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).
87th ASMA ANNUAL SCIENTIFIC MEETING
ATLANTIC CITY - April 24 - 28, 2016
(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
Disclosure Information 87th 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.
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 new problems for the flight surgeon
The advent of Direct Oral Anticoagulants (DOACs)
First use in France : 2008
! Raises some problems for the flight surgeon
We will only discuss about oral medication: VKA & DOACs heparin, specific anticoagulants (danaparoïde…)
Only prophylaxic treatment
Why were VKA initially prohibited for pilots ?
It’s a family problem:
" an unpredictable dose-response relationship
" multiple drug interactions
" multiple diet interactions
! Narrow therapeutic index
Variable dietary control during flight can cause problems.
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
# 15% of patients having at least one minor event a year
Initially Prohibited for pilots in France
Stroke Intracranial Bleeding
Flight safety
Palareti Lancet 1996
Medical regulation changes
Why ? - Limited bleeding risk in the
therapeutic zone
- Knowledge on anticoagulants in specific population
« young » population No comorbidity High intellectual ability
Medical regulation changes
Why ? - Limited bleeding risk in the
therapeutic zone
- Knowledge on anticoagulants in specific population
- Identification of bleeding risk factor
Major bleeding risk : - intracranial hemorrhage,
- bleeding requiring hospitalization, - Hb drop of more than 2g/dL for systemic anticoagulation in pts with atrial fibrillation
Camm AJ. Eur Heart J. 2010 Pisters R. Chest. 2010 .Lip GYHEuropace. 2011
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
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?
Case report
Pilote – 50 yo Class 3 50 flight hours - Aortic dissection - Stanford type A - Biscupid aortic valve
! Bentall procedure Treatment: Bisoprolol 5mg
Fluindione 20mg
Is VKA the only problem ?
First step: evaluation of underlying disease
Case report
Pilote – 50 yo Class 3 50 flight hours - Aortic dissection - Stanford type A - Biscupid aortic valve
! Bentall procedure No surgery complication Asymptomatic Good fonction of the mechanical
valve No arrythmias Treatment: Bisoprolol 5mg
Fluindione 20mg
First step: evaluation of underlying disease
Is VKA the only problem ?
o Symptoms o Complications o Prognosis o Consequences on flight safety
o … and treatment
Case report
Pilote – 50 yo Class 3 50 flight hours - Aortic dissection - Stanford type A - Biscupid aortic valve
! Bentall procedure No surgery complication Asymptomatic Good fonction of the mechanical
valve No arrythmias Treatment: Bisoprolol 5mg
Fluindione 20mg
Stable anticoagulation ? ! 6-5-4 Rule ! INR target range : 2-3
month
Case report
Pilote – 50 yo Class 3 50 flight hours - Aortic dissection - Stanford type A - Biscupid aortic valve
! Bentall procédure No surgery complication Asymptomatic Good fonction of the mechanical
valve No arrythmias Treatment: Bisoprolol 5mg
Fluindione 20mg
Stable anticoagulation ? ! 6-5-4 Rule ! INR target range : 2-3
month
Case report
Pilote – 50 yo Class 3 50 flight hours - Aortic dissection - Stanford type A - Biscupid aortic valve
! Bentall procédure No surgery complication Asymptomatic Good fonction of the mechanical
valve No arrythmias Treatment: Bisoprolol 5mg
Fluindione 20mg
Stable anticoagulation ? ! 6-5-4 Rule ! INR target range : 2-3
month
6-5-4 rule is a theoretical rule Anticoagulant stability is a case by
case medical evaluation
Case by case evaluation
the significance of abnormal INR depends on the medical condition
Bleeding
Thromboembolism Thromboembolism CHA2DS2 VASC
HASBLED
Bleeding
If phlebitis
If aortic valve
Prophylaxis only
Bleeding
Thromboembolism
- Dabigatran
- Apixaban
- Rivaroxaban
- Edoxaban
• Prophylaxisinorthopaedics
• Prophylaxisinnon-valvularAfib• TreatmentandprophylaxisofrecurrenceinTEdisease
• NotformechanicalvalveApprovedEMA/FDA;notinFrance
UpdatedEuropeanHeartRhythmAssocia?onPrac?calGuideontheuseofnon-vitaminKantagonistan?coagulantsinpa?entswithnon-valvularatrialfibrilla?on.HeinHeidbuchel,PeterVerhamme,MarcoAlings,MaDhiasAntz,Hans-ChristophDiener,WernerHacke,JonasOldgren,PeterSinnaeve,A.JohnCamm,andPaulusKirchhof.Europacedoi:10.1093/europace/euv309
Different DOACs
Efficacy: DOACs vs VKA
At least as effective as VKA
Dataregardingfulldosage.
Chris?anTRuff,RobertPGiugliano,EugeneBraunwald,ElaineBHoffman,NaveenDeenadayalu,MichaelDEzekowitz,AJohnCamm,JeffreyIWeitz,BasilSLewis,AlexanderParkhomenko,TakeshiYamashita,EllioTMAntman.ComparisonoftheefficacyandsafetyofneworalanQcoagulantswithwarfarininpaQentswithatrialfibrillaQon:ameta-analysisofrandomisedtrials.Lancet2014;383:955–62.
Safety: DOACs vs VKA
Less major bleeding. Less Intracranial bleeding.
More GI bleeding.
Chris?anTRuff,RobertPGiugliano,EugeneBraunwald,ElaineBHoffman,NaveenDeenadayalu,MichaelDEzekowitz,AJohnCamm,JeffreyIWeitz,BasilSLewis,AlexanderParkhomenko,TakeshiYamashita,EllioTMAntman.ComparisonoftheefficacyandsafetyofneworalanQcoagulantswithwarfarininpaQentswithatrialfibrillaQon:ameta-analysisofrandomisedtrials.Lancet2014;383:955–62.
DOACs interactions
Some drug interactions But no diet interaction
Possiblemonitoring
Possiblesupervision
DOACs monitoring
Without proportionality
Expensive…
Elimina?onhalf-life
DOACs vs DOACs
• NoDOACsVsDOACsstudy.• Atfulldosage:
ApixabanVsVKA:seemstobemoresaferDabigatranVsVKA:seemstobemoreefficient
• Nearhalf-life-->samestabilityConnolly 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):1139‑1151. (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):2342‑2352. (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):883‑891. (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):2499‑2510. (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):981‑992. (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):799‑808. (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):2093–2104. (ENGAGE-AF). Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406–15.
(HOKUSAI).
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?
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
Aircrew members/flight surgeon relationship
If you have a reasonnable doubt and for first evaluation:
- Number and dates of prescriptions ! PT or aPTT
Delay ?
! 3 months
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.
Take home message
Thank you for your attention
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