Specific Reversal Agents for Direct Oral Anticoagulants in Acute Stroke

Abstract

Direct oral anticoagulants (DOACs) changed stroke prevention and decreased the risk of ischemic and hemorrhagic complications in patients on oral anticoagulation (OAC) therapy. The numbers of patients prescribed DOACs has increased rapidly. Availability of specific reversal agents opened new avenues in the prevention and management of DOAC complications. An ideal specific reversal agent for a DOAC in acute stroke is an agent which lacks safety concerns and immediately reverses DOAC anticoagulation activity, thereby enabling effective treatment. Reversal of anticoagulant activity is mandatory in patients with acute ischemic stroke (AIS) before performing therapeutic procedures such as intravenous thrombolysis (IVT) and neurosurgery in intracranial hemorrhage (ICH) in order to improve clinical outcomes. In this manuscript we pursue an interdisciplinary approach in discussing advantages and concerns of specific reversal agents in acute stroke DOAC-treated patients in everyday clinical practice.

Introduction

Large randomized controlled trials (RCTs) and real-world data have shown efficacy and safety of direct oral anticoagulants (DOACs) when compared to warfarin in patients with nonvalvular atrial fibrillation (AF)^1–6 and acute venous thromboembolism (VTE) ⁷ making DOACs the first line therapy in these patients.^8,9 Among DOACs, factor Xa inhibitors have the largest market share.^10,11 A multinational population-based cohort study of 527 226 patients revealed that factor Xa inhibitors were initiated in 466 218 patients (88.4%). ¹¹

Although DOACs are effective and safe, results from the pivotal RCTs indicate that about 1%-2% of DOAC-treated individuals suffer from acute ischemic stroke (AIS)^1–4 annually and 0.1%-0.2% are affected by intracranial hemorrhage (ICH).^1–4

In patients with AIS the first line recommended therapy is revascularization by intravenous thrombolysis (IVT).^12,13 In DOAC-treated AIS patients the American Heart Association/ American Stroke Association ¹³ guidelines recommend IVT only if the last DOAC intake was >48 h prior to symptoms onset or if the anticoagulant activity is proven to be absent. ¹³ Similarly, the European stroke organization ¹² and European Heart Rhythm association ¹⁴ guidelines recommend IVT if DOAC intake was >48 h prior to AIS symptoms. In case DOAC was taken <48 prior to symptoms the recommendation depends on the type of DOAC. In dabigatran-treated AIS patients the use of its specific antidote idarucizumab prior to IVT is recommended. On the contrary, in AIS patients taking factor Xa inhibitors guidelines oppose to antagonization by andexanet alfa. However, in a recent international, multicentre, observational, retrospective cohort study ¹⁵ the authors assessed the risk of symptomatic ICH (SICH) in DOAC-treated AIS patients undergoing IVT. They suggest that recent ingestion of DOACs within 48 h before IVT was not associated with an increased risk of SICH compared with patients not taking DOACs, regardless of the use of a reversal agent or measurement of DOAC plasma levels. The authors pointed out several methodological issues that could affect the results. ¹⁵ A prospective registry and trial (DO-IT: DOAC International Thrombolysis trial & registry) is currently collecting data further investigating this important clinical issue.

For spontaneous ICH normalization of hemostasis, neurointensive care and instant lowering of systolic blood pressure (BP) to 140 mm Hg aiming at the prevention of hematoma expansion as well as neurosurgical ICH evacuation if indicated, are established therapeutic strategies not only in patients treated with oral anticoagulants.^16,17 Moreover, in anticoagulated ICH patients EHRA, ESO and AHA/ASA guidelines recommend idarucizumab application in dabigatran-treated patients and andexanet alfa in rivaroxaban and apixaban-treated patients suffering ICH, respectively.^14,16,17 Current recommendations, however, are not based on data from RCTs but mainly on the open-label pivotal trials,^18,19 retrospective case collections^20–22 and expert opinions. At least, for andexanet alfa results from the randomized Andexanet Alfa, a Novel Antidote to the Anticoagulation effects of FXa inhibitors (ANNEXA)-I trial ²³ are now available but it remains elusive at this point, how these results will be incorporated into international guidelines, in particular when patients are treated with edoxaban. The RCT ANNEXA-I demonstrated superior hemostatic efficacy at 12 h compared to usual care (85.5% prothrombin complex concentrate (PCC)). ²³ The trial was terminated early by the data and safety monitoring board due to the overwhelming efficacy. ²³

Beyond doubt, introduction of DOACs changed the approach to oral anticoagulation and decreased the risk of hemorrhagic complications and availability of their specific reversal agents opened new avenues in the prevention and management of DOAC complications. Currently, reversal of anticoagulant activity is mandatory in patients with AIS before performing therapeutic procedures such as IVT and neurosurgery to improve clinical outcomes.

In this manuscript, a group of physicians with different backgrounds and expertise discusses advantages and concerns of specific DOAC reversal agents in acute stroke patients in everyday clinical practice (vascular neurology, internal medicine, neurosurgery, interventional neuroradiology, cardiology).

Specific Reversal Agents for DOAC-Treated Patients

Currently, two specific reversal agents, idarucizumab and andexanet alfa are in use for DOAC-treated patients, idarucizumab since the year 2015 and andexanet alfa since 2018.

Idarucizumab, the specific reversal agent for dabigatran, enables complete and immediate reversal of dabigatran anticoagulation ¹⁸ when used as 2 vials of 2.5 gm each for total of 5 gm given intravenously (i.v.) as bolus injection or infusion. ¹⁸ Use of idarucizumab is indicated in dabigtran-treated patients suffering life-threatening/uncontrolled bleeding or in need of urgent interventions. Its safety (low mortality rate, no intrinsic pro-or anti-coagulant activity) and efficacy has been shown in the REVERSal Effects of idarucizimab on Active Dabigatran (RE-VERSE AD) study. ¹⁸ There is accumulating real-world evidence on safe^15,20 and effective use of idarucizumab in patients with AIS. ²⁰ Large real-world cohorts^21,22 and reviews ²⁰ evaluating safety and efficacy of idarucizumab use in ICH patients confirm low mortality rates in real-world clinical practice.

Andexanet alfa is a specific reversal agent for factor Xa inhibitors, currently indicated only for use in apixaban and rivaroxaban-treated patients suffering life-threatening or uncontrolled bleeding. ¹⁹ Application as intravenous bolus and continuous 2 h infusion has been approved in 2018. Immediate reversal of anti-Xa activity with high hemostatic efficacy and low mortality rate has been shown in the ANNEXA-4 trial. ¹⁹ However, a significant rate of complications was described. Namely, 10% of patients in the ANNEXA-4 trial suffered thrombotic events. ¹⁹ The prospective ANNEXA-I RCT, ²³ performed according to FDA requirements, compared the efficacy and safety between andexanet alfa and usual care (including PCC or no PCC). ²³ Due to high hemostatic efficacy in ICH patients treated with andexanet alfa ANNEXA-I trial was terminated early due to the overwhelming efficacy in June 2023. ²³ Thrombotic events were reported at identical levels (10.3%) as for the ANNEXA-4 trial. ²³ Real-world data ²⁴ regarding hemostatic efficacy of AA in ICH patients treated with rivaroxaban and apixaban seems to be comparable to the findings in ANNEXA-4 trial, but there are still some concerns regarding prothrombotic activity, although in the 70% of patients who received at least one dose of anticoagulant, the thrombotic event difference is completely negated (4.9% and 4.8%). ²⁵

Use of Specific Reversal Agents in DOAC-Treated Patients with Acute Stroke

Regarding DOAC-treated patients suffering AIS an ideal specific reversal agent must enable immediate reversal of DOAC anticoagulation activity and result in regain of eligibility for IVT as well as neurosurgical procedures like decompressive craniectomy, if needed. Alteplase is mainly used as fibrinolytic agent in IVT, but tenecteplase has recently been approved for IVT in AIS in Europe. Tenecteplase, a genetically modified version of alteplase, has higher fibrin specificity, ²⁶ potentially enhancing thrombolysis and improving clinical outcomes. Hence, more data has to be collected on the use of specific reversal agents prior to tenecteplase.

Regarding DOAC-treated patients suffering ICH an ideal specific reversal agent should normalize DOAC anticoagulation activity quickly, prevent hematoma expansion and have excellent hemostatic efficacy resulting in better functional outcomes. Importantly, the ENRICH trial, evaluating functional outcome after minimally invasive ICH evacuation within 24 h of symptom onset, showed better functional outcomes at 3 months in ICH-evacuated patients compared to conservatively treated ICH patients. ²⁷ Therefore, a specific reversal agent should be promptly given to DOAC-treated ICH patients prior to neurosurgery to reverse anticoagulant effect as quickly as possible.

Neurosurgery and Coagulation

Neurosurgery in patients under oral anticoagulation (OAC) therapy carries a significant risk of procedural morbidity, since merely every step of the surgical procedure is hampered by insufficient coagulation.

Extracerebral Neurosurgery Under Conditions of Compromised Coagulation

In patients suffering subdural hematomas and malignant middle cerebral artery infarctions, decompressive craniectomies (DHC) in conjunction with wide dural openings are performed to reduce intracranial pressure (ICP). In patients under anticoagulant medication, hemostasis can be impeded by diffuse bleeding in the epidural and/or subdural space and wound closure under these circumstances results in early recurrent hematomas. In absence of a watertight dural closure, the use of subgaleal suction drains to prevent hematoma formation is contraindicated, since these can trigger high ICP gradients and significant morbidities (upward herniation) when rapidly draining large volumes of cerebrospinal fluid (CSF).^28–31 In absence of a bone flap over the osteoclastic craniectomy, pressure dressings to prevent subgaleal hematoma formation are also contraindicated. Under these circumstances, every subgaleal hematoma resembles an epidural hematoma and in patients with compromised coagulation, these hematomas can reach significant sizes early after surgery and can exert life threatening mass effect. Pharmacologic antagonization of anticoagulant medication is a key factor to overcome this problem.

Intracerebral Neurosurgery Under Conditions of Compromised Coagulation

In patients suffering hypertensive ICH, the role of surgery is in a process of being defined. The STICH trials^32,33 have not proven the insufficiency of neurosurgical ICH management but rather demonstrated that acute surgery within 72 h of onset may not be required in the majority of patients. Whereas the SWITCH trial failed to demonstrate a benefit of DHC without ICH evacuation, ³⁴ the recent ENRICH trial showed a significant benefit of minimally invasive lobar ICH removal within 24 h of onset when compared to conservative management. ²⁷ Regardless the surgical technique used, intracerebral neurosurgery depends on intact coagulation since the mechanical properties of the subcortical brain parenchyma prevent hemostasis by mechanical compression of the bleeding site. Whereas passive hemostasis is obtained during ICH surgery by rinsing with artificial CSF, active bleeding in large ICH cavities may be difficult to manage via keyhole corticotomies or endoscopic approaches. In ICH patients under anticoagulant medication, passive hemostasis in the subcortical parenchyma will not occur and active surgical hemostasis is hindered as outlined above. Elective intracerebral surgeries in patients under anticoagulant medication are therefore contraindicated and the benefits of acute interventions must carefully be weighed against the consequences of recurrent ICH. Sufficient pharmacologic antagonization of anticoagulant medication is the key factor to overcome this problem. A large retrospective multicenter observational cohort study found that patients hospitalized with major bleeding due to rivaroxaban or apixaban who were treated with andexanet alfa had a 50% lower odds of in-hospital mortality compared to those treated with PCC. ³⁵ Importantly, a higher percentage of patients with ICH in the andexanet alfa cohort received hematoma evacuation (21.8% vs 16.2%) and decompression surgery (14.6% vs 9.5%) compared to those in the PCC cohort. ³⁵ A systematic review and meta-analysis comparing andexanet alfa to PCC for factor Xa inhibitor revealed andexanet alfa superiority in enhancing hemostatic efficacy and reducing in-hospital and 30-day mortality. ³⁶

Neurosurgery for Rupture Prone Arterial Pathologies Under Conditions of Compromised Coagulation

In patients suffering space occupying hemorrhages from ruptured aneurysms or arteriovenous malformations, prevention of both herniation and rebleeding are the tenets of treatment. When these patients are under anticoagulant medication, active surgical management carries high risks of procedural morbidity and mortality and neurointerventional attempts should be made first. ICH evacuation can be considered thereafter, depending on the severity of coagulation impairment and intracranial hypertension. ICH evacuation after endovascular treatment is easier than during aneurysm surgery, because proximal arterial access to control intraoperative rupture is not required. Attempts to achieve early surgical proximal arterial control in patients with compromised coagulation and post-hemorrhagic brain swelling can result in brain contusions from the use of spatulas, which can subsequently undergo hemorrhagic transformation and will per se act as space occupying lesions. Endovascular management of the ruptured arterial pathology in conjunction with pharmacologic antagonization of anticoagulant medication is the key factor to overcome this problem.

Idarucizumab is indicated in dabigatran-treated patients suffering life-threatening bleeding such as ICH is or in need of urgent interventions ¹⁸ while andexanet alfa is currently indicated only for use in apixaban and rivaroxaban-treated patients suffering life-threatening bleedings not in need for neurosurgery procedures. ¹⁹

Interventional Neuroradiology and Coagulation

Interventional procedures have become standard treatment in many cerebrovascular pathologies. Due to the global ageing of the population and due to the fact that these vascular patients often need anticoagulants, they are frequently used by patients with acute stroke due to or suffering from a pre-existing underlying illness. ³⁷ With the development of endovascular therapies for both hemorrhagic and ischemic cerebrovascular diseases, it is becoming more and more indispensable to address the medical side of neuro-interventional therapies. The aims will be not just to permit treatment under good conditions but to avoid and eventually treat potential complications. In the emergency situation, when PPSB (Prothrombine Proconvertine (facteur) Stuart (facteur antihémophilique) B) or fresh frozen plasma cannot be obtained fast, traditionally PCC be the best solution. ³⁸ More and more PPSB is being preferred if bleeding occurs during an intervention, eg, by a perforation or by a bleeding from the vascular process itself in case of vascular malformations. This can also be done in the occurrence of secondary hemorrhage in severe ischemia. In patients who are undergoing endovascular treatment and who are on dabigatran, reversion can be done with idarucizumab for both the ischemic and hemorrhagic types of stroke. ³⁹ Especially in acute hemorrhagic stroke, anticoagulation reversal may be necessary in order to safely treat the underlying occlusion. ⁴⁰ While endovascular techniques have been developed for more than half a century it is only in the last decades that evidence of its effectiveness for both hemorrhagic and ischemic stroke has been shown in large studies. This has led to an increase in these neuro-endovascular procedures, urging interventionalists and the interdisciplinary teams handling these patients to deal with adjusting other therapies that might be set in place in these often elderly patients. At the moment, also due to evolving techniques and concepts in the endovascular treatment of hemorrhagic and/or ischemic stroke, a clear consensus has still to be reached. Reports such as that of Balakumar et al seem to point to the potential utility of idarucizumab in acute subarachnoid hemorrhage. ⁴¹

Stroke Medicine and Coagulation

Use of Idarucizumab in Patients with AIS

The use of idarucizumab in dabigatran-treated patients with acute ischemic stroke who are eligible for intravenous thrombolysis or thrombectomy was proposed in in an expert-opinion statement in 2017. ⁴² REVERSE-AD ¹⁸ as well as a growing body of evidence from real-world data regarding idarucizimab use prior IVT^15,20 showed no increased risk for thrombotic events. Hence, stroke physicians are quite confident in using idarucizimab prior to IVT as therapeutic strategy if last dabigatran intake was <48 h since symptoms of AIS development and if time of last dabigatran intake is unknown. Importantly, the 2021 EHRA ¹⁴ and the 2021 ESO ¹² guidelines recommend IVT after dabigatran reversal with idarucizumab in patients who are eligible for IVT and have no other contraindications. A guidance/algorithm on the use of idarucizumab followed by recombinant tissue plasminogen activator (rt-PA) in patients with AIS pretreated with dabigatran was provided in year 2022. ⁴³ Patients eligible for IVT based on time window and/or functional imaging under dabigatran anticoagulation can easily be identified by introduction of thrombin time (TT) and/or diluted thrombin time (dTT) parameters into emergency laboratory parameters. Directly following infusion of 2 × 2.5 g idarucizumab dabigatran plasma concentration dropped by more than 99% in REVERSE-AD. Since this effect lasted for more than 12 h in more than 90% of patients ¹⁸ it is suggested that control of TT following idarucizumab infusion should not be mandatory but optional. With restoration of effective hemostasis patients can thereby regain their eligibility for in-label intravenous thrombolysis with rt-PA. Start of thrombolysis should not be delayed by laboratory parameter controls. ⁴³

For application of idarucizumab prior to tenecteplase there are also some data available, yet. ²² In an observational study 46 dabigatran-treated patients with AIS received idarucizumab prior IVT with tenecteplase with good safety outcomes. ²²

Use of Idarucizumab in Patients with ICH

There is a growing body of reassuring real-world data on low mortality rates and low thrombotic complications in dabigatran-treated patients suffering ICH in whom idarucizimab was used.^20,21 Most importantly, current guidelines^14,16,17 recommend use of idarucizimab in dabigatran-treated patients suffering from acute ICH. The comparison between idarucizumab and standard treatment with PCC has not yet been carried out. It should be considered that idarucizumab is expensive and of limited availability compared to PCC. Considering the comparison, it is worth mentioning the new study that did not show superiority of PCC over standard routine treatment in patients with ICH while treated with DOACs, including dabigatran. ⁴⁴ On the other hand, the superiority of idarucizumab over standard treatment has been demonstrated, at least indirectly.^20,21

Use of Andexanet Alfa in Patients with AIS

Thrombotic events after andexanet alfa use were described in the ANNEXA-4 ¹⁹ and ANNEXA-I ²³ trials. ESO guidelines oppose to andexanet alfa use prior to IVT in patients taking factor Xa inhibitors suffering AIS. ¹² If last factor Xa-inhibitor intake appeared >48 h prior to AIS symptoms IVT is recommended without reversal.^12,14 The successful and effective IVT after andexanet alfa in a rivaroxaban ⁴⁵ and apixaban-treated patient ⁴⁶ has been already been reported in the literature.

Use of Andexanet Alfa in Patients with ICH

Regarding patients treated with factor Xa inhibitors suffering ICH andexanet alfa had good hemostatic efficacy in clinical trials as also found in an increasing number of real-world data. ²⁴ It's also important to mention that sufficient data regarding andexanet alfa use in edoxaban-treated patients suffering ICH are still lacking. Guidelines^16,17 recommend use of andexanet alfa in rivaroxaban and apixaban-treated patients with acute ICH. The indirect comparison showed superiority of andexanet alfa over PCC. ⁴⁷ The major concern regarding andexanet alfa use are thrombotic events. Since the majority of patients with spontaneous ICH are elderly patients with probable concomitant diseases identifying patients in whom application of andexanet alfa would be in favor compared to possible thrombotic side effects is still a challenge. Nonetheless, the results of ANNEXA-I trial ²³ ) showed identical rates of thrombotic events as found in ANNEXA-4 trial. In a retrospective, single center study 8,9% of patients treated with andexanet alfa suffered thrombotic events. ⁴⁸ In a multicentre, retrospective chart review ⁴⁹ comparing outcomes of patients treated with andexanet alfa versus PCC no significant differences in hemostatic efficacy, in-hospital mortality and thrombotic complications were found. ⁴⁹ In a study analysing the safety and efficacy in preventing hematoma expansion in ICH patients treated with andexanet alfa versus nonspecific approaches treatment with andexanet alfa seems to be safe and effective. ⁵⁰ In an observational multicentre retrospective study in 50 patients with ICH both treatment with andexanet alfa or PCC appears safe and effective. ⁵¹ In a special report “Code ICH: A call to Action” the widespread adoption of an early bundle of care for patients with ICH, focused on active blood pressure lowering and use of reversal agents is advocated. ⁵² As already mentioned above, as minimally invasive neurosurgery is becoming more important in patients with ICH, there is a lack of knowledge regarding andexanet alfa use prior to neurosurgery in ICH patients if indicated. Up to now, andexanet alfa is still not indicated prior to neurosurgery (https://www.ema.europa.eu/en/documents/product-information/ondexxya-epar-product-information_en.pdf), and the results of the prospective, randomized ANNEXA-RS trial (NCT05926349), evaluating urgent neurosurgery after andexanet alfa application, are urgently needed.

Conclusions

DOACs changed stroke prevention and their specific reversal agents facilitated prevention and management of complications. However, despite increasing availability of data, and standard operating procedures and guidelines on the management of IVT in DOAC-treated individuals are encouraging while application of reversal agents in patients suffering from ICH seems to be established, many questions remain. In particular, questions on clinical outcome parameters, hematoma size, history of thrombotic events, antidote application prior to neuroradiologic and neurosurgical interventions, etc should warrant further studies and collection of real-world data.