Successful thrombolysis for acute ischaemic stroke after reversal of dabigatran etexilate with idarucizumab

Abstract

We report the experience of reversing dabigatran prior to administering systemic thrombolysis for acute ischaemic cerebellar stroke, which was well tolerated with no haemorrhagic complications after thrombolysis. Given the increasingly common use of dabigatran for atrial fibrillation, the use of idarucizumab to reverse of dabigatran is a novel treatment that should be considered as an important adjunct to facilitate thrombolysis for ischaemic strokes and minimise haemorrhagic complications.

Background

Cerebrovascular disease causes significant disease burden, becoming the second leading cause of mortality and the third leading cause of disability worldwide.¹ Atrial fibrillation is a well-recognised cause of ischaemic stroke, affecting approximately 33 million people globally.² Dabigatran is a direct oral anticoagulant (DOAC) that is now widely used for stroke prophylaxis in atrial fibrillation, thus management of DOAC becomes critical when stroke thrombolysis is being considered. Therapeutic anticoagulation with direct thrombin inhibitors or direct Xa inhibitors is a contraindication to stroke thrombolysis in major clinical guidelines,^{3 4} thus posing challenges to the use of potentially life-saving thrombolysis in acute ischaemic stroke. Idarucizumab is an effective agent for rapid reversal of the anticoagulant effect of dabigatran.^{5 6} Therefore, dabigatran reversal with idarucizumab is an uncommon but feasible management approach in minimising bleeding complications before administration of acute stroke thrombolysis.

Case presentation

We report a case of a 77-year-old man who presented to a local metropolitan hospital in Sydney, Australia, with left-sided weakness and speech difficulties.

This report is to highlight the novelty of reversing the anticoagulant activity of dabigatran before intravenous thrombolysis for acute cerebral infarction, in order to minimise the risk of haemorrhagic transformation after thrombolysis.

Due to non-valvular atrial fibrillation and chronic renal impairment, the patient has been commenced on a renally adjusted dose of dabigatran 110 mg two times per day. In addition, he is also taking perindopril 8 mg once daily, nebivolol 5 mg once daily, rosuvastatin 10 mg once daily and spironolactone 25 mg once daily. He also suffers from hypertension, hyperlipidaemia and ischaemic cardiomyopathy with a reduced ejection fraction of 25%. He has a combined pacemaker and automated implantable cardioverter–defibrillator (AICD) inserted for ischaemic cardiomyopathy. He is a life-long non-smoker and his body mass index is 25.2 (81.7 kg, 180 cm). The patient self-ceased his regular dabigatran 3 days prior to his presentation because of traumatic minor skin bleeding.

On the day of presentation, the patient developed acute onset of left-sided weakness and slurred speech at 17:45. Following the onset of symptoms, the patient self-administered a single dose of dabigatran 110 mg immediately.

The patient presented into our emergency department at 19:03. Clinical assessment by the stroke team revealed left upper limb weakness, dysarthria and expressive dysphasia. His National Institutes of Health Stroke Scale (NIHSS) score on assessment was 8, with a premorbid modified Rankin Scale score of 1.

Investigations

The patient promptly underwent a CT brain scan (CT brain) at 19:37, which demonstrated no acute intracranial haemorrhage or infarction (figure 1), no large arterial vessel occlusion and no clinically significant perfusion mismatch. At 19:20, his international normalised ratio (INR) was 1.1, platelet count was 186×10⁹/L and his anti-Xa dabigatran level was less than 35.0 ng/mL (table 1).

Figure 1.

Non-contrast CT brain scan on presentation to the emergency department showed no acute ischaemic stroke or acute haemorrhage detected.

Table 1.

Pathology results

Pathology	Day 0 (19 April 2018) 19:20	Day 0 (19 April 2018) 23:12	Day 1 (20 April 2018) 00:25	Day 1 (20 April 2018) 03:45	Day 2 (21 April 2018) 09:57	Day 2 (21 April 2018) 17:03	Reference range
Creatinine	117			98	104	–	60–110 μmol/L
eGFR	52			64	60	–	>60 mL/min/1.73m2
INR	1.1			1.3	1.2	–	0.9–1.2
APTT	28.6			29.1	26.1	–	24.0–36.0
PT	14.0			15.7	15.0	–	11.0–15.0
Platelet count	186			149	166		150–400×109/L
Antifactor Xa dabigatran level	<35.0	<35.0	35.0	–	–	–	<35.0 ng/mL
Troponin I (Abbott HS)	52	2310	4585	9627	–	1667	<26 ng/L
Glucose				7.1

APTT, activated partial thromboplastin time; eGFR, estimated glomerular filtration rate; INR, international normalised ratio; PT, prothrombin time.

Treatment

A decision was made to proceed with thrombolysis with intravenous alteplase at 19:44 as he was still within the thrombolysis time window of 4.5 hours after symptom onset. In consultation with the local haematologist, we reversed his anticoagulation with idarucizumab at 20:48, given as two vials of 2.5 g each, through a rapid intravenous infusion over 10 min. A total dose of 75 mg of alteplase was administered, with a bolus of 7.5 mg given over 1 min at 21:00, followed by an intravenous infusion of 67.5 mg given over 60 min. Intravenous thrombolysis was given at 195 min after the onset of symptoms. His repeat anti-Xa dabigatran level was <35.0 ng/mL at 23:12 (table 1).

Outcome and follow-up

A subsequent post-thrombolysis non-contrast CT brain performed at 23:59 demonstrated evolving acute infarction in the left superior cerebellar hemisphere with no haemorrhagic transformation (figure 2). A second repeat non-contrast CT brain at 24 hours post-thrombolysis demonstrated stable appearances of left superior cerebellar hemispheric infarction with no haemorrhagic transformation. His NIHSS score on day 1 post-thrombolysis was 8. An MRI brain was not performed as his AICD is not MRI-compatible.

Figure 2.

Non-contrast CT brain scan performed 24 hours after admission showed new interval infarction in the left cerebellar region.

His serial troponins were elevated and clinical assessment by the cardiology team concluded a non-ST elevation myocardial infarction, and this was complicated with an apical thrombus in the left ventricle that was confirmed on a transthoracic echocardiogram. He was initially commenced on unfractionated heparin to minimise the risk of haemorrhagic transformation and later bridged onto warfarin. Our patient was subsequently discharged to rehabilitation on the 7th day of his admission.

Discussion

Dabigatran is now widely used for stroke prophylaxis in atrial fibrillation, because of evidence from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial,⁷ which showed dabigatran to be equivalent or if not superior to warfarin in term of stroke prevention and has similar bleeding rates as warfarin. There is now a reversal agent for dabigatran—idarucizumab, which is a fully humanised monoclonal antibody fragment that binds directly to dabigatran at a high affinity,⁵ effective for rapid reversal of the anticoagulant effect of dabigatran.⁶ In the context of acute stroke thrombolysis, use of dabigatran poses an increased risk of haemorrhagic transformation. Therefore, dabigatran reversal is thought to reduce the risk of intracranial haemorrhage after thrombolysis.

A case series published by Shahjouei et al ⁸ showed that thrombolysis in six patients taking DOAC did not suffer any haemorrhagic complications after acute stroke thrombolysis. Even though this seems to suggest that dabigatran reversal is a safe adjunct prior to thrombolysis, most clinicians are still conservative in their approach and would not consider thrombolysis in the context of recent anticoagulation. Rybinnik et al ⁹ reported in a study on clinicians who were surveyed and found that more than half of these clinicians were not in favour of thrombolysis for patients on dabigatran. Ng et al ¹⁰ reported two cases of complications associated with dabigatran reversal to facilitate stroke thrombolysis; however, in both of these cases, the patients have inherent risk factors for adverse outcomes post-thrombolysis, but it cannot be concluded if there was a direct relationship between these adverse outcomes and dabigatran reversal.

In a recent systemic review by Giannandrea et al,¹¹ 55 cases of patients who met inclusion criteria were included for analysis. Of these, 81.9% (n=45) of patients had favourable outcomes with page 4 of 10 thrombolysis after dabigatran reversal, with an improvement of median NIHSS score by 5 points. Adverse outcomes were reported in six patients, of which there were four deaths, two had worsening NIHSS scores and one suffering another stroke after thrombolysis. There were four cases that had suffered intracranial haemorrhage post-thrombolysis. Overall, there is a trend towards positive outcome with dabigatran reversal before thrombolysis, suggesting that dabigatran reversal is likely to minimise haemorrhagic complications.

There are no clinical guidelines available to assist clinicians in managing thrombolysis in patients taking dabigatran. A thrombin time (TT)-based protocol proposed by Kate et al ¹² selected patients on dabigatran with a serum level of less than 10 ng/mL and TT of less than 38 s for thrombolysis, and two patients in the cohort were successfully thrombolysed without haemorrhagic transformation. This represents a method of selecting patients with a low predicted risk of bleeding for thrombolysis, but this remains to be validated in a large clinical trial and still not widely adopted in clinical practice.

Most patients compliant on dabigatran are expected to have therapeutic levels of anticoagulation, making them ineligible for systemic thrombolysis. Reversal of anticoagulation with idarucizumab can facilitate patients who present within the 4.5-hour window to be eligible for acute stroke thrombolysis. For our patient, the left ventricular (LV) thrombus with concurrent non-ST-elevation myocardial infarction causing an embolic stroke is the most likely explanation of the patient’s symptoms. At the time of presentation to the emergency department, our patient was considered not to be suitable for activated charcoal to absorb dabigatran. As dabigatran levels are expected to peak 2–3 hours after ingestion, serial dabigatran levels were performed and these remained less than 35 ng/mL for our patient. Our patient did not suffer any haemorrhagic transformation after thrombolysis. It is possible that the use of dabigatran did not prevent the formation of an LV thrombus in our patient. Dabigatran is only approved for the treatment of venous thromboembolic events and reduction of stroke risk in non-valvular atrial fibrillation; hence, it is possible that recent use of dabigatran in our patient did not prevent the formation of an LV thrombus related to an acute coronary syndrome. Conventional clinical guidelines suggest vitamin K antagonist (VKA) for treatment of LV thrombus.¹³ However, dabigatran has been reported to be effective in the treatment of LV thrombus with complete resolution of thrombus in some cases.^14–17 Dabigatran may be an alternative method of anticoagulation for LV thrombus given its stable pharmacokinetic profile and the availability of rapid reversal with idarucizumab in the event of severe bleeding. The 2014 American Heart Association/American Stroke Association stroke prevention guidelines advised that dabigatran, rivaroxaban or apixaban may be considered as an alternative to VKA for stroke prevention in patients with LV thrombus and an LV ejection fraction of less than 40%.¹⁸

However, this therapeutic advantage of dabigatran is not observed in the treatment of left atrial appendage thrombus, with many reports showing variable responses from increasing the clot size to complete clot resolution.^19–22

The 2018 American Heart Association/American Stroke Association guidelines³ state that thrombolysis in patients taking direct thrombin inhibitors may be harmful, and do not recommend thrombolysis unless laboratory tests of anticoagulant activity, such as INR, TT and direct factor Xa activity assay, are normal, or the patient has not received a dose of dabigatran for more than 48 hours before the onset of stroke symptoms. Hence, recent use of direct thrombin inhibitors in the last 48 hours is a class III contraindication (potentially causing harm) for acute stroke thrombolysis. Similarly, the Royal College of Physicians (UK) National Guidelines for Stroke⁴ have recommended that administration of alteplase for the stroke thrombolysis is not recommended with the reversal of dabigatran using idarucizumab. The Canadian Heart and Stroke Foundation stroke guidelines have recommended that alteplase should not be routinely administered to patients on DOAC who presents with ischaemic stroke.²³ Overall, most clinical guidelines are not in favour of recommending stroke thrombolysis in patients who have recently taken DOACs.

The outcome of this case report is in alignment with evidence from the current literature, suggesting that dabigatran reversal followed by stroke thrombolysis is associated with a largely favourable outcome. Therefore, recent anticoagulation with dabigatran as an absolute contraindication to stroke thrombolysis could be reconsidered. However, further data on the safety and efficacy with using idarucizumab to facilitate stroke thrombolysis is required before this therapeutic regimen can widely be accepted into routine clinical practice.

Learning points.

• Current stroke guidelines do not recommend thrombolysis in patients who are taking active anticoagulation with dabigatran in the last 48 hours prior to thrombolysis. The Royal College of Physicians(UK) stroke guidelines do not recommend thrombolysis for acute ischaemic strokes even in patients who have their dabigatran reversed with idarucizumab.

• We report a case of acute ischaemic stroke in a patient who has taken a dose of dabigatran in the 48 hours prior to presentation, and following reversal of dabigatran with idarucizumab, underwent successful thrombolysis with no haemorrhagic transformation.

• The current state of the literature suggests a largely favourable outcome associated with stroke thrombolysis after dabigatran reversal. Therefore, current guidelines recommending recent active anticoagulation with DOAC as a contraindication to stroke thrombolysis could be reconsidered in the light of new emerging evidence.

• The use of idarucizumab for reversal of dabigatran should be considered as an important therapeutic adjunct to facilitate acute stroke thrombolysis and minimise the risk of post-thrombolysis haemorrhagic transformation.