Idarucizumab is a monoclonal antibody fragment that acts as a reversal agent to the direct thrombin inhibitor dabigatran. It specifically binds protein bound and unbound dabigatran and its active metabolites to form complexes, thus stopping dabigatran’s anticoagulant effects. It irreversibly binds to dabigatran and has a rapid onset and slow offset. Idarucizumab binds dabigatran with an affinity 350 times stronger than dabigatran binds thrombin. While a 2g IV dose has been shown to be capable of reversing dabigatran in healthy subjects given 220mg orally twice a day of dabigatran, a 5g dose is used.1 Idarucizumab was first registered in New Zealand in December 2015. It was included in PHARMAC’s Hospital Medicines List (HML) in June 2016 for the reversal of the anticoagulant effects of dabigatran when required in situations of life-threatening or uncontrolled bleeding, or for emergency surgery or urgent procedures. It is licensed to be given as two consecutive doses of 2.5g, the second dose within 15 minutes of finishing the first dose.2 Each 5g dose of idarucizumab has a PHARMAC listed cost of $4,250.

Aims

1. To examine the use of idarucizumab via the emergency department at Christchurch Hospital
2. To examine adherence to PHARMAC’s HML, licensed dosing regimens and Canterbury District Health Board local guidelines (Canterbury Hospital HealthPathways)

Methods

All patients given idarucizumab via the emergency department were recorded prospectively during September to December 2017 on a data collection form situated next to the idarucizumab supply in the emergency department. This was completed by the nurse retrieving the idarucizumab and included the date and the NHI of the patient. Further data was collected from the paper medicine chart, the electronic patient management system Health Connect South, the electronic prescribing and administration system MedChart™ and the electronic dispensing system ePharmacy™. Data collected included demographics, idarucizumab dosing and timing, coagulation tests, dabigatran dosing and renal function. These were analysed using Microsoft ExcelTM.

Table 1: Idarucizumab HML criteria, local guidelines and licensed dosing regimen.

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Results

Twelve patients were identified as having received idarucizumab; nine patients had stock obtained from ED while three patients had idarucizumab dispensed by the hospital pharmacy. The median age (range) was 73 (56–83) years and the M:F ratio was 4:8.

Idarucizumab was given to six patients for a life-threatening bleed (upper gastrointestinal bleed, rectal bleed, intracranial haemorrhage); to five patients before urgent surgery or procedure and once outside HML criteria to a patient with a high risk of bleeding due to poor dabigatran clearance from an acute kidney injury (AKI).

For the six patients considered to have a life-threatening bleed, five had a haemoglobin reduction of >20g/L. The one patient with a <20g/L haemoglobin decrease presented with intracranial haemorrhage.

Ten patients received idarucizumab as a 5g stat dose or as two 2.5g doses within 15 minutes of each other as recommended. Two patients received two 2.5g doses with an interval longer than 15 minutes.

All 12 patients had coagulation tests taken prior to idarucizumab administration. In 11 of these the coagulation tests thrombin clotting time (TT) and activated partial thromboplastin time (APTT) were consistent with being on dabigatran. The one patient with normal TT and APTT who received idarucizumab was to have alteplase thrombolysis pre-clot retrieval. Eight patients had coagulation tests done 12 hours post-idarucizumab administration and in seven patients these were within normal limits. The median thrombin clotting times pre- and post-idarucizumab were 153 and 16 seconds respectively post-idarucizumab. TT and APTT were above normal limits at 12 hours in one patient possibly due to rebound dabigatran effect in the setting of AKI (this patient’s coagulation tests were within normal limits immediately after idarucizumab administration).

Of the five patients who received idarucizumab prior to surgery or a procedure, two patients had coagulation tests measured at 15 minutes post-administration, which showed full dabigatran reversal.

The dabigatran dosing regimens for all 12 patients is shown in Table 2. The date and time of the last dose of dabigatran was available for only two patients. One had their last dabigatran dose 25 hours prior to idarucizumab. The other had their last dose of dabigatran 8–9 days prior, however an AKI prevented dabigatran clearance.

Atrial fibrillation was the indication for dabigatran in all but one patient who was as anticoagulated to treat a deep vein thrombosis.

Table 2: Dabigatran regimens.

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*Cockcroft and Gault adapted **eGFR as not all information available to calculate CrCl.

Discussion

Our findings suggest idarucizumab is prescribed to reverse dabigatran in most instances for serious, life-threatening bleeds or pre urgent surgery/procedures, in accordance with licensed indication and PHARMAC HML funding criteria. One of our patients fell outside of these indications—accumulation of dabigatran in a patient with an AKI.

In a case report for a patient with high plasma concentrations of dabigatran as a result of an intentional overdose, although no active bleeding was present the decision was made to administer idarucizumab on the basis of increased bleeding risk. Fifteen hours after idarucizumab administration, TT showed a slight rebound but without any bleeding.3

A review by Levy et al suggests adding “high risk of recurrent bleeding associated with high dabigatran body load from either overdose or reduced clearance” as a further indication. 4

PHARMAC have not further defined the meaning of urgent surgery/procedures or life-threatening bleeds. Local guidelines define life-threatening bleeding as bleeding with a reduction in haemoglobin of 20g/L or more, or requiring red blood cell transfusion of two units or more; or involving a critical area or organ, eg, intracranial, intraspinal, pericardial.

Thrombolysis is contraindicated by the manufacturer in patients receiving effective anticoagulation as the combination might theoretically increase the risk of bleeding. This has not been well studied in direct oral anticoagulants (DOACs) and the precaution is extrapolated from warfarin and subsequent haemorrhage post thrombolysis.5,6 It has been suggested that a dabigatran concentration of <10 micrograms/L (or corresponding thrombin time) would be reasonable for thrombolysis; with further study that threshold may increase.6

Xian et al observed no significant difference in bleeding outcomes between patients who were thrombolysed following an ischaemic stroke and patients on warfarin with INR <1.7, DOACs, or no anticoagulants. However, compliance, coagulation results and time of prior DOAC administration were not recorded.7

Evidence around administration of idarucizumab prior to thrombolysis is limited to case-series. Outcomes from these studies have indicated dabigatran reversal prior to thrombolysis is likely to be safe and effective shown by patient improvement via the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scal (mRS).8,9

Although 5g stat is the recommended idarucizumab dose, the way it was prescribed and administered varied. The licensed dosing regimen for idarucizumab is two 2.5g consecutive injections. The New Zealand Formulary prescribing guidelines have since changed to 5g stat, with separate administration instructions.

All patients had coagulation testing prior to idarucizumab administration as per local guidelines which show whether or not an anticoagulant effect from dabigatran is present, as shown particularly by raised TT and often raised APTT.

The date and time of the last dabigatran dose was not obtained in many of the patients so an investigation would require confirmation of patient compliance. The collection of such data may not have been possible in situations where the patient is unable to communicate, such as aphasia in acute ischaemic stroke, prior to idarucuzumab administration.

The demographic in this audit tended to be older adults. The reason behind this is likely that both older people are more likely to have a bleeding event and AF increases in prevalence with advancing age. The majority of patients in this cohort were taking dabigatran for thromboprophylaxis in AF.

In our cohort, idarucizumab use appears to be within HML and licensed indications. Extension of indications into idarucizumab overdose and dabigatran low clearance patients might be useful. Appropriate monitoring of coagulation parameters was carried out in all patients prior to idarucizumab administration and thrombin clotting times pre and post were as expected for all but one patient. Dabigatran dosing at the time of idarucizumab administration was variable in relation to manufacturer’s guidelines. Further investigation may be needed to influence future guidance for dose-adjustment to prevent serious bleeding.

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