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

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

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: 85-825 1977 -1988: mortality among 6018 PWH VIH - de 1977 à 1988 Median expectancy of life: 63 Yrs

Cardiovascular diseases in PWH (Darby S et al. 2007 ) 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

Does hemophilia protect against CVD?

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

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 283 (70%) 2 (1,8%) Liver 47 (12%) 13 (11,4%) Bleeding 18 (4%) 25 (21,9%) Cardiovascular 3 (0,7%) 20 (17,5%) Other 55 (13%) 54 (47 %)

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

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?

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

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

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 >>>

STEMI: European guidelines

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

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

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

Atrial Fibrillation in PWH FA paroxystic or chronic Cardioversion

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

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

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%

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

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)

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