectomy-alone group and 18.8% in the combination-therapy group. Conclusions In Chinese patients with acute ischemic stroke from large-vessel occlusion, endovascular thrombectomy alone was noninferior with regard to functional outcome, within a 20% margin of confidence, to endovascular thrombectomy preceded by intravenous alteplase administered within 4.5 hours after symptom onset. (Funded by the Stroke Prevention Project of the National Health Commission of the People’s Republic of China and the Wu Jieping Medical Foundation; DIRECT-MT ClinicalTrials.gov number, NCT03469206.)

Dabigatran Reversal Before Intravenous Tenecteplase in Acute Ischemic Stroke

Article

Mar 2020

Background and Purpose— Reversal of dabigatran before intravenous thrombolysis in patients with acute ischemic stroke has been well described using alteplase but experience with intravenous tenecteplase is limited. Tenecteplase seems at least noninferior to alteplase in patients with intracranial large vessel occlusion. We report on the experience of dabigatran reversal before tenecteplase thrombolysis for acute ischemic stroke. Methods— We included consecutive patients with ischemic stroke receiving dabigatran prestroke treated with intravenous tenecteplase after receiving idarucizumab. Patients were from 2 centers in New Zealand and Australia. We reported the clinical, laboratory, and radiological characteristics and their functional outcome. Results— We identified 13 patients receiving intravenous tenecteplase after dabigatran reversal. Nine (69%) were male, median age was 79 (interquartile range, 69–85) and median baseline National Institutes of Health Stroke Scale score was 6 (interquartile range, 4–21). Atrial fibrillation was the indication for dabigatran therapy in all patients. All patients had a prolonged thrombin clotting time (median, 80 seconds [interquartile range, 57–113]). Seven patients with large vessel occlusion were referred for endovascular thrombectomy, 2 of these patients (29%) had early recanalization with tenecteplase abrogating thrombectomy. No patients had parenchymal hemorrhage or symptomatic hemorrhagic transformation. Favorable functional outcome (modified Rankin Scale score, 0–2) occurred in 8 (62%) patients. Two deaths occurred from large territory infarction. Conclusions— Our experience suggests intravenous thrombolysis with tenecteplase following dabigatran reversal using idarucizumab may be safe in selected patients with acute ischemic stroke. Further studies are required to more precisely estimate the efficacy and risk of clinically significant hemorrhage.

Stroke reperfusion therapy following dabigatran reversal with idarucizumab in a national cohort

Article

Feb 2020

Objective To assess the frequency and utilization trends of dabigatran reversal with idarucizumab and compare associated complications, outcomes, and door-to-needle times to those of patients not exposed to idarucizumab in a nationwide cohort of thrombolyzed patients over a 24-month period. Methods This is an observational cohort study of all New Zealand patients with stroke treated with stroke reperfusion entered into a mandatory online national registry. Each hospital records data including patient demographics, treatment delays, complications, 7-day outcomes, and idarucizumab use. Results Between 1 January 2017 and 31 December 2018, 1,336 patients received thrombolysis. Fifty-one patients received idarucizumab prior to thrombolysis (median [interquartile range] age 73 [57–83] years): 8 (1.3%) in 2017 and 43 (6%) in 2018 ( p < 0.001). Over the same 24-month period, 386 patients had stroke clot retrieval, of whom 8 (2.1%) were first treated with idarucizumab. Idarucizumab-treated patients had slower door-to-needle times (83 [54–110] minutes vs 61 [43–85] minutes, p = 0.0006). Symptomatic intracerebral hemorrhage occurred in 2 (3.9%) of the idarucizumab-treated patients and 49 (3.8%) of the other thrombolyzed patients ( p = 0.97). None of the idarucizumab-treated patients had significant thrombotic complications. At 7 days, 3 (5.9%) idarucizumab-treated and 101 (7.9%) of the other thrombolyzed patients had died ( p = 0.61). Conclusion Idarucizumab was used in 6% of all thrombolyzed patients in a national cohort during 2018, up from 1.3% in 2017. Idarucizumab appeared to be safe with similar clinical outcomes to routinely managed patients, despite a 22-minute door-to-needle time delay. Idarucizumab can facilitate thrombolysis in patients with stroke taking dabigatran. Classification of evidence This study provides Class III evidence that idarucizumab use is associated with similar early post-thrombolysis outcomes compared with patients not exposed to this drug.

Cerebral Ischemia in Patients on Direct Oral Anticoagulants: Plasma Levels Are Associated With Stroke Severity

Article

Mar 2019

Background and Purpose— In patients with ischemic stroke on therapy with vitamin K antagonists, stroke severity and clinical course are affected by the quality of anticoagulation at the time of stroke onset, but clinical data for patients using direct oral anticoagulants (DOACs) are limited. Methods— Data from our registry including all patients admitted with acute cerebral ischemia while taking oral anticoagulants for atrial fibrillation between November 2014 and October 2017 were investigated. The activity of vitamin K antagonists was assessed using the international normalized ratio on admission and categorized according to a threshold of 1.7. DOAC plasma levels were measured using the calibrated Xa-activity (apixaban, rivaroxaban, and edoxaban) or the Hemoclot-assay (dabigatran) and categorized into low (<50 ng/mL), intermediate (50–100 ng/mL), or high (>100 ng/mL). Primary objective was the association between anticoagulant activity and clinical and imaging characteristics. Results— Four hundred sixty patients were included (49% on vitamin K antagonists and 51% on DOAC). Patients on vitamin K antagonists with low international normalized ratio values had higher scores on the National Institutes of Health Stroke Scale and a higher risk of large vessel occlusion on admission. For patients on DOAC, plasma levels were available in 75.6% and found to be low in 49 (27.7%), intermediate in 41 (23.2%), and high in 87 patients (49.2%). Low plasma levels were associated with higher National Institutes of Health Stroke Scale scores on admission (low: 8 [interquartile range, 3–15] versus intermediate: 4 [1–11] versus high: 3 [0–8]; P <0.001) and higher risk of persisting neurological deficits or cerebral infarction on imaging (85.7% versus 75.6% versus 54.0%; P <0.001). Low DOAC plasma levels were an independent predictor of large vessel occlusion (odds ratio, 3.84 [95% CI, 1.80–8.20]; P =0.001). Conclusions— The activity of anticoagulation measured by specific DOAC plasma levels on admission is associated with stroke severity and presence of large vessel occlusion.

Rivaroxaban plasma levels in acute ischemic stroke and intracerebral hemorrhage

Article

Feb 2018

Objective: Information about Rivaroxaban plasma levels (RivLev) may guide treatment decisions in patients with acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH) taking rivaroxaban. Methods: In a multicenter registry-based study (Novel-Oral-Anticoagulants-In-Stroke-Patients collaboration;NOACISP;ClinicalTrials.gov:NCT02353585) of patients with stroke while taking rivaroxaban, we compared RivLev in patients with AIS and ICH. We determined how many AIS-patients had RivLev≤100ng/ml, indicating possible eligibility for thrombolysis and how many ICH-patients had RivLev≥75ng/ml, possibly eligible for the use of specific reversal agents. We explored factors associated with RivLev (Spearman correlation; regression models) and studied the sensitivity and specificity of INR-thresholds to substitute RivLevs using cross tables and ROC curves. Results: Among 241 patients (median age 80 years[IQR73-84], median time-from-onset-to-admission 2 hours[IQR1-4.5hours], median RivLev 89ng/ml[31-194]), 190 had AIS and 51 had ICH. RivLev were similar in AIS-patients (82ng/ml[IQR30-202] and ICH-patients (102ng/ml[IQR 51-165]; p=0.24). Trough RivLev(≤137ng/ml) occurred in 126/190 (66.3%) AIS- and 34/51 (66.7%) ICH-patients. Among AIS-patients, 108/190 (56.8%) had RivLev≤100ng/ml. In ICH-patients 33/51(64.7%) had RivLev≥75ng/ml. RivLev were associated with rivaroxaban dosage, inversely with renal function and time-since-last-intake (each p<.05). INR≤1.0 had a specificity of 98.9% and a sensitivity of 25.7% to predict RivLev≤100ng/ml. INR≥1.4 had a sensitivity of 59.3% and specificity of 90.1% to predict RivLev≥75ng/ml. Interpretation: RivLev did not differ between patients with AIS and ICH. Half of the patients with AIS under Rivaroxaban had RivLev low enough to consider thrombolysis. In ICH-patients, 2/3 had RivLev high enough to meet the eligibility for the use of a specific reversal agent. INR-thresholds perform poor to inform treatment decisions in individual patients. This article is protected by copyright. All rights reserved.

Coagulation Testing in Acute Ischemic Stroke Patients Taking Non–Vitamin K Antagonist Oral Anticoagulants

Article

Nov 2016

Background and purpose: In patients who present with acute ischemic stroke 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 acute ischemic stroke. Methods: Prospective multicenter observational RASUNOA registry (Registry of Acute Stroke Under New Oral Anticoagulants; February 2012-2015). Results of locally performed nonspecific (international normalized ratio, activated partial thromboplastin time, and thrombin time) and specific (antifactor 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 activated partial thromboplastin time and international normalized ratio did not reliably rule out peak drug levels at the time of the diagnostic tests (false-negative rates 11%-44% [95% confidence interval 1%-69%]). Twelve percent 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: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01850797.