What is controversial in adult congenital heart disease Gerhard-Paul Diller Adult Congenital Heart Center and Center for Pulmonary Hypertension, Royal Brompton Hospital, London, UK, National Heart Institute, Imperial College of Science and Medicine, London, UK &
Disclosures Received grants from Actelion UK, Pfizer UK, GSK UK. Served on the advisory board of Actelion, Germany
What is controversial in adult congenital heart disease Eisenmenger s Syndrome 1. Anticoagulation 2. Medical therapy
Eisenmenger s Syndrome / Cyanosis Dick Ket (1902 1940)
Prognosis Hislop A, Heart 2009
Cyanosis Evolution of Eisenmenger s syndrome Left-to-right shunt Bidirectional shunt Right-to-left shunt 10 20 30 Disease progression (years)
Survival prospects Hopkins WE, et al. J Heart Lung Transplant 1996;15:100
Survival prospects Daliento L, EHJ 1998 Cantor WJ, Am J Cardiol 1999 Diller GP, EHJ 2006
Lammers AE, Exp. Rev. Resp. Med. 2011
fetal phenotype Hopkins WE, AJC 2002
What is controversial in adult congenital heart disease Eisenmenger s Syndrome 1. Anticoagulation 2. Medical therapy
Anticoagulation p=0.02 Fuster V, Circulation 1984
Semin Ophthalmol Downloaded from informahealthcare.com b For personal use only. Role of anticoagulation DISCU SSION Eisenmenger syndrome, a consequence of congenital heart disease w hich has not been surgically corrected, is a chronic disease of adulthood which causes signi cant mortality and morbidity. 6 We screened four patients w ith Eisenmenger syndrome w ho had no ocular complaints and found retinal vascular tortuosity in all eyes. These ndings are to We propose that hypoxia as well as erythrocytosis plays a key role in the retinal vascular patterns of adults w ith cyanotic congenital heart disease, a hypothesis that has already been proposed in children. 13 In our adult patients, mean systemic arterial oxygen saturation w as 77% (range 71 81%) and mean hematocrit w as 64.5% (range 53.7 69.5%). The reversal of retinal tortuosity after surgical repair and relief of cyanosis, hypoxemia, and erythrocytosis supports this hypothesis. 1,3 As pharmacological treat- CYANOSIS RETINAE.Eyeground in a cyanotic child aged 3 1/2 yrs. Painting by Harriet Blackstock McGill University FIGURE 2 Color fundus photograph of a 27-year -old man with truncus arteriosus showing arterial greater than venous tortuosity and venous dilation. This eye also had peripheral intraretinal hemorrhages (not shown). FIGURE 3 The rst published image of retinal vascular tor - tuosity in cyanotic congenital heart disease (Maude Abbott s 1936 Atlas). Seminars in Ophthalmology Perloff JK. Int. J. Cardiol 2004;97: Tsui I, Sem. Ophthal. 2009
Haemoptysis Z. Klin. Med 1897
Prevalence of Haemoptysis Year Institution N Clot Percent 1957 (Wood, BMJ, 5099) Brompton 127 42 33% 1998 (Daliento, EHJ, 1998;19:1845) Torino, Padua, London 188 38 20% 1999 (Niwa, JACC 1999, 34:223) UCLA 77 35 46% 1999 (Canor, AJC, 1999,:677) Univ. of Toronto 109 12 11% 2004 Brompton 40 19 47% Cyanosis has been linked to a number of abnormalities in clotting factors Broberg C. 2007
Impact on Survival: Haemoptysis Accounts for roughly 8% of reported deaths overall Mayo Clinic (1968): 58 patients, 46 deaths haemoptysis is a risk factor (Clarkson, Circ. 1968 Jul;38(1):129-35) Torino/Padua/London (1998): 188 patients, 7/61 deaths Did not impact survival (HR=1.01, p=0.95) (Daliento, EHJ. 1998 Dec;19(12):1845-55) Toronto (1999): 109 patients, 1/33 deaths Did not impact survival (HR=0.35, p=0.09, CI=0.10-1.21) (Cantor, AJC. 1999 Sep 15;84(6):677-81)
Broberg C. Heart 2004;90:e63.
Prevalence of Pulmonary Thrombosis approx. 10-30% Year Institution N Clot Percent 1998 (Daliento, EHJ 1998,19:1845) Torino, Padua, London 188 25 13.2% (age 13-62) 1999 (Niwa, JACC 1999,34:223) UCLA 77 20 38% 2003 UCLA 31 31 100% (Perloff, AJC 2003,92:182) (none on anticoagulants) (mild in 22 mod-massive in 9) (29%) 2003 (Silversides, JACC 2003,42:1982) Univ. of Toronto 34 (15% on anticoagulants) 7 21% (age 43 +/- 9) 2004 (Broberg, AHA 2004) Brompton 40 (32% on warfarin, 15% on ASA) 12 30% (age 23-69) Broberg C. 2007
Impact on Survival: Thrombus Torino/Padua/London (1998): (Retrospective) 188 patients, 25 clots, 61 deaths HR=1.7, p=0.13. Daliento, EHJ 1998
Should we routinely anticoagulate Eisenmenger patients? Broberg CS, JACC 2008
Routine anticoagulation/aspirin: currently available data do not support any benefit in cyanotic patients to prevent thromboembolic complications. There is, however, an increased risk of bleeding.
What is controversial in adult congenital heart disease Eisenmenger s Syndrome 1. Anticoagulation 2. Medical therapy
Galie N, Circulation 2006
BREATHE V RCT in patients with Eisenmenger s syndrome (16 weeks Bosentan/Placebo-therapy) R-L Shunt (SpO 2 ) Haemodynamics (PVRi) Exercise capacity (6MWD)
BREATHE-5: Study Design Screening Bosentan 62.5 mg bid 2:1 Randomization Placebo 62.5 mg bid Bosentan 125 mg bid Placebo 125 mg bid 2 weeks 4 weeks 12 weeks Baseline 16 Weeks
Primary Endpoints 1. Primary endpoint (safety): SpO 2 at rest (Baseline vs. week 16) [non-inferiority testing] 2. Primary endpoint: PVRI (Baseline vs. Woche 16) [superiority testing]
Secondary Endpoints Haemodynamics mpap mrap SaO 2 Qsi Qpi SVRi 6MWTd Borg Dyspnea score WHO functional class
No detrimental effect on SpO 2 Placebo (n=17) Mean (SE) Bosentan (n=35) Mean (SE) Baseline (%) 83.6 (1.2) 82.4 (0.9) Week 16 (%) 84.0 (1.6) 83.8 (0.9) Change from baseline 0.4 (0.9) 1.5 (0.4) Therapy effect: + 1.0 (0.9) 95 % CI =[-0.7, 2.8] > -5
PVRi (dyn sec cm -5 ) Change from baseline Bosentan reduced PVRI 300 200 100 0-100 -200-300 -400 Placebo (n=17) Bosentan (n=36) T.E. = - 472 dyn.sec.cm -5 p=0.04 Galie et al for Breathe-5, Circulation 2006
6MWD (m) Change from baseline Galie et al for Breathe-5, Circulation 2006 6MWTD 60 50 40 30 20 10 0-10 -20-30 Placebo (n=17) Bosentan (n=37) T.E. = 53.1 m p=0.008
BREATHE V OLE Bosentan/placebo BREATHE-5 Bosentan 62.5 mg bid Bosentan 125 mg bid BREATHE-5 OLE 16 weeks 4 weeks 20 weeks Baseline OLE
Change 6MWD (m) 6 SMWTd 80 70 60 50 40 30 20 10 0 10 Baseline BREATHE-5 BREATHE-V Ex-bosentan Ex-placebo n = 26 n = 9 Baseline BREATHE-5 OLE OLE n = 26 n = 9 +33.2 m (23.9) End BREATHE-5 OLE mean (± SEM) +61.3 m (8.0) Gatzoulis et al for Breathe-5 OLE, Eur Heart J (Suppl) 2006
N = 3 Age 28 bis 59 yrs. - 2 ASD, 1 Sinus venosus defect Symptomatic improvement in all patients, SpO2 (range 8 19%) 6MWTd ( 88 m und 56 m in 2 pat.). RVF und PAP syst. (TR Doppler) Mean PAP (range 4 to 14 mm Hg). In one pat. PVR 7.6 to 3.8 Wood's units considered for corrective surgery Zek S, Int J Cardiol. 2006
WHO Prospektiv open-label study Sildenafil 50tds 6 months SpO 2 7 Eisenmenger pts. 6 IPAH pts. 6MWTD mpap PVRI Chau EMC, Int. J. Cardiol. 2006
PVRI R-L Shunt SpO 2 Mukhopadhyay S, Circ. 2006
Dimopoulos KD, Circulation. 2010
N=79 Diller GP, unpublished
N=171 Diller GP, unpublished
Diller GP, unpublished
Diller GP, unpublished
Should we treat all Eisenmenger patients with disease targeting therapies? What is the target? RV vs. Saturations? Int J Cardiol 2010
Baumgartner H. Eur Heart J 2010
Conclusion Optimal management of Eisenmenger s syndrome unclear Pulmonary thrombosis and haemoptysis are common the role of anticoagulation unclear Disease targeting therapies improve symptoms and possibly survival Patient selection not well defined. Only FC 3?, oxygen saturations?, 6MWTd? etc. Role of dual/triple therapy remains to be established.