What is controversial in adult congenital heart disease

Transcription

1 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 &

2 Disclosures Received grants from Actelion UK, Pfizer UK, GSK UK. Served on the advisory board of Actelion, Germany

3 What is controversial in adult congenital heart disease Eisenmenger s Syndrome 1. Anticoagulation 2. Medical therapy

4 Eisenmenger s Syndrome / Cyanosis Dick Ket ( )

5 Prognosis Hislop A, Heart 2009

6 Cyanosis Evolution of Eisenmenger s syndrome Left-to-right shunt Bidirectional shunt Right-to-left shunt Disease progression (years)

7 Survival prospects Hopkins WE, et al. J Heart Lung Transplant 1996;15:100

8 Survival prospects Daliento L, EHJ 1998 Cantor WJ, Am J Cardiol 1999 Diller GP, EHJ 2006

9 Lammers AE, Exp. Rev. Resp. Med. 2011

10 fetal phenotype Hopkins WE, AJC 2002

11 What is controversial in adult congenital heart disease Eisenmenger s Syndrome 1. Anticoagulation 2. Medical therapy

12 Anticoagulation p=0.02 Fuster V, Circulation 1984

13 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 %). 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

14 Haemoptysis Z. Klin. Med 1897

15 Prevalence of Haemoptysis Year Institution N Clot Percent 1957 (Wood, BMJ, 5099) Brompton % 1998 (Daliento, EHJ, 1998;19:1845) Torino, Padua, London % 1999 (Niwa, JACC 1999, 34:223) UCLA % 1999 (Canor, AJC, 1999,:677) Univ. of Toronto % 2004 Brompton % Cyanosis has been linked to a number of abnormalities in clotting factors Broberg C. 2007

16 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 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 Dec;19(12): ) Toronto (1999): 109 patients, 1/33 deaths Did not impact survival (HR=0.35, p=0.09, CI= ) (Cantor, AJC Sep 15;84(6):677-81)

17 Broberg C. Heart 2004;90:e63.

18 Prevalence of Pulmonary Thrombosis approx % Year Institution N Clot Percent 1998 (Daliento, EHJ 1998,19:1845) Torino, Padua, London % (age 13-62) 1999 (Niwa, JACC 1999,34:223) UCLA % 2003 UCLA % (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

19 Impact on Survival: Thrombus Torino/Padua/London (1998): (Retrospective) 188 patients, 25 clots, 61 deaths HR=1.7, p=0.13. Daliento, EHJ 1998

20 Should we routinely anticoagulate Eisenmenger patients? Broberg CS, JACC 2008

21 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.

22 What is controversial in adult congenital heart disease Eisenmenger s Syndrome 1. Anticoagulation 2. Medical therapy

23 Galie N, Circulation 2006

24 BREATHE V RCT in patients with Eisenmenger s syndrome (16 weeks Bosentan/Placebo-therapy) R-L Shunt (SpO 2 ) Haemodynamics (PVRi) Exercise capacity (6MWD)

25 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

26 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]

27 Secondary Endpoints Haemodynamics mpap mrap SaO 2 Qsi Qpi SVRi 6MWTd Borg Dyspnea score WHO functional class

28 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: (0.9) 95 % CI =[-0.7, 2.8] > -5

29 PVRi (dyn sec cm -5 ) Change from baseline Bosentan reduced PVRI Placebo (n=17) Bosentan (n=36) T.E. = dyn.sec.cm -5 p=0.04 Galie et al for Breathe-5, Circulation 2006

30 6MWD (m) Change from baseline Galie et al for Breathe-5, Circulation MWTD Placebo (n=17) Bosentan (n=37) T.E. = 53.1 m p=0.008

31 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

32 Change 6MWD (m) 6 SMWTd Baseline BREATHE-5 BREATHE-V Ex-bosentan Ex-placebo n = 26 n = 9 Baseline BREATHE-5 OLE OLE n = 26 n = m (23.9) End BREATHE-5 OLE mean (± SEM) m (8.0) Gatzoulis et al for Breathe-5 OLE, Eur Heart J (Suppl) 2006

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35 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

36 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

37 PVRI R-L Shunt SpO 2 Mukhopadhyay S, Circ. 2006

38 Dimopoulos KD, Circulation. 2010

39 N=79 Diller GP, unpublished

40 N=171 Diller GP, unpublished

41 Diller GP, unpublished

42 Diller GP, unpublished

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45 Should we treat all Eisenmenger patients with disease targeting therapies? What is the target? RV vs. Saturations? Int J Cardiol 2010

46 Baumgartner H. Eur Heart J 2010

47 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.