Summary

What should you know, now that idarucizumab is available in Australia? 

Idarucizumab is a specific reversal agent for dabigatran. Its safety and efficacy have been demonstrated in an open-label phase III study, but clinical experience with idarucizumab is still accumulating. 

Some people do not restart anticoagulant medicines after being prescribed idarucizumab, putting them at risk of thrombotic events. Therefore, appropriate follow-up is an essential part of emergency reversal.

Key points

  • Idarucizumab is a specific non-vitamin K antagonist oral anticoagulant (NOAC) reversal agent that will only reverse the anticoagulant effects of dabigatran.
  • Idarucizumab is the first specific NOAC reversal agent approved in Australia, but others are under development.
  • Idarucizumab is used in hospital, when rapid reversal of the anticoagulant effect of dabigatran is required for emergency situations.
  • Idarucizumab was shown to be effective in the open-label, phase III RE-VERSE AD study. 
  • Safety data for idarucizumab are limited, although no safety concerns have been identified to date.
  • In RE-VERSE AD, 6.3% of participants experienced thrombotic events within 90 days of idarucizumab administration – approximately two-thirds were not taking an anticoagulant medicine.
  • During follow-up it is important for health professionals to check that patients are taking their anticoagulant medicines as prescribed. 

What is idarucizumab?

Idarucizumab is a monoclonal antibody fragment that can reverse the anticoagulant effects of dabigatran, a medicine belonging to the group of anticoagulants collectively known as non-vitamin K antagonist oral anticoagulants, or ‘NOACs’.1,2

In May 2016, idarucizumab became the first specific NOAC ‘antidote’ approved in Australia.1

Idarucizumab is a specific reversal agent for dabigatran. It will not reverse the anticoagulant effects of warfarin or the other NOACs.1

How is idarucizumab used?

Because idarucizumab is used only for dabigatran reversal, only people being treated with dabigatran can be prescribed idarucizumab.1

Idarucizumab is only administered in hospital. However, it may not be available in all facilities. Hospital-based health professionals should verify availability with their relevant drug and therapeutics committee and pharmacy department.1-3

Idarucizumab can be used when rapid reversal of the anticoagulant effects of dabigatran is required for emergency surgery or urgent procedures, or in cases of life-threatening or uncontrolled bleeding.1

Idarucizumab is administered intravenously, as a 5 g dose (2 × 2.5 g / 50 mL vials) given as two consecutive infusions over 5–10 minutes each or as a bolus injection.1

Idarucizumab can be used alongside standard supportive measures, when medically appropriate.1

For more information on use of idarucizumab see the primer on idarucizumab and NOAC-associated bleeding.

Why is idarucizumab used?

Although clinical data to support the use of idarucizumab are still limited, idarucizumab was shown to rapidly and completely reverse the anticoagulant effects of dabigatran in the open-label, phase III RE‑VERSal Effects of idarucizumab on Active Dabigatran (RE‑VERSE AD) study.4,5

Updated results from RE-VERSE AD were presented in November 2016, from the first 494 of 503 planned participants.5,6

In accordance with idarucizumab’s approved indication, enrolled participants were prescribed dabigatran, then presented with uncontrolled or life-threatening bleeding (bleeds group, n = 298) or the need for urgent surgery or procedure (surgery group, n = 196).5

Median maximum reversal of dabigatran’s anticoagulant effects within 4 hours of idarucizumab administration was 100% (95% confidence interval 100% to 100%).5

In participants with non-intracranial bleeds, median time to confirmation of haemostasis was
3.5–4.5 hours.5

Normal haemostasis was reported in 93% of 191 participants who underwent surgery or procedures.5

Other reversal agents are under development, but in contrast to idarucizumab, they are not yet approved for use and require further clinical evaluation.2,7

Are there any risks associated with idarucizumab?

Precautions from the idarucizumab Product Information

There are no contraindications to idarucizumab use, although there are precautions.

When there are precautions, risk of idarucizumab use needs to be weighed against the potential benefit of emergency treatment.1

A summary of idarucizumab precautions is provided below. See the idarucizumab Product Information for complete information.1

  • Thromboembolic events: reversal of dabigatran exposes patients to the thrombotic risk of their underlying disease.
  • Hereditary fructose intolerance: the recommended dose of idarucizumab contains 4 g sorbitol as an excipient.
  • Urinary protein testing: idarucizumab causes transient proteinuria as a physiological reaction to renal protein overflow.
  • Re-elevation of coagulation parameters: in a limited number of patients, recurrence of plasma concentrations of unbound dabigatran and concomitant elevated coagulation parameters have occurred up to 24 hours after idarucizumab administration.
  • Sodium: idarucizumab contains 2.2 mmol (50 mg) of sodium per dose, which should be taken into consideration for patients on a controlled sodium diet.

Based on pharmacokinetic analyses in healthy volunteers, sex, age, race and body weight are not expected to have a clinically meaningful effect on the pharmacokinetics of idarucizumab.1

Idarucizumab may be used during pregnancy, if the expected clinical benefit outweighs the potential risks.1

The safety and efficacy of idarucizumab in children has not been established.1

No dose adjustment is required in patients with renal impairment, and hepatic impairment is not expected to impact the pharmacokinetics of idarucizumab.1

Safety data from RE-VERSE AD

Safety data for idarucizumab are limited, although no safety concerns have been identified to date.5,6

In RE-VERSE AD, mortality rates after 90 days of follow-up were 18.7% (n =  148) in the bleeds group and 18.5% (n = 105) in the surgery group.5,6

Causes of death are not yet summarised for the updated RE-VERSE AD study, but all reported serious adverse events were considered to be related to the index event or comorbidities.6

In a full publication of results from the first 90 participants enrolled in RE-VERSE AD there were 18 deaths, 10 due to vascular causes.8

Deaths within 96 hours of idarucizumab administration were associated with the index event (septic shock, intracranial haemorrhage, multi-organ failure, haemodynamic collapse, respiratory failure or cardiac arrest).8

Deaths at later timepoints were associated with coexisting conditions, including Parkinson’s disease (43 days) and progression of cancer (101 days).8

In total, 21 patients experienced a serious adverse event. In addition to the 18 deaths and the thrombotic events that occurred in five patients, these included gastrointestinal haemorrhage, postoperative wound infection, delirium, right ventricular failure, and pulmonary oedema.8

Some people do not restart anticoagulant medicines after idarucizumab …

… and those who do restart anticoagulant medicines after idarucizumab may not be restarted on dabigatran.

Due to the risk of experiencing a thrombotic event, resumption of anticoagulant medicines after emergency reversal should be considered as soon as medically appropriate.1

Dabigatran may be started as soon as 24 hours after administration of idarucizumab.1 However, data from RE-VERSE AD showed that 28% of participants (n = 82) in the bleeds group and 10% (n = 19) in the surgery group were not prescribed anticoagulant medicines within 90 days of being administered idarucizumab.5

In total, 29% and 61% of participants in the bleeds group and surgery group respectively, were restarted on dabigatran.5 About 16% of participants in each group were switched to anticoagulant medicines other than dabigatran.5

In the RE-VERSE AD study thrombotic events occurred in 6.3% of participants (n = 31) within 90 days of idarucizumab administration – about two-thirds were not prescribed an anticoagulant medicine before the event.5

Appropriate follow-up is an essential part of emergency reversal

Health professionals working in primary care are unlikely to prescribe idarucizumab. However, they have a key role to play during patient follow-up.

During follow-up it is important for health professionals to check if their patients:

  • are taking – and are able to take – their anticoagulant medicines as prescribed
  • understand the risks of thrombotic events if they do not take their anticoagulant medicines
  • recognise the signs of bleeding and thrombotic events.

Re-starting anticoagulant medicine after emergency reversal

Health professionals are advised to consult the Therapeutic Goods Administration approved Product Information and local protocols, and seek specialist advice when starting or transitioning between anticoagulants.2

In Australia, NOACs are still generally considered as alternatives to warfarin. It is still recommended that patients who are stable on warfarin continue on warfarin.2,9,10 However, international guidelines may be moving in favour of using a NOAC before warfarin.7

Some patients may need or want to switch anticoagulant medicines. However, there is a risk of bleeding or thrombosis when transitioning between anticoagulant medicines.2

Discuss the Consumer Medicine Information (CMI) with each patient on an anticoagulant medicine, and remind patients to seek emergency medical help if they see signs of a bleeding or thrombotic event.

Useful resources

Further information can be found in the following resources.

References

  1. Boehringer Ingelheim Pty Limited. Idarucizumab (Praxbind) Product Information 2016 (accessed 17 October 2016).
  2. Clinical Excellence Commission. Non-vitamin K antagonist oral anticoagulant (NOAC) guidelines. Sydney, Australia.
  3. Australian Government Department of Health. Therapeutic Goods Administration. Scheduling delegate's final decisions: NCEs, April 2016 (accessed 13 January 2017).
  4. Pollack CV, Jr. Evidence supporting idarucizumab for the reversal of dabigatran. Am J Med 2016;129:S73-S9.
  5. Pollack CV, Reilly PA, van Ryn J, et al. Idarucizumab for dabigatran reversal: Updated results of the RE-VERSE AD Study. American Heart Association Scientific Sessions. New Orleans, Louisiana: 2016 (accessed 15 November 2016).
  6. Boehringer Ingelheim. Press Release. Updated phase III results reinforce safety and efficacy of Praxbind (idarucizumab) in urgent situations. 2016 (accessed 24 November 2016).
  7. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS: The Task Force for the management of atrial fibrillation of the European Society of Cardiology (ESC). Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Endorsed by the European Stroke Organisation (ESO). Eur Heart J 2016;37:2893-2962.
  8. Pollack CV, Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015;373:511-20.
  9. Australian Medicines Handbook. Blood and Electrolytes: Anticoagulants. Adelaide: Australian Medicines Handbook Pty Ltd, 2016 (accessed 9 January 2017).
  10. Tran H, Joseph J, Young L, et al. New oral anticoagulants: a practical guide on prescription, laboratory testing and peri-procedural/bleeding management. Australasian Society of Thrombosis and Haemostasis. Intern Med J 2014;44:525-36.