PRACTICAL ISSUES OF ANTICOAGULANT ACCEPTANCE IN AVIATION MEDICINE

Transcription

1 87 th ASMA ANNUAL SCIENTIFIC MEETING ATLANTIC CITY - April 24-28, 2016 PRACTICAL ISSUES OF ANTICOAGULANT ACCEPTANCE IN AVIATION MEDICINE S. BISCONTE (1), A. HORNEZ (2), J. MONIN (2), D. DUBOURDIEU (2), X. ZIRPHILE (3), S. NGUYEN (1), O. MANEN (2),E. PERRIER (2). (1) Aeromedical Center, Robert Picqué Military Hospital, Bordeaux, France (2) Aeromedical Center, Percy Military Hospital, Clamart, France (3) Cardiology, Robert Picqué Military Hospital, Bordeaux, France

2 Disclosure Information 87 th AsMA Annual Scientific Meeting Sebastien BISCONTE I have no financial relationships to disclose. I will not discuss off-label use or investigational use in my presentation.

3 For 60 years, vitamin K antagonists (e.g., warfarin sodium) were the only available oral anticoagulant medications Benefit / Risk Balance! incapacitation!thromboembolism.. stroke! Intra cranial bleeding! consequences on flight safety Evolution of knowledge! Fit to fly with limitations! Raises some problems for the flight surgeon The advent of Direct Oral Anticoagulants (DOACs) First use in France : 2008! Raises new problems for the flight surgeon We will only discuss about oral medication: VKA & DOACs heparin, specific anticoagulants (danaparoïde ) Only prophylaxic treatment

4 Why were VKA initially prohibited for pilots? It s a family problem: " an unpredictable doseresponse relationship " multiple drug interactions " multiple diet interactions Variable dietary control during flight can cause problems.! Narrow therapeutic index

5 Why were VKA initially prohibited for pilots? It s a family problem:! Narrow therapeutic index " <65% of time in the therapeutic zone " 0.25% fatal bleeding " 1% major bleeding " 6.5% minor bleeding Stroke Intracranial Bleeding # 15% of patients having at least one minor event a year Palareti Lancet 1996 Flight safety Initially Prohibited for pilots in France

6 Medical regulation changes Why? - Limited bleeding risk in the therapeutic zone - Knowledge on anticoagulants in specific population «young» population No comorbidity High intellectual ability

7 Medical regulation changes Why? - Limited bleeding risk in the therapeutic zone - Knowledge on anticoagulants in specific population Major bleeding risk : - intracranial hemorrhage, - bleeding requiring hospitalization, - Hb drop of more than 2g/dL for systemic anticoagulation in pts with atrial fibrillation - Identification of bleeding risk factor Camm AJ. Eur Heart J Pisters R. Chest Lip GYHEuropace. 2011

8 Medical regulation changes Why? - Knowledge on anticoagulants and take into account work accidentology due to VKA - Limited risk in the therapeutic zone - Identification of bleeding risk factor (limited in air crew members) - French to European regulation

9 European regulation for civil aircrew Implementing Rules: «Applicants with an established history or diagnosis of cardiovascular condition requiring systemic anticoagulant therapy shall be referred to the licencing authority» Acceptable means of compliance Referred to the licencing authority Multi-pilot limitation - What is really a stable anticoagulation? «6-5-4 rule» What about DOACs?

10 Case report Pilote 50 yo Class 3 50 flight hours - Aortic dissection - Stanford type A - Biscupid aortic valve! Bentall procedure Is VKA the only problem? First step: evaluation of underlying disease Treatment: Bisoprolol 5mg Fluindione 20mg

11 Case report Pilote 50 yo Class 3 50 flight hours - Aortic dissection - Stanford type A - Biscupid aortic valve! Bentall procedure Is VKA the only problem? First step: evaluation of underlying disease No surgery complication Asymptomatic Good fonction of the mechanical valve No arrythmias Treatment: Bisoprolol 5mg Fluindione 20mg o o o o o Symptoms Complications Prognosis Consequences on flight safety and treatment

12 Case report Pilote 50 yo Class 3 50 flight hours - Aortic dissection - Stanford type A - Biscupid aortic valve Stable anticoagulation?! Rule! INR target range : 2-3! Bentall procedure No surgery complication Asymptomatic Good fonction of the mechanical valve No arrythmias Treatment: Bisoprolol 5mg Fluindione 20mg month

13 Case report Pilote 50 yo Class 3 50 flight hours - Aortic dissection - Stanford type A - Biscupid aortic valve Stable anticoagulation?! Rule! INR target range : 2-3! Bentall procédure No surgery complication Asymptomatic Good fonction of the mechanical valve No arrythmias Treatment: Bisoprolol 5mg Fluindione 20mg month

14 Case report Pilote 50 yo Class 3 50 flight hours - Aortic dissection - Stanford type A - Biscupid aortic valve Stable anticoagulation?! Rule! INR target range : 2-3! Bentall procédure No surgery complication Asymptomatic Good fonction of the mechanical valve No arrythmias Treatment: Bisoprolol 5mg Fluindione 20mg month rule is a theoretical rule Anticoagulant stability is a case by case medical evaluation

15 Case by case evaluation If aortic valve Bleeding Thromboembolism Bleeding Thromboembolism HASBLED CHA 2 DS 2 VASC If phlebitis Bleeding Prophylaxis only Thromboembolism the significance of abnormal INR depends on the medical condition

16 Different DOACs - Dabigatran - Apixaban - Rivaroxaban - Edoxaban Prophylaxis in orthopaedics Prophylaxis in non-valvular Afib Treatment and prophylaxis of recurrence in TE disease Not for mechanical valve Approved EMA/FDA; not in France Updated European Heart Rhythm Associa?on Prac?cal Guide on the use of non-vitamin K antagonist an?coagulants in pa?ents with non-valvular atrial fibrilla?on. Hein Heidbuchel, Peter Verhamme, Marco Alings, MaDhias Antz, Hans-Christoph Diener, Werner Hacke, Jonas Oldgren, Peter Sinnaeve, A. John Camm, and Paulus Kirchhof. Europace doi: /europace/euv309

17 Efficacy: DOACs vs VKA Data regarding full dosage. At least as effective as VKA Chris?an T Ruff, Robert P Giugliano, Eugene Braunwald, Elaine B Hoff man, Naveen Deenadayalu, Michael D Ezekowitz, A John Camm, Jeff rey I Weitz, Basil S Lewis, Alexander Parkhomenko, Takeshi Yamashita, EllioT M Antman. Comparison of the effi cacy and safety of new oral anqcoagulants with warfarin in paqents with atrial fibrillaqon: a meta-analysis of randomised trials. Lancet 2014; 383:

18 Safety: DOACs vs VKA Less major bleeding. Less Intracranial bleeding. More GI bleeding. Chris?an T Ruff, Robert P Giugliano, Eugene Braunwald, Elaine B Hoff man, Naveen Deenadayalu, Michael D Ezekowitz, A John Camm, Jeff rey I Weitz, Basil S Lewis, Alexander Parkhomenko, Takeshi Yamashita, EllioT M Antman. Comparison of the effi cacy and safety of new oral anqcoagulants with warfarin in paqents with atrial fibrillaqon: a meta-analysis of randomised trials. Lancet 2014; 383:

19 DOACs interactions Some drug interactions But no diet interaction

20 DOACs monitoring Possible supervision Without proportionality Possible monitoring Expensive Elimina?on half-life

21 DOACs vs DOACs No DOACs Vs DOACs study. At full dosage: Apixaban Vs VKA : seems to be more safer Dabigatran Vs VKA : seems to be more efficient Near half-life --> same stability Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 17 sept 2009;361(12): (RE-LY). Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, et al. Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism. N Engl J Med. 10 déc 2009;361(24): (RECOVER). Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N Engl J Med. 8 sept 2011;365(10): (ROCKET-AF). The Einstein Investigators, Rupert Bauersachs, Scott D. Berkowitz, Benjamin Brenner. Oral Rivaroxaban for Symptomatic Venous Thromboembolism. N Engl J Med. 23 déc 2010;363(26): (EINSTEIN). Granger CB, Alexander JH, McMurray JJV, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 15 sept 2011;365(11): (ARISTOTLE). Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al. Oral Apixaban for the Treatment of Acute Venous Thromboembolism. N Engl J Med. 29 août 2013;369(9): (AMPLIFY). Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22): (ENGAGE-AF). Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15): (HOKUSAI).

22 Place of DOACs in aviation medicine Use DOACs doesn t change: evaluation of underlying cardiopathy Requirement to refer to the licencing authority Requirement of Multi-pilot limitation Main Advantages of DOACs : At least as effective as VKA Less intracranial bleeding Less overall bleeding No diet interaction Less drug interactions Main Disadvantages of DOACs: Short half-time Monitoring not easy! New problematic compliance?

23 DOACs compliance Pharmocalogical test: - very expensive - without proportionnality Short Half life! stability of the last few days Quality of relationship between Aircrew members and fight surgeon Understand his disease - Importance of daily compliance If you have a reasonnable doubt and for first evaluation: - Number and dates of prescriptions! PT or aptt Aircrew members/flight surgeon relationship Delay?! 3 months

24 Take home message The perfect anticoagulant still remains elusive; That s why referring to licensing authority and multi pilot license is always necessary. However, the advent of the direct oral anticoagulants represents a real improvement. DOACs are at least as safe and efficient as VKAs. The monitoring compliance difficulties are not a real problem. Like all new treatment in aviation medicine, anticoagulants require long term survey.

25 Thank you for your attention