Effective anticoagulant reversal and management of stroke patients while on DOACs | Latest news for Doctors, Nurses and Pharmacists

Case 1: An elderly male patient with ischaemic stroke while on dabigatran

A 65-year-old male patient with a history of hypertension, hyperlipidaemia, nonvalvular atrial fibrillation (NVAF) and a CHA2DS2-VASc (congestive heart failure, hypertension, age 75 years, diabetes mellitus, prior stroke/transient ischaemic attack [TIA]/thromboembolism, vascular disease, age 65–74 years, sex category) score of 2 was taking dabigatran 110 mg BID with good compliance for stroke prevention. He presented with left-sided weakness and slurred speech at 19:00 and was admitted to hospital. Physical examination revealed dense hemiplegia with left-sided power of 0/5 in his upper and lower limbs, left-sided inattention and forced eye deviation to the right. His National Institutes of Health Stroke Scale (NIHSS) score was 19. Dabigatran was last administered at 08:00 on the same day. Brain CT at 21:30 showed mild reduced grey-white differentiation over the right frontal and temporal region. (Figure 1A)

The patient was given idarucizumab 5 g intravenously, followed by intravenous thrombolysis (IVT) with tissue-plasminogen activator. Within 2 hours after idarucizumab and IVT administration, his stroke symptoms significantly improved. His limb power improved to 4/5, with 24-hour post-IVT NIHSS score of 7. Repeated brain CT 24 hours after IVT showed established infarct over right frontotemporal region. (Figure 1B) Anticoagulant therapy was resumed 14 days after stroke and was switched to rivaroxaban 20 mg QD.

The patient was discharged after 5 weeks of hospitalization. After rehabilitation, he could walk unaided, with a 6-month modified Rankin score (mRS) of 3. He remained well without recurrent stroke or systemic embolism (SE) during his 2.5 years of follow-up.


Case 2: An elderly male patient with ischaemic stroke while on apixaban

A 74-year-old male patient with hypertension, NVAF and a CHA2DS2-VASc score of 2 was taking apixaban 5 mg BID with good compliance for stroke prevention. He presented with left-sided weakness and slurred speech at 17:20 and was admitted to hospital. His last dose of apixaban was administered at 07:00 on that day. Physical examination revealed left-sided power of 3/5 in his upper and lower limbs, left-sided inattention and right gaze preference. His NIHSS score was 9. Brain CT showed no signs of early ischaemic changes, but CT angiography revealed right-middle cerebral artery occlusion. Intra-arterial thrombectomy (IAT) was performed with successful reperfusion.

The patient’s post-IAT NIHSS score improved to 6. His cortical signs resolved, but left-sided weakness persisted. Brain MRI showed an established infarct over the right internal capsule and corona radiata. His anticoagulant therapy was switched from apixaban to dabigatran 150 mg BID at 10 days after stroke. His left-sided weakness gradually improved, and he was discharged after 7 weeks of hospitalization.

The patient could walk unaided with a 6-month mRS of 3 after rehabilitation. As of October 2022, he was well and had no recurrent stroke.

Case 3: An elderly male patient with ICH while on dabigatran

An 83-year-old male patient with a history of hypertension, diabetes mellitus, NVAF and a CHA2DS2-VASc score of 4 was taking dabigatran 110 mg BID with good compliance for stroke prevention. He presented with dizziness, slurred speech and vomiting at 16:15 and was admitted to hospital. His last dose of dabigatran was taken at 07:00. Physical examination revealed mild dysarthria and bilateral limb ataxia. On admission, his blood pressure (BP) was 224/125 mm Hg, and NIHSS score was 3. Brain CT showed a 42 x 28 mm intracerebral
haemorrhage (ICH) at the cerebellar vermis. (Figure 2A) Idarucizumab 5 g was
immediately administered, and his BP was controlled with intravenous labetalol.
His neurological status remained stable, and CT reassessment on the following
day showed no significant haematoma expansion. (Figure 2B) The patient was
hospitalized for 3 weeks.


After rehabilitation, the patient could walk with assistance. Left atrial appendage occlusion (LAAO) was performed 6 months after stroke, and his 6-month mRS was 4. Anticoagulant therapy was not resumed. As of October 2022, the patient was well, with no recurrent stroke or SE since LAAO was performed.

Case 4: An elderly female patient with ICH while on rivaroxaban

An 81-year-old female patient with hypertension, previous ischaemic stroke, NVAF and a CHA2DS2-VASc score of 6 was taking rivaroxaban 20 mg QD with good compliance for stroke prevention. She presented with right-sided weakness and speech disturbance at 17:00 and was admitted to hospital. Her last dose of rivaroxaban was taken at 19:00 the day before. Physical examination revealed right-sided weakness of 4/5 with mild aphasia and slurred speech. Her BP was 232/150 mm Hg on hospital admission, and NIHSS score was 7. Brain CT showed an ICH measuring 36 x 26 mm at the left lentiform nucleus and external capsule.

The patient was given prothrombin complex concentrate (PCC) for anticoagulant reversal and intravenous labetalol for BP control, but developed neurological deterioration 3 hours afterwards. Her right-sided power worsened to 3/5, and NIHSS score increased to 10. Repeat CT showed an enlarged haematoma of 46 x 28 mm. Her neurological condition subsequently stabilized. She was hospitalized for 6 weeks.

After rehabilitation, the patient could walk with assistance with a 6-month mRS of 4. LAAO was offered but was declined by the patient and family. Aspirin 80 mg QD was prescribed for secondary stroke prevention. About 3 years later, she succumbed to a recurrent ischaemic stroke.


Direct oral anticoagulants (DOACs) have substituted warfarin as the anticoagulant of choice for NVAF. However, amongst DOAC users, there is still a 2 percent risk of ischaemic stroke/SE and a 0.6 percent risk of intracranial bleeding, which is predominantly due to ICH.1,2 According to 2020–2021 data from our stroke registry, 6 percent of patients with ischaemic stroke and 8 percent of those with ICH were receiving DOACs.3

Risk factors for ischaemic stroke during anticoagulant therapy include DOAC underdosing, poor drug compliance and suboptimal control of cardiovascular risk factors, such as hypertension and hyperlipidaemia.4 Uncontrolled hypertension is also a major risk factor of ICH. The recommended BP target for prevention of ICH recurrence is 130/80 mm Hg.5 A recent study showed that systolic BP <120 mm Hg is associated with the lowest risk of recurrent ICH.6

Management of ischaemic stroke in DOAC-treated patients

For DOAC-treated patients presenting with ischaemic stroke within the reperfusion time window, treatment depends on the time of the last DOAC dose. (Figure 3) IVT can be given to patients who took the last DOAC dose >48 hours from stroke onset or to those within 48 hours of onset with normal specific coagulation tests. However, unless point-of-care testing is available, arranging these tests may erode valuable time for IVT eligibility. The notion of DOAC reversal with an antidote for IVT can be considered. For dabigatran users with ischaemic stroke, the European Stroke Organisation (ESO) guidelines recommend administration of idarucizumab followed by IVT in eligible patients.7


Idarucizumab is the only DOAC-specific anticoagulant reversal agent which is widely available in Hong Kong. The RE-VERSE AD study of dabigatran-treated patients (n=503) demonstrated that a standard 5g dose of idarucizumab produced rapid, complete and sustained reversal of dabigatran’s effects within 15 minutes.8,9 In RE-VERSE AD, no direct procoagulant effects were observed with the use of idarucizumab for dabigatran reversal, although a 5 percent thrombotic risk was reported.9 A systematic review of 49 studies (n=251) revealed comparable haemorrhagic transformation and mortality rate in ischaemic stroke patients receiving idarucizumab and IVT vs IVT-treated noncoagulated patients.10 

As for factor Xa (FXa) inhibitor users with ischaemic stroke, data on the use of the combination of andexanet alpha, a FXa inhibitor reversal agent, followed by IVT is scarce. There are also a few concerns for this approach, such as 2-hour infusion of andexanet alpha, potential rebound anticoagulant effect after 4 hours, and higher thrombotic risk. Thus, FXa inhibitor users are not eligible for IVT after DOAC reversal.7 (Figure 3)

Re-initiation of DOAC after acute ischaemic stroke

The same DOAC can be re-initiated in patients with ischaemic
stroke, especially in cases of previous DOAC underdosing or poor drug
adherence. There is limited evidence showing benefits of a DOAC-to-DOAC
switch or coadministration of aspirin.11
Dabigatran 150 mg BID is the only DOAC that has demonstrated superiority
to warfarin in preventing stroke and SE among the landmark DOAC
trials; hence, switching to dabigatran 150 mg BID may be beneficial in eligible

The optimal timing for DOAC resumption after an ischaemic stroke remains uncertain. Recent publications demonstrated that early re-initiation of DOAC after ischaemic stroke was not associated with a significantly increased risk of symptomatic intracranial haemorrhage.13 In theory, early DOAC re-initiation would reduce the risk of early recurrent stroke and SE. Our centre has adopted the ‘1-3-7-14’ approach for the timing of early DOAC reinitiation based on infarct size, as outlined in the 2018 European Heart Rhythm Association (EHRA) guideline: after ≥1 day for a TIA; ≥3 days for a mild stroke or small-sized infarct; ≥6–8 days for a moderate stroke or moderate-sized infarct; and ≥12–14 days for a severe stroke or large-sized infarct.14

Our patient in case 1 had rapid improvement of early stroke symptoms with idarucizumab that enabled IVT. At that time, as limited guidance was published on DOAC re-initiation, the multidisciplinary team decided to switch anticoagulation to another DOAC. However, in hindsight, he could have restarted dabigatran at 150 mg BID, similar to the patient in case 2.

Management of DOAC-related ICH

In patients with DOAC-associated ICH, DOAC should be discontinued immediately,
with rapid reversal of anticoagulant attempted as soon as possible
regardless of availability of coagulation test results. (Figure 4) Acute BP lowering
is also important to prevent further haematoma expansion.5


Idarucizumab is recommended in managing dabigatran-associated ICH due to its good haemostatic efficacy.5 In a retrospective study on idarucizumab application (acute ischaemic stroke, n=120; acute ICH, n=40), haematoma expansion with clinical deterioration was observed in only 11 percent of idarucizumab-treated patients, which was below the reported rates associated with DOACs in the literature (25–35 percent).The mortality rate of idarucizumab-treated patients with dabigatran-associated ICH was reported to be 11.4 percent in a recent systematic review, which was also substantially lower than the expected mortality rate of DOAC-treated ICH patients (18–27 percent).15

For FXa inhibitor users, anticoagulant reversal with andexanet alpha is preferred but is currently not widely available in Hong Kong. Four-factor PCC can be used for nonspecific reversal of anticoagulant effects. Despite good haemostasis, PCC reversal was found to be associated with a higher mortality rate (19 percent) in DOAC-related ICH, compared with idarucizumab and andexanet alpha reversal.16 

In case 3, idarucizumab played an important role in acute ICH management by promptly reversing the anticoagulant effect of dabigatran without haematoma expansion.

Anticoagulant resumption after DOAC-related ICH

ICH recurrence is a concern with anticoagulant resumption after a DOAC-related ICH. However, studies have demonstrated that anticoagulant resumption after anticoagulant-related ICH reduced the risk of all strokes, SE and all-cause mortality without a significant increase in recurrent ICH.17,18 Based on the updated 2022 ICH guideline, anticoagulant resumption can be considered after weighing the benefits and risks.5 Nonetheless, our clinical practice is to refer patients for LAAO first. As the LAAO procedure harbours risk, the decision for LAAO or DOAC resumption should be a joint decision among the patient, neurologist, and cardiologist. In patients deemed not suitable for LAAO or those who decline LAAO, DOAC could be resumed in patients with low risk of ICH recurrence (ie, in hypertension-associated ICH patients with well-controlled BP after ICH [systolic BP <130 mm Hg, or <120 mm Hg if tolerable]).


Specific reversal of anticoagulant therapy is crucial for improving outcomes of stroke in DOAC users. Idarucizumab – the only specific antidote for DOAC available in Hong Kong – rapidly reverses the anticoagulant effect of dabigatran, which facilitates acute management of acute ischaemic stroke and DOAC-related ICH.