Acute stroke in patients on new direct oral anticoagulants: how to manage, how to treat?

Review

Acute stroke in patients on new direct oral anticoagulants: how to manage, how to treat? 1.

Introduction

2.

Coagulation tests

3.

Ischemic stroke during

Corina Epple† & Thorsten Steiner †

Department of Neurology, Klinikum Frankfurt H€ ochst, Frankfurt am Main, Germany

treatment with novel oral

Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Dalhousie University on 07/13/14 For personal use only.

anticoagulants 4.

ICHs in patients receiving OAT

5.

Resumption of OAT after stroke

6.

Conclusion

7.

Expert opinion

Introduction: For a long time, vitamin K antagonists (VKA) were the only available oral anticoagulants for clinical use. It is conceivable that the number of patients treated with novel direct oral anticoagulants (NOAC) will increase, due to the easy handling and the favorable risk--benefit profile compared with VKA. It is, therefore, expected that clinicians will be increasingly confronted with the question on how to treat acute ischemic stroke (AIS) if there is an indication for thrombolysis or how to manage intracranial bleedings. Areas covered: In this review, we discuss controversies on thrombolysis in patients anticoagulated with NOAC, the dilemma of when to restart anticoagulation after AIS, and whether (and when) to re-institute oral anticoagulation after a brain hemorrhage. We provide suggestions for the management of these situations. Expert opinion: Thrombolysis for patients with ischemic stroke who were given warfarin at subtherapeutic International normalized ratio values (£ 1.7) may be considered according to guideline. Thrombolysis is contraindicated if intake of NOAC is reported in a patient, but no other information is available on-time of last intake of NOAC. Prothrombin complex concentrate have been proposed as a plausible, but unproven therapy to reverse the anticoagulant effects of NOACs. Keywords: acute stroke, apixaban, dabigatran, edoxaban, novel oral anticoagulants, oral factor Xa inhibitor, oral thrombin inhibitor, rivaroxaban, stroke management, warfarin Expert Opin. Pharmacother. [Early Online]

1.

Introduction

Anticoagulants are recommended for a broad range of indications. For > 50 years, vitamin K antagonists (VKA) were the only available oral anticoagulants for clinical use. Novel direct oral anticoagulants (NOAC) have been developed that directly inhibit the key coagulation factors thrombin or factor Xa. Several studies reported on the direct thrombin inhibitor dabigatran-etexilate (DE or only dabigatran in the following) and the three factor Xa inhibitors rivaroxaban, apixaban and edoxaban for primary and secondary stroke prevention in patients with atrial fibrillation (AFib), prevention and treatment of venous thrombembolism and thromboprophylaxis in patients undergoing total hip or knee arthroplasty. Four clinical trials established that the four NOACs were non-inferior concerning efficacy and safety compared to the oral VKA warfarin in patients with AFib: RE-LY (dabigatran) [1], Rocket-AF (rivaroxaban) [2], ARISTOTLE (apixaban) [3] and ENGAGE AF TIMI 48 (edoxaban) [4]. The trials were all designed to provide evidence that the preventive effect of the NOAC is not inferior to that of warfarin with regard to stroke and systemic embolism in patients with non-valvular AFib. All four trials had the same efficacy end point: stroke or systemic embolism, where ‘stroke’ included ischemic and hemorrhagic stroke. Dabigatran was approved for use in patients with 10.1517/14656566.2014.938638 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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C. Epple & T. Steiner

lower therapeutic range are not accurately detected. Table 1 summarizes effects of NOAC on coagulation tests.

Article highlights. .


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In patients receiving dabigatran, normal values for thrombin time, ecarin clotting time or the Hemoclot test rule out residual dabigatran plasma concentrations. For patients taking rivaroxaban or apixaban, residual plasma concentrations are definitively ruled out, if an antifactor-Xa assay does not detect antifactor-Xa activity in plasma. Thrombolysis for patients with ischemic stroke who were given warfarin at subtherapeutic International normalized ratio values (£ 1.7) may be considered according to guideline. Thrombolysis is contraindicated if intake of novel direct oral anticoagulant (NOAC) is reported in a patient but no other information is available on time of last intake of NOAC. Prothrombin complex concentrates have been proposed as a plausible -- but unproven therapy to reverse the anticoagulant effects of NOACs. Future treatments for NOAC-associated intracerebral hemorrhage promise to include specific antidotes to dabigatran (e.g., aDabi-Fab, PER977) and factor Xa inhibitors (e.g., r-Antidote PRT064445, PER977).

This box summarizes key points contained in the article.

Coagulation tests for direct thrombin inhibitors The ecarin clotting time (ECT) and thrombin time (TT) are sensitive to changes in dabigatran concentrations, and both show a linear correlation with dabigatran [9]. The most sensitive test to detect the presence of dabigatran is the TT. A normal-range TT assay excludes the presence of relevant plasma concentrations of dabigatran. Unlike TT, the ECT is not influenced by the use of other anticoagulants; however, the ECT is not as readily available as TT. The Hemoclot thrombin inhibitor assay (a diluted TT assay) is less sensitive than the TT and correlates linearly with plasma concentrations of dabigatran; however, it is not widely available yet. The aPTT is prolonged but not in a dose-dependent manner, because the correlation between dabigatran plasma concentrations and aPTT results is non-linear. aPTT can only be used as a qualitative measures [10]. The International normalized ratio (INR) is prolonged by dabigatran but is not sensitive enough to detect clinical relevant changes in drug concentration. 2.1

Coagulation tests for direct factor Xa inhibitors Direct factor Xa inhibitors do not influence TT but have a strong effect on anti-factor Xa assays. Rivaroxaban prolongs PT, with sensitivity depending on reagent used, and antifactor Xa assay, which may be a more appropriate surrogate for plasma concentrations [11]. Like the aPTT for dabigatran, the PT provides only a qualitative indication of the presence of rivaroxaban or apixaban. Apixaban and edoxaban have minimal impact on INR and aPTT at therapeutic concentrations, but factor Xa inhibition seems appropriately sensitive to detect its presence [12]. There are a variety of anti-factor Xa assays, which do correlate with plasma concentrations of rivaroxaban, apixaban and edoxaban, but these tests must be calibrated individually for each type of therapy being assessed (e.g., rivaroxaban, apixaban or edoxaban) [13]. Furthermore, they are not yet readily and rapidly (the tests takes about 45 -- 60 min) available worldwide. In summary, in patients receiving dabigatran, normal values for TT, ECT or the Hemoclot test rule out residual dabigatran plasma concentrations. For patients taking rivaroxaban or apixaban, residual rivaroxaban or apixaban plasma concentrations are definitively ruled out, if an antifactor-Xa assay does not detect antifactor-Xa activity in plasma [14]. 2.2

non-valvular AFib and additional risk factors in the European Union in September 2011, rivaroxaban in December 2011 and apixaban in November 2012. Edoxaban is not approved yet for AFib. Increasing ageing of the population is associated with a higher rate of cerebrovascular diseases, and every sixth stroke is the consequence of AFib. In AFib, VKA were routinely used to prevent cardioembolic strokes. NOACs appear to be safe and more convenient alternatives to warfarin. Due to the easy handling and the favorable risk--benefit profile compared to warfarin (reduced risk of intracranial hemorrhage, fewer drug and food interactions than warfarin and convenience), it is conceivable that the number of patients treated with NOAC will increase. For this reason, physicians are faced with new challenges, especially in emergency situations, where a rapid assessment of the coagulation status is mandatory, because they are not readily detected by standard coagulation tests. 2.

Coagulation tests

Each of the new oral anticoagulants prolongs certain relevant coagulation tests in a concentration-dependent manner, but no therapeutic ranges have been delineated. However, with conventional methods, it is difficult to assess the coagulation status of patients on these new treatments [5]. Thrombin inhibitors [6], as well as factor Xa inhibitors [7], have an effect on coagulation assays like prothrombin time (PT) and activated partial thromboplastin time (aPTT), but this effect is highly variable, depending on the reagents and laboratory instruments used for measurement [8]. Although these assays may be used for detecting a possible overdose, levels within the 2

Ischemic stroke during treatment with novel oral anticoagulants

3.

An acute ischemic stroke (AIS) despite anticoagulant therapy represents an ‘anticoagulation failure’. Concerning oral anticoagulant therapy (OAT) with VKA, subtherapeutic INR levels at the time of the stroke are reported to be present in 62 -- 68% of AFib patients [15]. The evaluation of data from the Oxford Community Stroke Project and the Oxford

Expert Opin. Pharmacother. (2014) 15(14)

Acute stroke in patients on new direct oral anticoagulants

Table 1. Effects of NOAC on coagulation tests.


Dabigatran aPTT PT INR TT Hemoclot test ECT Anti-factor Xa activity Peak values (hours after ingestion) ‘Peak level test’* Trough values (hours after ingestion) ‘Trough level test’z Drug specific test systems

Rivaroxaban

Apixaban

Edoxaban

"" " " """" " """" $ 2h

" to $ " to "" " to "" $ $ $ """ 2 -- 4 h

$ to " $ to " " $ $ $ """ 1 -- 4 h

" " " $ $ $ """ 1 -- 2 h Anti-Xa-activity

aPTT 12 -- 24 h

Anti-Xa-activity (PT) 16 -- 24 h



TT Hemoclot

Anti-Xa-activity Anti-factor Xa (calibrated)



Data taken from [58]. *Global available tests, which can register peak levels and are able to attest cumulation at time of peak level. ‡ Global available tests, which are sensitive enough to detect a therapeutic dose of DOAC within 12 -- 24 h trough levels. " indicates increase. $ indicates no change. aPTT: Activated partial thromboplastin time; ECT: Ecarin clotting time; INR: International normalized ratio; NOAC: Novel direct oral anticoagulant; PT: Prothrombin time; TT: Thrombin time.

Vascular Study between 1981 and 2004 revealed that the number of patients receiving OAT at the time of stroke is rising (from 1.1 to 3.8%) [16]. Each year, ~ 1.0 -- 2.0% of individuals with AFib who are receiving NOACs can be expected to experience an AIS [1,3,4,17]. Often, an inadequate dosing for stroke prevention or omission of at least one dose was reported. So far, there has been little information on medication adherence to NOAC. Interestingly, in the randomized controlled trial, discontinuation rate in both dabigatran arms in comparison to the warfarin arm was higher (21 and 21 vs 17% after 2 years, p < 0.001) in the RE-LY trial [18,19]. The main reasons were ‘patient’s decision’ and ‘gastrointestinal symptoms’. While in a study that used data from the US Department of Defense with 1775 patients on warfarin and 3370 on dabigatran, Zalesak et al. found a better adherence for dabigatran [20]. It can be assumed that these factors weigh even more profoundly on medication adherence in daily clinical practice than in a careful selected study population with regular follow-up. During warfarin treatment with regular coagulation monitoring, patients and physicians receive a regular feedback on medication adherence. In case of NOAC, these ‘check-ups’ are missing [19]. On the other hand, despite this coagulation monitoring the per cent time in therapeutic INR range (TTR) varies a lot and in many countries, TTR is lower than 60%, a generally accepted threshold above which warfarin confers significant benefit [21]. Thrombolytic treatment receiving NOAC therapy Intravenous thrombolysis in anticoagulated patients

3.1

3.1.1

Thrombolytic treatment with recombinant tissue-type plasminogen activator (rt-PA) within a 4.5-h time window

after symptom onset is an established therapy for selected patients with AIS [22]. Even without anticoagulants, intravenous thrombolysis (IVT) increases the risk of secondary hemorrhage more than fivefold [23]. In principle, anticoagulation represents a contraindication for thrombolytic therapy in acute stroke. Although European guidelines do not define an INR limit and IVT in acute stroke patients on oral VKA is considered as ‘contraindicated’, most clinicians follow the American guidelines, in which thrombolysis is recommended if the INR is £ 1.7 [24,25]. This recommendation was largely based on assumptions but is supported by the results of one large registry [26,27]. Data on thrombolysis in patients with AIS and treated with NOACs are limited. Before considering thrombolysis in a patient with AIS who is receiving a NOAC, it is important to perform an assessment of benefits and risks, with the main risk of bleedings, particularly intracranial hemorrhages. The key information that need to gathered are: When was the last intake of the drug? What was the dose of the drug? How are renal and liver functions? These factors influence the current plasma concentration, which drives the anticoagulant effect of the drug and thus the risk of hemorrhage. The time of last intake is important for interpreting of the coagulation test, because these assessments reflect the peak levels of the drug, ensuring that the assays are performed at or after peak levels of the drugs have occurred. Under normal circumstances, the half-life of the NOACs is between 12 and 24 h [28]. Thrombolysis in AIS patients taking NOAC is contraindicated because of a presumed increased risk of symptomatic hemorrhagic transformation. Anticoagulant drugs, including the direct thrombin and factor Xa inhibitors increase the


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porosity of fibrin clots [29]. It is to be expected that clots developing in the presence of dabigatran, rivaroxaban, apixaban, edoxaban or other direct thrombin or factor Xa inhibitors are more responsive to fibrinolytic therapy. This may result in increased risk of intracranial hemorrhage associated with fibrinolytic therapy, although it is a matter of speculation whether the anticoagulant drug needs to be present already during clot formation to cause the effect or presence of the drug during fibrinolysis is sufficient [30]. Using recent recommendations, it is unlikely that patients on NOAC who experience an AIS would be suitable for thrombolysis, unless they have missed their NOAC dose for the last 24 -- 48 h (2 -- 4 half-lives elapsed) [27,31]. In Europe, approved commercial assays for the newer agents, such as BIOPHEN DiXaland TECHNOVIEW Rivaroxaban CAL Set, are now becoming available [32]. IVT in dabigatran-treated patients We found several case reports on thrombolysis for AIS in patients receiving dabigatran without secondary intracerebral hemorrhage (ICH) [33-36]. One patient with several risk factors for hemorrhagic transformation (diabetes mellitus with hyperglycemia upon presentation and a large perfusion deficit on CT) who received IVT suffered a fatal secondary ICH after thrombolysis despite normal coagulation parameters [37]. These cases indicate that thrombolysis might be safe, if the aPTT is in the normal range, indicating that little dabigatran is present. Of course, general risk factors for thrombolysisassociated hemorrhage as hyperglycemia, severe strokes and large perfusion deficits or extensive early infarct signs have to be taken into consideration. Experimental studies in murine stroke models have shown that effective dabigatran anticoagulation with plasma levels up to 400 ng/ml does not lead to an increase in secondary ICH after rt-PA application [38] or to an increase of hemorrhagic transformation in case of a continued [39] or early initiated [40] anticoagulation after experimental stroke. One possible consequence might be the opportunity to start early anticoagulation after a cardioembolic stroke, because NOAC might be safer than warfarin in terms of ICH. The implications of this finding for stroke patients have to be determined in the clinical setting. 3.1.2

IVT in rivaroxaban-treated patients In the first case report of a patient with AIS undergoing IVT despite rivaroxaban pretreatment, Fluri et al. report a favorable clinical outcome, which may be related to a reduced dose of rivaroxaban (15 mg) as well as the relatively long interval between the last drug intake and the thrombolytic treatment (21 h) [41]. A second case report recently published also reports a gradually clinical improvement after administration of IVT in a patient treated with 20 mg rivaroxaban. The control CT scan of the brain showed an infarction with hemorrhagic transformation. Similar to the first case report, a long dosing interval before IVT (24 h) was present, which 3.1.3

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may be associated with the good functional outcome in both cases [42]. Ploen et al. examined the risk of secondary postischemic hemorrhage after thrombolysis in rodents pretreated with rivaroxaban or warfarin. In contrast to warfarin, rivaroxaban did not increase the rate of secondary hemorrhage after thrombolysis, which may be due to smaller effects of rivaroxaban on postischemic blood--brain barrier permeability [43]. IVT in apixaban-treated patients Cases of thrombolysis in acute stroke patients on treatment with apixaban have not been published or reported to date. 3.1.4

Thrombectomy Neurointerventional recanalization of proximal intracranial artery occlusion represents an alternative option in OAC patients, but the available evidence regarding efficacy and safety of such procedures in general and in this particular setting is limited. Data from three randomized trials comparing IVT with thrombectomy alone or combined thrombolysis and thrombectomy (bridging concept) confirmed that endovascular treatment of stroke is as safe as intravenous rt-PA, without increasing mortality and hemorrhagic risk, although they showed no superiority to the interventional approach compared with systemic thrombolysis with rt-PA [44-47]. Patients receiving anticoagulation were not included; furthermore, it must be noted that in all three trials, first-generation recanalization devices were used. In 2010, modern catheters with high flow aspiration and stent-retriever technology in combination with balloonmounted aspiration-guiding catheters were developed in Europe and showed efficient recanalization rates. On the basis of the limited evidence from the small non-randomised observational studies (all of which have several potential biases), previous treatment with antithrombotic therapy and altered hemostasis did not seem to be associated with a substantial increase in risk of symptomatic intracranial hemorrhage if individualized revascularization strategies are applied and if endovascular microsurgical thrombectomy is done by an expert team of interventional neuroradiologists [27]. Whether this is also the case for thrombectomy in patients treated with NOAC needs to be investigated. 3.2

4.

ICHs in patients receiving OAT

ICHs account for 10 -- 17% of all strokes [48]. Hemorrhages into the brain occur unexpectedly and are often lethal events. ICH like ischemic stroke has a clear age-dependent incidence rate, occurring slightly earlier in life than ischemic strokes. The use of oral anticoagulants such as warfarin or phenprocoumon, also a contributing rather than a causative factor, does not only lead to a higher incidence of ICH but also lead to hematoma expansion in 27 -- 54% of the cases, and well beyond the 24-h time window (where most of hematoma expansion has already occurred in spontaneous ICH) [49]. This



might at least partly explain a substantial increase in mortality of up to 70%. Underlying causes of spontaneous ICH and ICH associated with OAT might be the same, with OAT being only a precipitating factor [50-52]. However, in the event of ICH related to NOACs we are concerned, that hematoma expansion does occur, although current data did not show this directly yet. Vitamin-K-antagonist-associated ICH VKA-associated ICH (VKA-ICH), which affects up to 0.6 -- 1% of patients per year, is the most feared and devastating complication of anticoagulant treatment [53]. Experts agree that anticoagulation has to be reversed rapidly, but the chosen ways to achieve this differ greatly [54]. Although the focus of this paper is on NOAC treatment, we wanted to point out that even in case of VKA-associated ICH there is an ongoing controversy with regard to treatment and different guidelines are inconsistent on an international level. None of the treatment regimens have been proven to be more effective than another. It is customary to discontinue oral VKA and substitute vitamin K, but this alone is insufficient for rapid normalization of coagulation, even when given intravenously, because it requires several hours to correct the INR. Therefore, vitamin K cannot be considered as an antidote. One retrospective study found faster INR reversal by prothrombin complex concentrate (PCC) compared to fresh-frozen plasma (FFP) in patients with acute VKA-ICH [55]. This attribute of PCCs might be explained by a higher concentration of coagulation factors in PCCs compared with FFP, which contains all coagulation factors in a non-concentrated form [56]. The INCH (INR Normalization in Coumadin associated intracerebral Hemorrhage)-trial, an ongoing multi-center randomized controlled trail to compare FFP with PCC, has been initiated 2009 to answer the question of INR early reversal [57].


4.1

NOAC-associated ICH Clinical trials of the NOAC suggest that ~ 0.2 -- 0.5% of individuals receiving a NOAC for the prevention of AFib-related stroke can be expected to experience an ICH each year [1,3,4,17]. In an emergency setting of ICH associated with NOAC treatment physicians face the problem that oral anticoagulation in comatose or aphasic patients might go undetected unless laboratory methods such as anti-factor Xa assays (in case of edoxaban or rivaroxaban), ECT, TT or hemoclot assays (in case of dabigatran) are applied [58]. ICH remains the most serious and lethal complication of longterm use of oral anticoagulation, but the risk of hematoma expansion with NOACs is not known. The optimal management of NOAC-associated-ICH is unknown, and no specific antidote is available. 4.2

Direct thrombin inhibitors-associated ICH In this section, we will only consider dabigatran, because it is the only direct thrombin inhibitor with approval for primary 4.2.1

and secondary preventions in patients with AFib. Anticoagulation with dabigatran was associated with significantly less primary intracerebral hemorrhagic complications compared with warfarin in the RE-LY trial (warfarin 0.74%/year, DE 110 mg 0.23%/year and DE 150 mg 0.3%/year) [1,59]. No preclinical model has been established to test potential hemostatic strategies so far. Zhou et al. therefore established a murine model of OAC-ICH that was sensitive to pretreatment with dabigatran and assessed the kinetics of hematoma expansion after collagenase-induced ICH in mice, and tested the efficacy of different hemostatic factors. The major findings of this study was that high doses of dabigatran caused an early excess hematoma expansion in this model, secondly administration of coagulation factors (particularly PCC) prevented excess hematoma expansion caused by dabigatran and last that PCC reversed the prolongation of tail vein bleeding time and prevented excess hematoma expansion in a dose-dependent manner and was associated with improved survival [60]. Because the pathophysiology of ICH in patients is only partially reflected in current experimental ICH models, the efficacy and safety of this strategy must be further evaluated in appropriate clinical studies. In summary, although data are lacking, it may be reasonable to give PCC in patients with dabigatran-associated ICH. Factor Xa-inhibitors-associated ICH The ROCKET AF trial showed less intracranial hemorrhages with rivaroxaban (warfarin 1.2%/year, rivaroxaban 0.8%/year) [2]. Similarly, therapy with apixaban (5 mg twice daily) led to significantly fewer intracranial hemorrhages (0.33%/year) than did warfarin (0.8%/year) in ARISTOTLE [61]. The ENGAGE AF-TIMI 48 trial showed significantly lower rates of intracranial bleeding (warfarin 0.85%/year, edoxaban 30 mg 0.26%/year and edoxaban 60 mg 0.39%/year) [4]. In addition, there is no antidote for acute reversal of rivaroxaban, apixaban or edoxaban available either. Eerenberg et al. [62]. presented a reversal of coagulation tests by PCC for rivaroxaban in volunteers, while the results for dabigatran are inconclusive because bleedings duration was not assessed. However, the efficacy of this treatment has not been demonstrated in clinical trials. 4.2.2

Therapeutic options in case of NOAC-ICH PCCs have been proposed as a plausible -- but unproven therapy to reverse the anticoagulant effects of NOACs. Some of the PCC preparations contain unactivated vitamin K-dependent clotting factors, whereas others (activated PCC) contain activated clotting factors. The latter preparations may be more potent but also have higher thrombogenic potential [63]. Diuresis with intravenous fluids may enhance the renal excretion of dabigatran. Acute hemodialysis might also be useful, because only about one-third of dabigatran is bound to plasma proteins and can therefore not be dialyzed. But it has admitted that hemodialysis may take hours to begin and complete. Hemodialysis is not suitable for apixaban, rivaroxaban and edoxaban, 4.2.3


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because of a plasma protein binding of 85 -- 95% for apixaban and rivaroxaban and 65% of edoxaban. Therefore, plasmapheresis seems more plausible for these drugs. However, in the emergency setting, hemodialysis and plasmapheresis may be difficult [10,64]. Target-specific antidotes are in clinical proving and hold promise for NOAC reversal but require further investigation [65,66]. The recombinant protein PRT064445 (also known as ‘r-Antidote’ or ‘andexanet a’) lacks the membrane-binding g-carboxyglutamic acid domain of native factor Xa inhibitors. r-Antidote may have the potential to be used as a universal antidote for a broad range of factor Xa inhibitors [67]. Schiele et al. reported of a future antidote for dabigatran (aDabi-Fab; BI 655075, idarucizumab), that achieves an affinity for dabigatran that is ~ 350 times stronger than its affinity for thrombin and despite the structural similarities it does not bind known thrombin substrates and has no activity in coagulation tests or platelet aggregation. aDabi-Fab rapidly reversed the anticoagulant activity of dabigatran in vivo in a rat model of anticoagulation [68]. The small synthetic molecule called PER977 is another antidote drug that might reverse the activity of all the new oral anticoagulation drugs -- both the factor Xa and factor IIa inhibitors -- as well as certain forms of heparin. However, studies on antidotes for dabigatran (completed: Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of BI 655075 Administered Alone or With Dabigatran Etexilate, www.clinicaltrials.gov; NCT01688830; or not yet recruiting: Phase III-Reversal of Dabigatran Anticoagulant Effect With Idarucizumab; NCT02104947), for rivaroxaban and apixaban (recruiting: Phase II Healthy Volunteer Study to Evaluate the Ability of PRT064445 to Reverse the Effects of Several Blood Thinner Drugs on Laboratory Tests; NCT017 58432) and edoxaban (completed: Effects of a Single-Blind, Single Dose of PER977 Administered Alone, and Following a Single Dose of Edoxaban, NCT01826266) are currently being conducted. 5.

Resumption of OAT after stroke

When start or resume OAT after ischemic stroke? In clinical practice, we face the problem when to start or restart the OAT, due to an elevated risk of hemorrhagic transformation. Personal opinion generally shapes the decision. Data concerning this conflicting issue are rare. Some guidelines recommend that after AIS in patients with non-valvular AF, OAT should be started 1 -- 2 weeks after stroke onset, by which time the risk of hemorrhagic transformation of the fresh brain infarct is likely to have subsided [31]. In general, resumption of NOAC can be restarted, when a treatment with intravenous heparin is possible without hesitation. This is an important difference to resumption of OAT with warfarin, because NOAC causes a complete anticoagulation effect within a few hours. Gliem et al. reported data for de novo anticoagulation after experimental ischaemic stroke in mice. Although warfarin increased the risk of hemorrhagic transformation, mice pretreated with dabigatran did not have a higher 5.1

6

rate of hemorrhagic complications than did anticoagulationnaive controls. All these findings show a reduced risk of dabigatran on hemorrhagic complications in AIS, with and without thrombolytic treatment [27,40]. A recent practice guideline by the European Heart Rhythm Association gives a personalized recommendation, taking into consideration, that the infarct size is important for the decision when to resume anticoagulation. Heidbuchel et al. advocate as a rule of thumb the 1-3-6-12-day rule with reinstitution of OAT in patients with a transient ischemic attack after 1 day, with small, non-disabling infarct after 3 days, and with a moderate stroke after 6 days; while large infarcts involving large parts of the arterial territory should not be treated before 2 (or even 3) weeks have elapsed [31,32]. When resume OAT after intracerebral bleeding? A related issue is whether or when to resume anticoagulation after ICH in patients with cardiac disease associated with high embolism risk, such as those who need mechanical valve prostheses or those with AFib, although the labels of the VKAs and the NOAC state that ICH constitutes a contraindication for oral anticoagulation and therefore re-starting anticoagulation after ICH would be off-label use. The decision on restarting OAT means to balance between two risks: ischemic stroke and rebleeding and is often made on the basis of a risk--benefit analysis in the context of the individual patient [69]. Anticoagulation has been estimated to double the risk or recurrent ICH compared with the overall recurrence risk of ICH, and the mortality rate associated with recurrent ICH can be as high as 50% [70,71]. There is no way of accurately estimate the bleeding risk of an individual patient after ICH occurring during OAT treatment. The HAS-BLED score is closely related to hemorrhagic risk and patients with a score 3 are considered at high risk, although this bleeding score does not include prior ICH in the basis of risk estimation [69,72]. The risk of recurrent ICH can depend on factors such as patient’s age and the location of ICH, presence of the apolipoprotein "2 or "4 alleles, and greater number of microbleeds on MRI. Patients with lobar hemorrhages are at higher risk of rebleeding, probably due to suspected amyloid angiopathy [73]. Patients with lobar hemorrhage or cerebral amyloid angiopathy remain at higher risk for anticoagulant-related ICH recurrence than thromboembolic events and, therefore would be best managed without anticoagulants, concerning Eckman et al. [74]. Patients with deep hemispheric ICH and a baseline risk of ischaemic stroke > 6.5%/year (that corresponds to CHA2DS2-VASc ‡ 5), may receive net benefit from restarting anticoagulation [74-76]. The optimum timing of the resumption of anticoagulation is a crucial issue with conflicting evidence. Although guidelines from the American Heart Association and American Stroke Association (AHA/ASA) suggest restarting warfarin 7 -- 10 days after ICH, the European Stroke Initiative (EUSI) after 10 -- 14 days, there are others who suggest the optimal time point during 10 -- 30 weeks [77]. Concerning 5.2



resumption of OAT with NOAC data are unavailable. We propose to restart NOAC not earlier than 2 -- 3 weeks after ICH, taking into consideration risk factors such as a greater number of microbleeds on MRI, lobar ICH, history of previous ischemic stroke or diabetes mellitus. Further investigations with observational trials as stroke register or prospective trials are needed to answer this question.


6.

Conclusion

In conclusion, OAT at the onset of AIS represents a frequent and highly relevant problem for the emergency management of ischemic stroke. In patients with AIS who are eligible for systemic thrombolysis, the uncertainty of anticoagulant intake causes new problems for stroke management. An effective anticoagulation with vitamin K antagonists is a contraindication for systemic thrombolysis. But, thrombolysis for patients with ischemic stroke who were given warfarin at subtherapeutic INR values (£ 1·7) may be considered according to guideline. Whether these principles can be transferred to thrombolysis of acute stroke patient receiving novel oral anticoagulants is not clear. Certainly, thrombolysis is contraindicated if intake of NOAC is reported in a patient but no other information is available on time of last intake of NOAC, dose and renal and liver function. Specific thresholds of coagulation tests or drug concentrations that indicate the risk of hemorrhagic events have not been established by prospective studies yet, although there are some suggestions available based on expert opinion. There is an urgent need for sensitive bed-site tests for these emergencies. Thrombectomy may be considered if thrombolysis is clearly contraindicated in these patients. The overall risk of intracranial hemorrhage (which includes hemorrhagic stroke) as a complication of NOACs is roughly the half of the risk in VKA-treated patients, which represents a substantial benefit of treatment with NOACs [78]. In case of a bleeding, methods to reverse NOAC are not yet well established. Findings from experimental studies of ICH associated with high-dose dabigatran and rivaroxaban treatment suggest that hematoma growth does occur with very high doses and might be prevented with PCC [79,80]. Whether this is true for apixaban and edoxaban has not been studied in animal models. Hemodialysis for dabigatran and charcoal ingestion for dabigatran and apixaban have been recommended to reduce drug concentration. Specific antidotes are currently tested in Phase II and III trials. 7.

Expert opinion

The number of emergency situation related to novel oral anticoagulants will increases the frequency of prescription of these drugs is increasing. It is, therefore, important to develop management protocol to be prepared for emergency situations like thrombolysis or life-threatening bleeding. In emergency situations, such as the occurrence of acute neurological symptoms in patients treated with dabigatran,

apixaban, edoxaban or rivaroxaban, TT and aPTT (for dabigatran) or adjusted antifactor-Xa assay (for direct factor Xa inhibitors) should be performed before invasive procedures, such as surgery or fibrinolytic therapy. However, these tests are only quantitative tests. Until point-of-care methods for the detection and measurement of plasma levels of NOAC are available the indication for thrombolytic treatment remains a difficult challenge and the risks of bleeding and the benefits of thrombolysis need to be balanced. Thrombolysis may be considered in case of either a normal TT, ECT or Hemoclot thrombin inhibitor assay ‡ 4 h after the final dose has been administered to patients taking dabigatran, or if the aPTT is in the normal range (indicating that little dabigatran is present) or a normal anti-Factor Xa assay ‡ 5 h after the final dose has been administered to patients taking rivaroxaban, apixaban or edoxaban, because a clinically relevant anticoagulant effect can be excluded in patients taking NOACs. An expert conclusion came to the following conclusion: “With mild or moderate prolongation of TT (< fourfold URN), ECT (< twofold URN) or Hemoclot (< 50 ng dabigatran/ml), or missing availability of these laboratory results, but normal PTT, thrombolysis may be considered after an individual risk benefit assessment”. For example, high (supratherapeutic) dabigatran concentrations, which can result from renal insufficiency, for example, were associated in mouse model with increased rates of hemorrhagic transformation [60]. Likewise, in acute stroke patients on factor Xa-inhibitors IVT might be considered if calibrated anti-factor Xa activity is normal or if plasma concentration is < 100 ng/l in rivaroxaban-treated patients or < 10 ng/l in apixaban-treated patients [58]. Although it is well known that patients may suffer ischemic strokes despite oral anticoagulation, prospective studies consecutively enrolling AIS patients and evaluating the impact of OAC use on stroke management in the neurological emergency room are sparse. Therefore, prospective registries are urgently needed that obtain information about this topic. The GLORIA-AF registry (NCT01428765) (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is designed to investigate patient characteristics influencing choice of antithrombotic treatment of stroke prevention in patients with non-valvular AFib and to collect data on outcomes of antithrombotic therapy in clinical practice [81]. The RASUNOA registry (NCT01850797) examines diagnostic and therapeutic aspects of ischemic and hemorrhagic stroke occurring during therapy with new oral anticoagulants [82]. Finally, the purpose of the GARFIELD registry (NCT01090362) is to evaluate the management and outcomes of patients with newly diagnosed non-valvular AFib at risk for stroke [83]. Neurointerventional recanalization of intracranial artery occlusion represents an alternative option in OAC patients with AIS but has clearly not been tested in this indication. Due to the lack of head-to-head comparisons, it cannot be decided whether Factor Xa inhibition or thrombin inhibition


7


has a better risk--benefit ratio. The question arises, if subtle differences among the new anticoagulant agents with respect to the prevention of ischemic stroke, myocardial infarction, bleeding or death reflect real differences in clinical efficacy and safety or if they are due to aspects of the trial design, such as patient population. Although it would be desirable to have such comparative studies in the future it is probably unrealistic since all new drugs have been introduced into the market.


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Declaration of interest T Steiner has received honoraria and consultation fees from Boehringer Ingelheim and Bayer and honoraria from Bristol Meyers Squibb and Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Affiliation

Corina Epple†1 MD & Thorsten Steiner1,2 MD PhD MME † Author for correspondence 1 Department of Neurology, Klinikum Frankfurt H€ochst, Frankfurt am Main, Germany E-mail: [email protected] 2 University of Heidelberg, Department of Neurology, Heidelberg, Germany

11

How we treat bleeding associated with direct oral anticoagulants.

How to manage thrombolysis interruptions in acute stroke?

[How to manage patients with CRPC?].

How to manage gynaecology on call.

Potential new uses of non-vitamin K antagonist oral anticoagulants to treat and prevent stroke.

How to manage asparaginase hypersensitivity in acute lymphoblastic leukemia.

Direct oral anticoagulants (DOACs) versus "new" oral anticoagulants (NOACs)?

How I treat and manage strokes in sickle cell disease.

Direct oral anticoagulants: key considerations for use to prevent stroke in patients with nonvalvular atrial fibrillation.

Geriatric syndromes: How to treat.

[Novel oral anticoagulants in patients with atrial fibrillation, how to avoid accidents?].

Direct oral anticoagulants in acute coronary syndrome.

How to manage mantle cell lymphoma.

Management of acute stroke in patients taking novel oral anticoagulants.

How to optimally manage elderly bladder cancer patients?

Erratum: How to manage warfarin therapy.

How best to manage gastrointestinal stromal tumor.

Hepatitis E: when to treat and how to treat.

How to Treat Obstructions in Patients with Hypertrophic Cardiomyopathy.

How to approach and treat viral infections in ICU patients.

How to treat fungal infections in ICU patients.

How to treat severe infections in critically ill neutropenic patients?

How to approach and treat VAP in ICU patients.

Generalized anxiety disorder: how to treat, and for how long?