
==== Front
Ann Indian Acad Neurol
Ann Indian Acad Neurol
AIAN
Ann Indian Acad Neurol
Annals of Indian Academy of Neurology
0972-2327
1998-3549
Wolters Kluwer - Medknow India

39196805
AIAN-27-345
10.4103/aian.aian_524_24
AIAN Review
Thrombolysis for Ischemic Stroke Despite Recent Ingestion of Direct Oral Anticoagulants – A Growing Dilemma Also in India
Meinel Thomas R.
Paramasivan Naveen K. 1
Menon Bijoy K. 2
Fischer Urs
Seiffge David J.
Department of Neurology and Stroke Research Center, Bern Inselspital, University of Bern, Bern, Switzerland
1 Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA
2 Department of Clinical Neurosciences, Radiology and Community Health Sciences, Cumming School of Medicine and the Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
Address for correspondence: Dr. Thomas R. Meinel, Department of Neurology and Stroke Research Center, Bern Inselspital, University of Bern, Bern, Switzerland. E-mail: thomas.meinel@insel.ch
Jul-Aug 2024
20 8 2024
27 4 345351
02 7 2024
06 8 2024
07 8 2024
Copyright: © 2024 Annals of Indian Academy of Neurology
2024
https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
The administration of intravenous thrombolysis (IVT) for patients with acute ischemic stroke who have recently ingested direct oral anticoagulants (DOACs) presents a clinical challenge due to the perceived increased risk of intracranial hemorrhage (ICH). Traditional guidelines from the US and European authorities advise against IVT within 48 h of last DOAC ingestion, unless specific coagulation tests indicate safety. However, emerging observational studies suggest that IVT might be safe in selected patients. A US stroke registry study and a global multicenter cohort study both reported no significant increase in symptomatic ICH among patients on DOACs compared to those not on anticoagulants. A systematic review of all published observational studies further supported these findings, showing comparable bleeding rates and functional outcomes in DOAC-treated patients. Reversal agents like idarucizumab for dabigatran have demonstrated potential in facilitating safer IVT administration, though logistical and cost-related barriers limit their widespread use. The variability in global guidelines reflects differing approaches to risk assessment and resource availability, highlighting the need for individualized treatment decisions. In India, the increasing prevalence of atrial fibrillation and stroke as well as prescription of DOACs necessitate adapted guidelines that consider local health-care infrastructure. Despite the promising observational data, the lack of randomized controlled trials underscores the need for further research to establish robust evidence for IVT use in this context. Collaborative international efforts and inclusion of diverse patient populations in future studies will be crucial to refine treatment protocols and improve outcomes for stroke patients on DOACs.

Anticoagulation
DOAC
thrombolysis
ischemic stroke
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pmcINTRODUCTION

Intravenous thrombolysis (IVT), with the agents alteplase and tenecteplase, are highly effective for treating acute ischemic stroke with a number needed to treat of 10 to reduce disability when administered soon after symptom onset.[1] To qualify for IVT, the neurological deficit has to be disabling, treatment should begin as early as possible, and there must not be any absolute contraindication with brain imaging (either computed tomography or magnetic resonance imaging) excluding intracranial hemorrhage (ICH).[234]

The use of direct oral anticoagulants (DOACs), including apixaban, edoxaban, dabigatran, and rivaroxaban, has become the primary method for preventing ischemic strokes in patients with nonvalvular atrial fibrillation (AF) in Western countries due to the lower risk of hemorrhagic complications with DOACs. In India, vitamin K antagonists (VKAs) remain the most frequently used anticoagulation for AF due to their lower cost and affordability.[56] The transition that has almost completely replaced VKAs by DOACs in Western countries[7] will likely take place in the upcoming years, but depends on the affordability and cost-effectiveness of DOACs in the local Indian setting.[89]

Among the DOACs available, dabigatran, rivaroxaban, and apixaban are the most used DOACs in India, while edoxaban is not much widely used.[610] In addition to AF, DOACs are increasingly being prescribed for new indications, such as treating vascular diseases like venous thrombosis, pulmonary embolism, and in lower doses for stable coronary artery disease and peripheral artery disease.[11] Since the shift from VKA to DOACs in Europe and North America, it is estimated that one in six stroke patients otherwise eligible for IVT is on a DOAC.[121314] The prevalence of AF, and consequently the number of individuals on long-term DOAC therapy, is expected to double in the coming decades in Western countries.[15]

In India, population-based studies have found the prevalence of AF to be at around 1% with poor rates of anticoagulation and adherence to anticoagulation in those detected with AF.[1617] Thus, the scenario of an ischemic stroke with preceding DOAC therapy will currently be less frequent compared to Western countries, but India has the second largest absolute burden of AF globally with high age-standardized incidence rates and a rapid increase in the projection of AF prevalence for the upcoming decades.[17] Furthermore, the detection rates, rates of anticoagulation, and the usage of DOAC for AF in India have increased in recent years.[61018] Thus, more and more patients with acute ischemic stroke who otherwise qualify for IVT will be on DOACs in the Indian subcontinent in the upcoming years.

However, recent DOAC intake within 48 h is seen as a contraindication for IVT due to the perceived increased risk of symptomatic ICH (sICH).[234] This often prevents these patients from receiving IVT. An analysis from the Swiss Stroke Registry showed that only 15% of otherwise eligible patients on DOACs received IVT, compared to 74% of those not on anticoagulants. In USA, less than 9% of eligible patients on DOACs received IVT in a Get With The Guidelines registry analysis.

International guidelines generally advise against routine IVT use in patients on DOACs. Practices vary, with different criteria for selecting these patients for IVT, such as the time since the last DOAC intake, DOAC plasma levels, and the use of DOAC reversal agents. These recommendations are mostly based on expert consensus, and thus, there is large uncertainty about whether patients on DOACs can safely receive IVT for acute ischemic stroke.

PRECLINICAL EVIDENCE

In experimental animal ischemic stroke models, pretreatment with DOACs did not significantly increase the risk of hemorrhage after IVT, whereas pretreatment with VKA did. Ploen et al.[19] showed that in an experimental ischemic stroke model, rivaroxaban did not increase the incidence of hemorrhage, suggesting its safety in the context of thrombolytic therapy. Sun et al.[20] examined the impact of dabigatran anticoagulation on secondary intracerebral hemorrhage after thrombolysis in a cerebral ischemia model. The findings showed that dabigatran did not elevate the risk of secondary hemorrhage, supporting its safe use in thrombolytic treatment. Pfeilschifter et al.[21] assessed the risk of hemorrhage when thrombolysis with recombinant tissue plasminogen activator (rt-PA) was performed under dabigatran anticoagulation in an experimental stroke setting. The study concluded that dabigatran did not increase hemorrhage risk, indicating compatibility with rt-PA therapy. However, the same group demonstrated a heightened risk of hemorrhagic transformation when pretreated with VKA, highlighting the potential dangers of VKA in this context.[22]

CLINICAL EVIDENCE OF IVT IN PATIENTS WITH RECENT DOAC INGESTION

There is no direct evidence from clinical trials regarding the use of IVT for acute ischemic stroke in patients taking DOACs since the pivotal IVT trials were performed before DOACs came to the market. Thus, only observational data and indirect evidence are available for this clinical situation.

In a retrospective cohort study from USA, Kam et al.[13] analyzed 2207 patients on DOACs and 160,831 patients not on anticoagulants. They found no significant increase in the risk of sICH after IVT in patients treated with DOACs compared to those not on anticoagulants (adjusted odds ratio [OR] 0.88, 95% confidence interval [CI], 0.70–1.10). However, the study’s main limitation was that DOAC intake was defined as within the last 7 days and only a tiny minority of patients had confirmed intake within the last 48 h. Another retrospective cohort study, conducted in Japan by Okada et al.,[23] included 40 patients on DOACs and 753 not on anticoagulants. The study concluded that DOAC treatment before stroke did not increase the risk of sICH after IVT (adjusted OR 0.95, 95% CI 0.17–5.28). The small sample size and high risk of bias were significant limitations. In another retrospective cohort study from Taiwan, Tsai et al.[24] assessed 91 patients on DOACs and 7210 patients not on anticoagulants. They also found no increased risk of ICH after IVT in patients on DOACs (OR 1.37, 95% CI, 0.62–3.03). The study faced limitations such as a small sample size.

Our group gathered a retrospective cohort study from Europe, Asia, Australia, and New Zealand involving 832 patients on DOACs and 32,375 patients not on anticoagulants. Somewhat counterintuitively, it showed a lower risk of sICH in patients treated with DOACs (adjusted OR 0.57, 95% CI, 0.36–0.92).[25] After adjustments, recent DOAC use (within 48 h) was not linked to an increased risk of sICH, irrespective of whether the treatment decision was based DOAC plasma levels, reversal with idarucizumab, or neither. However, clinicians may have selectively offered IVT to those with a lower risk of sICH.

Furthermore, our recent report indicated that after liberalizing the approach for offering IVT regardless of recent DOAC intake, no safety concerns were observed in a target trial analysis.[14] Among 98 consecutive DOAC patients eligible for IVT, 49 (50%) received IVT at a median of 178 min (interquartile range 134–285) after symptom onset, with a median DOAC plasma level of 77 ng/ml. Of these, 15 patients had plasma levels over 100 ng/ml and 25 (51%) were treated within 12 h of their last DOAC dose. sICH occurred in 0 out of 49 patients receiving IVT, compared to two out of 49 patients without IVT (adjusted difference -2.5%, 95% CI, -5.9 to 0.8), with similar rates of any radiological ICH.

Indirect evidence stems from the randomized controlled trial ARAIS from China comparing IVT patients to an active arm that received additional argatroban, an intravenous thrombin inhibitor. This multicenter, open-label, randomized controlled trial was conducted in China and involved 817 patients: 402 received argatroban plus alteplase and 415 received alteplase alone. The argatroban group received a 100 μg/kg bolus within 1 h of the alteplase bolus, followed by a 1.0 μg/kg/min infusion for 48 h. The rates of sICH were similar between the two groups across four commonly used definitions.[26] However, the evidence is indirect since argatroban is not fully comparable to oral DOAC treatment, which mostly consists of factor Xa antagonists. In addition, there is concern for inadequate statistical power and potential bias from differing dropout rates between treatment groups.

The MOST study (NCT03735979)[27] used a design similar to the ARAIS trial with even higher doses of argatroban given in addition to IVT patients, corresponding to about 150% of therapeutic anticoagulation. This trial was halted for futility, but without a signal of harm in the high-dose argatroban arm that enrolled 59 patients (ISC 2024, Phoenix, AZ).

A 2023 systematic review and meta-analysis comprised 14 retrospective cohort studies comparing the risk of ICH after IVT in patients on DOACs to those not on anticoagulants before their ischemic stroke.[28] The pooled analyses showed no difference in the rates of sICH (3.4% vs. 3.5%; OR 0.95 [95% CI, 0.67–1.36]) or any ICH (17.7% vs. 17.3%; OR 1.23 [95% CI, 0.61–2.48]) between the DOAC and non‐DOAC groups. In parallel, there was no difference in serious systemic bleeding (0.7% vs. 0.6%; OR 1.27 [95% CI, 0.79–2.02]) and 90‐day modified Rankin scale score 0–2 (46.4% vs. 56.8%; OR 1.21 [95% CI, 0.400–3.67]). However, the authors cautioned that these findings are not based on randomized clinical trials, and further large-scale prospective studies are needed to confirm these results. In addition, significant methodological heterogeneity, missing data, lack of complete clinical data, potential misclassification biases, and differences in intervention and control groups as well as variations in IVT dosing and assessment scales further limit the validity and power of the results.

CURRENT GUIDELINE RECOMMENDATIONS

The latest Indian Stroke Association Consensus Statement states that the use of IVT in patients on DOACs remains uncertain, and relevant laboratory tests (thrombin time, activated partial thromboplastin time [aPTT], and prothrombin time) should be reviewed to assess residual anticoagulant effects.[4]

The Canadian Stroke Best Practice Recommendations advise against routinely giving IVT to patients on DOACs with acute ischemic stroke. However, at comprehensive stroke centers with specialized tests for DOAC levels and reversal agents, IVT may be considered based on individual patient characteristics.[29]

The American Heart Association/American Stroke Association recommends against using IVT in patients taking DOACs unless specific lab tests (platelet count, aPTT, ecarin clotting time, international normalized ratio [INR], thrombin time, or appropriate factor Xa activity assays) are normal. IVT may also be considered if these medications have not been taken for over 48 h and the patient has normal kidney function.[3]

The European Stroke Organisation (ESO) advises against IVT for ischemic stroke patients within 4.5 h of onset if they have taken a DOAC within the last 48 h and if specific coagulation tests (like thrombin time for dabigatran or calibrated anti-Xa activity for factor Xa inhibitors, or DOAC blood concentration) are not available.[2]

The Japan Stroke Society recommends against IVT with alteplase (0.6 mg/kg) if the last DOAC dose was taken less than 4 h ago, if aPTT is ≥1.5 times the baseline value, or if INR is >1.7 for patients on factor Xa inhibitors. They suggest considering IVT after idarucizumab for dabigatran patients or direct endovascular thrombectomy without idarucizumab and without bridging IVT at capable institutes.[30]

Thus, overall, there are global variations from very liberal approaches (like the Japanese one) to very strict recommendations excluding all patients with any intake of a DOAC pill within the last 48 h regardless of the DOAC dose.

AVAILABILITY OF ANTICOAGULANT ACTIVITY MEASUREMENTS IN INDIA

Assessing the anticoagulant activity in DOACs in emergency settings, similar to the INR value for VKA patients, is challenging.[31] Difficulties include test accessibility, turnaround times, absence of clear cut-off values, and test inconsistency. Both conventional, nonspecific tests (INR, aPTT, thrombin time) and drug-specific plasma levels have been suggested for monitoring DOAC activity.

Systematic reviews[32] and recommendations from the International Committee for Standardization in Haematology and the International Committee on Thrombosis and Haemostasis[3334] highlight the following: (1) prothrombin time/INR and activated partial thrombin time are unreliable for assessing DOAC plasma concentrations, (2) current unspecific point-of-care tests are inadequate for detecting DOAC presence, and lastly, (3) tandem mass spectrometry is the gold standard for DOAC measurement.

Although not ideal, some information can be obtained from nonspecific coagulation tests. For example, a normal thrombin time can rule out significant concentrations of dabigatran.[35] The plasma activity of anti-Xa inhibitors shows some correlation with aPTT and Prothrombin Time (PT)/INR, but these results are often inconsistent due to reagent sensitivities and assay variability.[35] Studies in acute stroke patients report normal INR and aPTT in up to 44% of patients with peak DOAC levels.[36]

While mass spectrometry remains the gold standard for DOAC measurement, it is not feasible in emergency situations. Apart from mass spectrometry, only calibrated anti-Xa assays (Xa inhibitors) and ecarin clotting time (IIa inhibitors) show linear, dose-dependent correlations with serum levels.[35] These assays have been used to guide IVT decisions, but their use and suggested cut-offs are primarily based on expert opinion and preliminary safety data.[373839] Turnaround time for these specific assays is getting better, and some centers can now provide results within 30 min for patient selection in IVT.[40] Several new approaches, such as urine dipstick tests and modified thromboelastography incorporating anti-Xa and ecarin clotting time, are under investigation, but their relevance and reliable cut-offs for IVT in acute stroke care remain unclear.[3334]

Although exact data are missing, most centers in India do not offer DOAC plasma level measurements, and thus provide potentially unreliable surrogate tests or have long turnaround times (of up to 2 weeks).[41] In addition, the availability of these specific tests is limited globally.[42] In addition to availability, associated costs limit the use of these laboratory assessments: DOAC activity using calibrated anti-Xa levels costs around USD 50 in Switzerland and about INR 18,000 in India, highlighting the financial challenges of using such tests.

REVERSAL AGENT USE

There are two main reversal agents for DOACs: idarucizumab and andexanet alfa. While idarucizumab is available in India (from Boehringer-Ingelheim India Pvt Ltd), andexanet alfa is not yet available in India. Idarucizumab is a humanized monoclonal antibody fragment with a high affinity for dabigatran, 350 times greater than dabigatran’s affinity for thrombin.[43] However, andexanet alfa represents a recombinant human FXa variant that acts as a decoy for anti-Xa medications, mimicking native Xa.[44] Both agents have shown dose-dependent reversal of DOAC activity in Phase 3 trials and have been used in observational studies for patients with major bleeding or requiring urgent (mostly surgical) intervention.[45] These studies demonstrated a return to normal drug-specific anti-Xa activity within a few minutes. Idarucizumab was approved by the European Medical Agency for dabigatran reversal including urgent procedures, and andexanet alfa was approved for reversing rivaroxaban and apixaban (though not yet for edoxaban) when reversal is needed due to life-threatening or uncontrolled bleeding.

While andexanet alfa is recommended against by the ESO for use before IVT due to its associated thromboembolic complications, idarucizumab is recommended for use before IVT.[2] There are numerous case reports and large case series documenting the use of idarucizumab before IVT, including from India.[46] In New Zealand, a national reperfusion registry showed that the risk of sICH in patients with dabigatran reversal was similar to that in non-anticoagulated patients (3.8%).[47] However, idarucizumab is expensive (approximately USD 2400, approximately INR 294,000 per 5 g injection), and the cost-effectiveness of this approach in IVT remains uncertain; therefore, treatment decisions must be individualized. For andexanet alfa, in addition to the thromboembolic complications, the logistics of administration require a bolus followed by a 2-h infusion, complicating its use in a time-sensitive condition like ischemic stroke. In addition, there is a rebound in Xa activity after the infusion ends. Given the recommendations against its use, the low availability, and its astronomical price of around USD 17,570, few case reports describe the use of andexanet alfa before IVT in ischemic stroke patients.[48]

ONGOING RESEARCH

The DOAC Intravenous Thrombolysis (DO-IT) study is a prospective, randomized controlled trial. It will evaluate the efficacy and safety of IVT with alteplase (0.9 or 0.6 mg/kg) or tenecteplase (0.25 mg/kg) versus best medical treatment alone in patients with acute ischemic stroke who took DOACs within the last 48 h. The trial will start recruiting in 2024, involving about 100 centers across 15 countries, and aims to randomize approximately 900 patients. The primary outcomes will be functional independence at 90 days and sICH. In addition, in the ACT-GLOBAL adaptive platform trial, the thrombolysis domain will include patients with recent (24 h) intake of any DOAC, evaluating the safety and efficacy of standard-dose (0.25 mg/kg body weight) and low-dose tenecteplase (0.18 mg/kg) compared to avoiding IVT in a randomized manner (NCT06320431). These trials are expected to provide robust, internationally relevant evidence for using IVT in this setting. Stratified analyses based on DOAC reversal treatment may offer insights for individualized treatment decisions. In addition to these randomized trials, observational studies such as the global DO-IT registry and other registries (NCT06241677) aim to target patients undergoing IVT with recent DOAC ingestion to capture potential safety signals associated with more liberal IVT decisions in DOAC patients.

RECOMMENDATION FOR FURTHER RESEARCH IN INDIA

Randomized trials and multicenter, international cohort studies are urgently needed, including in the Indian population, to ensure diverse representation. Observational studies should elucidate the following areas: frequency including time trends of ischemic stroke in patients with preceding anticoagulation and the subtypes of DOACs; availability of nonspecific and DOAC-specific coagulation tests (and their turnaround times) as well as specific DOAC reversal agents on a national scale in India; the relationship between DOAC plasma levels or the time since the last dose and sICH in a dose-dependent manner; treatment delays and costs associated with laboratory methods; and the cost-effectiveness of IVT with and without the use of idarucizumab in patients taking dabigatran.

SUGGESTION FOR MANAGEMENT UNTIL BETTER EVIDENCE IS AVAILABLE

Although most expert consensus guidelines recommend avoiding IVT unless laboratory studies indicate normal coagulation, we suggest an individualized risk–benefit approach [Figure 1]. The first step is to check the principal eligibility for IVT. The second step is to assess whether alternative treatment options, mainly endovascular stroke treatment, are available in a timely manner. If so, IVT can be skipped. If the patient fulfills IVT eligibility and immediate endovascular treatment is not available, reversal and laboratory assays to exclude extreme DOAC concentrations can facilitate decision-making if they are available immediately and are affordable.

Figure 1 Proposed method for managing patients with acute ischemic stroke and recent intake of direct oral anticoagulants based on expert opinion. We suggest an individualized risk–benefit approach. This involves assessing IVT eligibility, the availability of alternative treatments like endovascular stroke treatment, and using reversal agents and lab assays to guide decisions if immediate endovascular treatment is not available. Clinicians should involve stroke specialists and inform patients or family members about potential risks, documenting these decisions in local or multicenter cohort studies. BA = basilar artery, DOAC = direct oral anticoagulant, ICA-T = internal carotid artery-T, INR = international normalized ratio, IVT = intravenous thrombolytics, LVO = large vessel occlusion, M1 = first segment of the middle cerebral artery, MT = mechanical thrombectomy, sICH = symptomatic intracranial hemorrhage

IVT may be beneficial for patients with a significant neurological deficit, short thrombus, and a low risk of sICH. Factors associated with a lower risk of sICH include a smaller infarct core, shorter time from symptom onset to treatment, and the absence of cerebral small vessel disease, diabetes, older age, hyperglycemia at presentation, additional antiplatelet therapy, and uncontrollable blood pressure.[49] Given the complexity and potential risks of IVT in this patient group, the decision to administer it should involve consultation with experienced stroke specialists.

Clinicians should inform the patient or family members about the uncertainty and potential risk of sICH and capture such liberal IVT decisions locally or even better in multicenter registries.

Financial support and sponsorship

This study was supported by a grant from the Baasch Medicus Foundation. It was also supported by research grants from the Bangerter-Rhyner Foundation, the Swiss Heart Foundation, the University of Bern, Inselspital Bern, and the Swiss National Science Foundation.

Conflicts of interest

Dr. Meinel has no relevant interests to declare. Prof. Menon has received consulting fees from Boehringer Ingelheim. Prof. Fischer reports receiving grants from the Swiss National Science Foundation, Swiss Heart Foundation, and Medtronic, as well as personal fees from CSL Behring, Boehringer Ingelheim, Medtronic, Stryker, and Portola/Alexion outside the submitted work. Dr. Seiffge reports receiving grants from Bangerter-Rhyner Foundation during the conduct of the study and personal fees from Bayer, Alexion, and VarmX outside the submitted work.
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