Recanalization therapy in anticoagulated patients

David Goldemund M.D.
Updated on 21/12/2023, published on 11/11/2021

ischemic stroke may occur despite anticoagulation, either due to subtherapeutic anticoagulation, non-compliance, or a prothrombotic condition that increases the clotting risk despite anticoagulation
anticoagulants complicate the decision-making process for thrombolysis and mechanical thrombectomy in acute ischemic stroke
iI is crucial to weigh the potential benefits against the risks and consider factors such as the timing of the last DOAC dose and the availability of reversal agents

Intravenous thrombolysis

in general, intravenous thrombolysis (IVT) is contraindicated in patients who are effectively anticoagulated (due to the presumed increased risk of ICH)
with the use of DOACs, this contraindication has become somewhat relative

Warfarin

INR ≤ 1.7 ⇒ IVT can be performed (ESO guidelines, 2021)
- two larger studies and data from the registry of nearly 24,000 patients have not shown an increased risk of bleeding among warfarin-treated patients with a baseline INR ≤1.7 [Xian, 2012]
INR > 1.7 or unknown INR ⇒ IVT not recommended (ESO guidelines, 2021)
NR > 1.7 + administration of 4F-PCC followed by thrombolysis ⇒ may be safe based on findings from small-scale studies; randomized trials are not available
- prothrombin complex concentrates may enhance coagulation with worsening of neurological deficits
- may be considered in highly selected patients (severe deficit + occlusion not treatable by thrombectomy)
- no clear recommendation can be made [Chausson, 2018]

Heparin / LMWH

prophylactic doses of LMWH are not a contraindication; IVT appears to be safe and is not associated with an increased risk of sICH (Cooray, 2019]
contraindications to IVT:
- aPTT above the upper limit of normal (> 40s)
- full (therapeutic) dose of LMWH administered in < 24 hours
limited data exists on the safety of IVT after protamine administration; there is a potential risk of ischemia progression ⇒ direct MT is preferable

Dabigatran (PRADAXA)

intravenous thrombolysis (IVT) in acute stroke patients on dabigatran is possible with dabigatran therapy if aPTT + TT, ECT, or HEMOCLOT values do not exceed upper limits of normal (AHA/ASA 2013 III/C)
- a normal aPTT alone is not sufficient as it does not completely rule out an elevated TT [Kermer, 2017] [Hankey, 2014]
- IVT may be considered with normal TT or TT <60 s AND normal APTT (ESO guidelines 2021)
  - expert opinion only; insufficient evidence to make an evidence-based recommendation
- Hemoclot – a dabigatran level < 50 ng/ml > 6h after the last dose of the drug indicates the absence of anticoagulant activity
administration of thrombolysis after prior neutralization with PRAXBIND is possible (IVT is an emergency procedure); registry data suggest that administration of the antidote PRAXBIND in patients with acute stroke followed by thrombolysis is effective, safe, and easy to perform [Kermer, 2017]
- expert consensus suggests a combination of idarucizumab and IVT for patients with acute ischemic stroke of <4.5 hours duration (ESO guidelines 2021) [Diener, 2017]

Xabans (ELIQUIS, XARELTO, LIXIANA)

Absence of relevant anticoagulant effect

a patient on DOAC may be eligible for thrombolysis according to the AHA/ASA guidelines 2018, provided:
- the drug was administered > 48 hours ago while the patient’s renal function is normal
- laboratory tests indicate no anticoagulant effect – specific anti-Xa test ruled out “residual anticoagulant activity” (standard blood tests do not effectively rule out anticoagulant activity of xabans)
safe cut-off levels of anti-Xa are not officially stated in current thrombolytic guidelines
- data from non-randomized studies suggest a safe level of anti-Xa < 30-50 ng/mL (ug/L) [Marsch, 2019] [Tsivgoulis, 2021] [Touzé, 2018] [Seiffge, 2020]
- other reports have found no increased risk of sICH in patients on DOACs regardless of drug levels (but this registry did not track the time of last DOAC use, among other things) [Xian, 2017]
- based on expert consensus, IVT can be administered when the anti-Xa level is < 0.5 IU/mL (equivalent to ~ 30 ng/mL) (ESO guidelines 2021)
for patients who have recently taken xaban, direct mechanical thrombectomy (dMT) should be preferred (if possible)

Thrombolysis in patients with high specific anti-Xa levels or uncertain anticoagulant effect (< 48h since the last dose)

ESO guidelines 2021 do not recommend the administration of andexanet and IVT – there are no data on the safety of thrombolysis after previous administration of andexanet; hypocoagulation must be considered after completion of the infusion
IVT should not be administered without specific tests
- there are anecdotal reports of successful use of normal and reduced doses of tPA (0.6 mg/kg) in patients without evidence of absent anticoagulant effect [Korya, 2014] [Chao, 2019]
- fatal extracranial bleeding has also been documented in such conditions [Anan, 2019]

since the shift from vitamin K antagonists (VKAs) to DOACs, it is estimated that one in six stroke patients otherwise eligible for IVT is on a DOAC
guidelines recommend that stroke patients with recent DOAC use (< 48 hours) be excluded from IVT (except for dabigatran, where idarucizumab can be used)
- this recommendation was based on the presumed increased risk of symptomatic intracranial hemorrhage (sICH)
recent data suggest that IVT may be safe in patients receiving DOACs
- according to a cohort study and a meta-analysis, IVT does not lead to an increased incidence of sICH in selected patients on DOACs (Kam, 2022) (Shahjouei,2019)
- DOAC-IVT trial (2023) also showed insufficient evidence of excess harm associated with off-label IVT in selected ischemic stroke patients who had recently used a DOAC

the use of anticoagulants or thrombocytopenia is not a contraindication to mechanical thrombectomy (MT); the benefit is evident for proximal occlusions
- MT may be performed on patients taking DOACs without antidote administration [Diener, 2017]
- idarucizumab may be considered in patients on dabigatran
- in the setting of thrombocytopenia, the risks and benefits of the procedure must be carefully evaluated; consider transfusion of platelets to increase the count, especially if the count is below a critical threshold (e.g., <50,000/µL, though the exact threshold is not established)
some data suggest that patients on warfarin (not DOACs) face a higher risk of sICH and increased mortality [Meinel, 2020]
intensive monitoring in a stroke unit is vital after the procedure to detect any early signs of intracranial hemorrhage