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Monday 11 December 2017
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Behind the headlines: innovations in anticoagulation


An international panel of distinguished experts gathered to discuss innovations in anticoagulation care, at a symposium hosted by Boehringer Ingelheim during the 2016 EAHP Congress in Vienna, Austria


Oweikumo Eradiri PhD FRSPH FFRPS 
Principal Pharmacist Quality Assurance
Colchester Hospital University NHS Foundation Trust, UK
Key considerations
The key considerations of the symposium were:
  1. Novel (or direct-acting) oral anticoagulants (NOACs or DOACs) dosing regimens to optimise patient protection
  2. The availability of the first specific reversal agent for a DOAC 
  3. Reducing the impact on healthcare resources in anticoagulation care.
Across the world, DOACs have become standard therapy in a variety of settings, including:
  • Stroke prevention in patients with non-valvular atrial fibrillation (NVAF)
  • Treatment of acute deep vein thrombosis (DVT) and pulmonary embolism (PE)
  • Preventing the recurrence of DVT/PE
  • Prevention of venous thromboembolism (VTE) following elective hip and knee replacement surgery.
DOACs have demonstrated comparable efficacy against the historic vitamin K antagonists (VKAs; for example, warfarin) and low molecular weight heparins (for example, enoxaparin), with similar or, in some cases, better safety profiles. They come with the advantage of a reduced need for monitoring because, although clotting parameters may not need to be monitored as for warfarin, there is still the need to monitor renal function and some drug–drug interactions. 
A major barrier to the use of DOACs had been the lack of reversal agents to deal with bleeding risks in emergency situations, such as unplanned surgery, unlike the VKAs or heparins, which have proven reversal agents, even though these are non-specific in their action. 
Real world evidence
Professor Leonardo De Luca (Department of Cardiovascular Sciences, European Hospital, Rome, Italy) provided real-world evidence confirming the clinical profile of dabigatran etexilate. Dabigatran and other DOACs are becoming increasingly popular because they overcome many of the practical limitations of warfarin. DOACs have a rapid onset of action, shorter half-life, predictable and consistent anticoagulant effects, low potential for drug–drug interactions, no drug–food interactions, and no requirement for routine coagulation monitoring. The resulting effect is a simpler management of anticoagulation. 
He outlined the RE-LY study, a randomised, controlled trial for stroke prevention in atrial fibrillation (SPAF) patients, comparing dabigatran 150mg twice daily (BID) and dabigatran 110mg BID with warfarin (International normalised ratio (INR) 2.0–3.0). This global non-inferiority trial included over 18,000 patients from 951 centres in 44 countries. The results are summarised in Figure 1.1,2
Professor De Luca also presented real-world data from over 250,000 patients confirming the positive safety and efficacy profile of dabigatran and a United States Food and Drug Administration (US FDA) analysis confirming the favourable benefit-risk profile of dabigatran (Figure 2).1–5
Compared with warfarin, dabigatran showed a drastic reduction in intracranial haemorrhage, and improved outcomes in patients who experienced a major bleed. He outlined that European, Canadian and American guidelines recommend dabigatran for SPAF in patients with one or more risk factors, and concluded that dabigatran has been rigorously studied in highly representative clinical trials, and is supported by a wealth of independent clinical practice evidence unparalleled among the DOACs.
Optimising patient protection
Professor Bernard Vrijens (WestRock Healthcare Associate Professor of Biostatistics University of Liège, Belgium) discussed various considerations in managing and optimising DOAC dosing regimens for patient protection. He intimated that medication adherence was a challenge in anticoagulation therapy, especially as the patients requiring these drugs were already on a number of other medicines – polypharmacy. Unless patients took their medicines consistently as prescribed, clinicians were unlikely to see the kind of benefits demonstrated under clinical trial conditions, where there were high adherence rates.
In order to manage non-adherence, he suggested that the dosing regimen for DOACs should be designed in such a way as to minimise the effect of missed doses. Professor Vrijens stated that although the half-lives of DOACs were similar, their dosing regimens in atrial fibrillation (AF), for instance, were different (Figure 3).6,7
He stated that the BID dosing regimen of dabigatran resulted in more consistent plasma levels than once daily (OD) dosing (Figure 4),8 was more forgiving if missed doses occurred (Figure 5),9 thereby providing greater protection for the patient. One missed OD dose was equivalent to missing three consecutive BID doses, the latter situation being less likely to occur. Most patients with AF were already poly-medicated, so find BID dosing acceptable. 
To improve adherence even further, drug-taking should be linked to a patient’s habits, such as ‘at breakfast’, rather than a time of the day, such as ‘at 8am’. In addition, greater adherence has been demonstrated with once-daily doses prescribed for the morning than for the evening. The reason for this is not quite clear, but could be linked to prioritisation at the start of the day, rather than in the evening when patients might be tired and more likely to forget.
A specific reversal agent
Dr Steve Austin (St George’s Haemophilia Centre, St George’s University Hospitals NHS Foundation Trust, London, UK) discussed idarucizumab, the first specific reversal agent for a DOAC to be approved; this is now in use in several hospitals in Europe and the US. Idarucizumab specifically reverses the anticoagulant activity of dabigatran within minutes, and has no procoagulant or anticoagulant effect of its own (Figure 6).
Dr Austin described the design of the RE-VERSE AD multicentre, open label Phase III study, and stated that the results so far indicated that there were no idarucizumab-related safety concerns or contraindications to date (Figure 7).10,11 Idarucizumab was easy to use (Figure 8), and dabigatran could be re-started 24 hours after dosing with idarucizumab; heparin can be re-started at any time after idarucizumab (Figure 9).12 He made a ‘call to action’ to the delegates to ensure that local protocols are updated to include idarucizumab.
Reducing the impact on healthcare resources
Dr Ian Menown (Craigavon Area Hospital, Northern Ireland, UK) appraised the evidence for the cost-effectiveness of dabigatran against other DOACs and warfarin. AF-related stroke is associated with substantial economic cost and personal burden. He presented UK data that showed dabigatran to be less costly than apixaban or rivaroxaban versus warfarin (total cost for dabigatran: £23,342; quality-adjusted life years (QALYs) 7.78; apixaban: £24,014, QALYs 7.63; rivaroxaban: £25,220, QALYs 7.47; warfarin: £24,680, QALYs 7.36).13
Dabigatran had the highest incremental net monetary benefit (Figure 10) and, by reducing delay to urgent or emergency procedures through the use of idarucizumab, and by helping management of life-threatening bleeding, may improve clinical outcomes and provide further cost savings.13
A case study discussed the impact of DOACs and reversal agents in clinical practice and the case of an elderly female admitted to hospital after a fall ‘onto her face’. Surgical fixation of an elbow fracture was required. Dabigatran anticoagulation was reversed with idarucizumab, which led to normal haemostasis during surgery. Dabigatran was restarted two days post surgery and the patient discharged after four days. 
Panel discussion and conclusions
In the ensuing lively discussions, the panel and the participants agreed that managing bleeding was cheaper with dabigatran than with warfarin; and major savings with dabigatran came from prevention of ischaemic stroke. Overall, the discussions indicated a greater uptake of, and preference for, DOACs over warfarin. Dabigatran is the only DOAC with a specific reversal agent. Idarucizumab is widely available, easy to use and may improve clinical outcomes and provide cost savings.
Support for the production of this report was provided by Boehringer Ingelheim
Figure 1: RE-LY®: at a glance 
Figure 2: Favourable risk-benefit profile of dabigatran
Figure 3: Similar half-lives, different dosing regimens
Figure 4: BID dosing results in more consistent plasma levels
Figure 5: BID regimen increases forgiveness for similar deviations in adherence
Figure 6: A specific reversal agent for dabigatran
Figure 7: Immediate, sustained and complete reversal of dabigatran anticoagulation
Figure 8: Easy to store, easy to use
Figure 9: Proposed algorithm for management in rare emergency situations
Figure 10: High incremental net monetary benefit 
  1. Connolly SJ et al. Newly identified events in the RE-LY trial. N Engl J Med 2010;363(19):1875-6.
  2. Connolly SJ et al. Additional events in the RE-LY trial. N Engl J Med 2014;371(15):1464-5.
  3. Connolly SJ et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361(12):1139-51.
  4. Pradaxa EU Summary of Product Characteristics. (accessed July 2016).
  5. Graham DJ et al. Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation 2015;131(2):157-64.
  6. Xarelto EU Summary of Product Characteristics. (accessed July 2016).
  7. Heidbuchel H et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 2015;17(10):1467-507.
  8. Clemens A et al. Twice daily dosing of dabigatran for stroke prevention in atrial fibrillation: a pharmacokinetic justification. Curr Med Res Opin 2012;28(2):195-201.
  9. Vrijens B, Heidbuchel H. Non-vitamin K antagonist oral anticoagulants: considerations on once- vs. twice-daily regimens and their potential impact on medication adherence. Europace 2015;17(4):514-23.
  10. Pollack CV Jr et al. Design and rationale for RE-VERSE AD: A phase 3 study of idarucizumab, a specific reversal agent for dabigatran. Thromb Haemost 2015;114(1):198-205.
  11. Glund S et al. Idarucizumab, a specific antidote for dabigatran: Immediate, complete and sustained reversal of dabigatran induced anticoagulation in elderly and renally impaired subjects. 56th ASH Annual Meeting and Exposition; December 2014: Abstr 344.
  12. Eikelboom JW et al. Idarucizumab: The antidote for reversal of dabigatran. Circulation 2015;132(25):2412-22.
  13. Zheng Y et al. Comparison of the cost-effectiveness of new oral anticoagulants for the prevention of stroke and systemic embolism in atrial fibrillation in a UK setting. Clin Ther 2014;36(12):2015-2028

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