1. CARDIOVASCULAR DISEASE in HEMOPHILIA
Jean-François Schved
Hemophilia Treatment Center
Montpellier University Hospital
Faculty of Medicine
University of Montpellier

4. AGEING PROBLEM in HEMOPHILIA
Cardiovascular diseases
Musculoskeletal diseases
Malignant diseases
Other diseases

5. Cardiovascular diseases in PWH
Darby S et al.
Mortality rates, life expectancy and causes of death in people with hemophilia A or B in UK
Blood 2007; 110:
: mortality among 6018 PWH VIH - de 1977 à 1988
Median expectancy of life: 63 Yrs

6. Cardiovascular diseases in PWH
(Darby S et al )
Mortality in PWH vs normal: O.R. 2,69 (2,37-3,05)
Main causes of death
Hemorrhage: O/E 14,55 (Severe: 55)
Injury : O/E 1,53
Hepatitis : O/E 8,21; Hepatocarcinoma: O/E 13,50
Hodgkin disease: O/E 4,95
Cardiovascular disease (CVD)
O/E 0,63 ( IC 95%: 0,51 - 0,76)
Identical in moderate as compared to severe

7. Does hemophilia protect against CVD?

8. Cardiovascular diseases in PWH
Reduced mortality
Rosendaal et al. (1990)
Mortality reduction due to CVD: 80%
Plug et al. ( 2006)
1992 – 2001: ( expected death/ observed) : 0,5
Problem: numerous bias
Risk factors, Death in young PWH due to HIV, VHC

9. Cardiovascular diseases in PWH
Arnold et al. Blood 2006
Mortality in Canadian hemophilia registry
HIV + (n=660) HIV – ( n=1767)
Death (%) 406 (61,5%) 114 ( 6,5%)
Causes
AIDS (70%) (1,8%)
Liver (12%) 13 (11,4%)
Bleeding (4%) 25 (21,9%)
Cardiovascular (0,7%) 20 (17,5%)
Other (13%) 54 (47 %)

10. Cardiovascular diseases in PWH
Triemstra et al. Ann Int Med 1995
Terminal CAD reduction : 80 in PWH
Sramek SA et al, Lancet 2003
Reduced mortality due to CAD in female hemophilia carriers
Sramek SA et al, Circulation 2001
No effect of hemophilia on atherogenesis
Fransen et al. Thromb Haemost 2012
Unafvourable CVD risk profile in a cohort of Dutch and British hemophilia patients

11. Cardiovascular diseases in PWH
Hemophilia may reduce the incidence of CVD in hemophilia
…but…
Are these data available with the increasing number of patient ( children+adults) under prophylaxis?

12. Cardiovascular diseases in PWH
Various problem in management of CVD
Coronary arterial disease
Stable angina
Acute coronary syndrome
STEMI
Unstable angina/ Non STEMI
Atrial fibrillation
Valvular diseases

13. Cardiovascular diseases in PWH
Coronary arterial disease
Stable angina
Acute coronary syndrome (ACS)
STEMI (ST elevation Myocardial infarction)
= Complete coronary occlusion)
NSTE
Unstable angina
Non STEMI
= Incomplete coronary obstruction
Atrial fibrillation
Valvular diseases

14. Cardiovascular diseases in PWH
Levels of evidence
IA , IB
- IIA, IIB
- III
- IV
… Case reports
Grades of Recommendations:
- A
- B
- C
- D
Good Old Boys Sitting Around a Table
GOBSAT >>>

15. STEMI: European guidelines

16. Cardiovascular diseases in PWH
Therapeutic possibilities
Invasive procedures
No invasive procedure without replacement therapy (Anti hemophilic factors)
Radial vasular access: 60% reduction of puncture related bleeding events
Antiplatelet therapy
Aspirin > aspirin + clopidogrel > Aspirin + Prasugrel/ticagrelor
Possible associated with AHF prophylaxis
Cases reports using aspirin alone in severe hemophiliacs, with on-demand therapy
Double therapy cannot be recommended in mild/sever hemophilia without prophylaxis
Assessment of platelet reactivity may help to detect high-responders whohave a higher risk of bleeding

17. Cardiovascular diseases in PWH
Therapeutic possibilities
OAT
No valid data in the literature
Moderate Hemophilia A : OAT possible (Mannucci et al., Blood 2009)
Problem may be different according to the type of hemophilia ( F IX is vitamin K dependent
NOAT : ???
Stent
Systematic use of dual therapy is a major recommendation afetr stenting (ESC Recommendations, in Wijns et al. Eur Heart J 2010)
=> Dual therapy, as short as possible, with prophylaxis
Choice of stent may be critical
Bare metal stents preferred to drug-eluting stent?
The problem is different with new DES which require a shorter dual therapy

18. Cardiovascular diseases in PWH
Therapeutic possibilities
Coronary Artery Bypass graft
Can be proposed in the case of triple-vessel or left main artery CAD
High levels of replacement therapy required
In moderate hemophilia: increased risk of inhibitor
Reperfusion using thrombolytic agents
No experience in the literature
Cannot be recommended

19. Atrial Fibrillation in PWH
FA paroxystic or chronic
Cardioversion

20. Atrial Fibrillation in PWH
Mannucci et al. Blood 2009
«  In the absence of evidence….
…our strategy is.. »
Coppola et al Sem Thromb Hemost 2010
Review on CVD in PWH
AF is forgotten
Schutgens et al. Hemophilia 2009
No AF
Miesbach et al. Hemophilia 2009
29 PWH from Germany: 3 AF

21. Atrial Fibrillation in PWH
Thrombotic Risk of an AF in PWH
The recommendations given by scientific Societies are based on :
The thrombotic risk of FA (evaluated in normal subjects)
Hemorrhagic risk of antplatelet therapies or OAC

22. Atrial Fibrillation in PWH
Some tracks
AVK with INR 2 - 3
2-3% severe hemorragic accidents every year
Death due to hemorrage in PWH (treated) : x 14Augmenté de 14% par rapport à une population normale
Sur score CHADS2 = 4
le risque annuel d’AVC est de 8%

23. Atrial Fibrillation in PWH
CHADS2
=0: 1,9%
=1: 2,8%
=2: 4%
= 3: 5,4%
=4: 8,5%
= 5: 12,5%
…Ischemic Stroke/yr
AVK 2<INR<3
2-3% severe bleeding / Yr
Hemophilia
Risk of
Hemorragic death
X 14

24. Atrial Fibrillation in PWH
Principles
No clinical data allow to expose a PWH with FA to the high bleeding risk linked to the association Hemophilia + antivitamin K,
Antiplatelet therapy may have a place in this case,
Propositions
CHADS2 = 0 ou 1 : no treatment
CHADS2 > 2 : Low-dose aspirin
Minor hemophilia + CHADS2 > 2: AVK with a low target 1,3<INR<1,8)? (Glosh et al, Hemophilia 2004)

25. Cardiovascular disease in patients with hemophilia: conclusions
CVD disease is an increasing problem in PWH due to ageing of population
CVD treatment in PWH is difficult, dangerous and quite hazardous
Literature is (will be?) of poor help
=> Hemophilia treatment center have to include detection and treatment of cardiovascular risk factors