Heart failure in adults with congenital heart disease - What is different about drug treatment?

Transcription

1 Heart failure in adults with congenital heart disease - What is different about drug treatment? G. P. Diller Adult Congenital Heart Disease Program, Royal Brompton Hospital, London, GB Division of Adult Congenital and Valvular Heart Disease, Department of Cardiology, University of Münster, Germany

2 No conflict of interest to declare 2

3 Definition of heart failure A state in which the heart fails to maintain an adequate circulation for the needs of the body despite a satisfactory filling pressure Paul Wood, 1950 A clinical syndrome caused by an abnormality of the heart and recognised by a characteristic pattern of haemodynamic, renal, neural and hormonal responses PooleWilson, 1985 I. Symptoms of heart failure (at rest or during exercise) and II. objective evidence of cardiac dysfunction (rest) and (in cases where the diagnosis is in doubt) III. response to treatment directed towards heart failure ESC Task Force 2005

4 Heart failure symptoms common in ACHD 22% dtga, 32 % cctga, 40% Fontan HF symptoms

5 Exercise Intolerance Diller, G.-P. et al. Circulation 2005

6 Bolger, A. P. et al. Circulation 2002 Bolger, A. P, EHJ 2003 Neurohormonal Activation 47 patients with chronic HF due to ischaemic or DCM vs 83 ACHD patients

7 Immune Activation Bolger, A. P. et al. Circulation 2002 Sharma et al. Am J Card 2003

8 Ohuchi et al Circulation 2002 Neurohormonal- / Immune Activation / Autonomic dysfunction (Fontan patients) Younger patients ANP/BNP in the APC vs TCPC group CANA and lower HR variability related to the number of previous surgeries

9 Underlying heart disease Impaired exercise capacity Signs and symptoms of heart failure Neurohormonal and immune activation Bolger et al. Eur Heart J. 2003

10 Reduced life expectancy TOF UVH Syst RV Nieminen HP, Circulation 2001

11 Heart failure common cause of death Nieminen HP et al JACC 2007

12 Treatment challeging Jessup M, NEJM 2003

13 Physiology and Anatomy different from acquired HF Extrapolating results to ACHD difficult RV LV? Ellipsoid Anderson, Becker 1980

14 Studies of HF medication in ACHD disappointing 1. ACE-I Randomized study n=18; Fontan pts. 10 wks. FU No change in pvo 2 oder CI Kouatli AA, Circulation 1997

15 Studies of HF medication in ACHD disappointing 1. ACE-I n=63, 10 ACE-I Therapy

16 Studies of HF medication in ACHD disappointing 1. ACE-I n=14, 6 mths. AJC 2001

17 Studies of HF medication in ACHD disappointing 1. ACE-I n=9, dtga, Enalapril 12 mths. Ped Cardiol 2002

18 Studies of HF medication in ACHD disappointing 1. ACE-I Abstract 2031: ACE Inhibitors for Potential PRevention of the Deleterious Effects of Pulmonary Regurgitation In Adults with TEtralogy of Fallot Repair - The APPROPRIATE Study - A Randomised, Double-Blinded, Placebo-Controlled Trial in Adults with Congenital Heart Disease Sonya V Babu-Narayan; Anselm Uebing; Periklis A Davlouros; Michael Kemp; Simon Davidson; Omer Goktekin; Stephanie Bayne; Philip J Kilner; Wei Li; Michael A Gatzoulis Royal Brompton Hosp, London, United Kingdom Background: Angiotensin Converting Enzyme (ACE) inhibitors have been regarded as useful in aortic regurgitation, but their effectiveness with volume loading of the right ventricle (RV) due to pulmonary regurgitation (PR), a cause of late morbidity and mortality after repair of tetralogy of Fallot (ToF), remains unknown. We therefore undertook what we believe to be the first randomised, double-blinded, placebo-controlled drug trial in adults with congenital heart disease, on the effect of ACE inhibition in patients with repaired ToF and PR. Methods and Results: Sixty-Four adults with repaired TOF and at least moderate PR were randomly assigned to six months ramipril 10 mg or six months placebo in a double-blinded fashion. New York Heart Association (NYHA) class, maximal VO 2, pulmonary regurgitant fraction (PRF), RV and left ventricular (LV) end-systolic volume index (ESVi) and ejection fraction (EF) by cardiovascular magnetic resonance, and RV and LV long axis function on M-Mode echocardiography, were similar in both groups at baseline. Treated patients demonstrated significant improvement in RV and LV amplitude of long axis shortening (16.2 ± 4.8 versus 17.8 ± 4.8; P = and 14.6 ± 4.3 versus 16.2 ± 3.6 mm; P = 0.008), RV and LV stroke volume index ( 74.1 ± 18.3 versus 78.9 ± 21.3; P = 0.06, 45.8 ± 7.3 versus 9.8 ± 9.7 mls/m 2 ; P = 0.02) and a trend to improvement in global RVEF (53.5 ± 8.3 versus 55.3 ± 7.0 %; P = 0.08). No significant difference was demonstrated in NYHA class (1.19 ± 0.4 versus 1.19 ± 0.4; P = 1.0), VO 2 max (25.7 ± 5.9 versus 25.3 ± 7.0 ml/min/kg; P = 0.58), PRF (39.2 ± 10.4 versus 37.8 ± 10.9 %; P = 0.17), RVESVi or LVESVi (66.6 ± 25.3 versus 66.9 ± 30.3 ml/m 2 ; P =0.9, 25.1 ± 9.2 versus 24.9 ± 9.0 ml/m 2 ; P = 0.9). Similar increases in atrial and brain natriuretic peptide (ANP;BNP) levels were seen in both groups between baseline and follow up (ANP: +4.2 ± 5.4 placebo versus +2.3 ± 4.6 treatment; P = 0.15 pmol/l, BNP: +3.7 ± 5.8 placebo versus +7.6 ± 8.8 treatment pmol/l; P = 0.25). Conclusions: Six months of ramipril treatment did not reduce pulmonary regurgitant fraction or decrease ventricular size. Increases in RV and LV long axis function, stroke volumes and RV ejection fraction are potentially beneficial but the changes were modest and their clinical significance remains open.

19 Studies of HF medication in ACHD disappointing 2. ARBs n=7, cross over, EF und Exercise capacity AJC 2001

20 Studies of HF medication in ACHD disappointing 2. ARBs 21 Mustard 8 cctga Multicenter, rand., double-blind, cross-over study 29 pts. (21 dtga, 8 cctga) 15 wk. Losartan 2x50 mg/die

21 Studies of HF medication in ACHD 2. ARBs

22 Studies of HF medication in ACHD 2. ARBs Van der Bom T, ESC 2012

23 Studies of HF medication in ACHD 3. b-blockers NYHA, RVED-area retrospective, 60 pts. (31 b-blockers) Doughan A, AJC 2007

24 Studies of HF medication in ACHD 3. b-blockers 8 pt. SRV 12 mths. Carvedilol Target dose 25 mg/die (reached 62% of pts.) RVEDV, RVESV & RVEF Giardini A, IJC 2006

25 Determinants of peak oxygen consumption Univariate analysis r - value P - value Peak pulse 0.49 < NYHA class < Cyanosis < Pulmonary hypertens < Gender < Age < Age at surgery < %FEV < %FVC 0.22 < SV function PV function Peak systolic BP Diller, G.-P. et al. Circulation 2005

26 Chronotropic Incompetence common in ACHD Diller, G.-P. et al. IJC 2008

27 Treating CI not necessarily beneficial Figure 1. Heart rate and peak oxygen consumption (peak VO2) with pre-existing pacemaker (PM) settings and with after active reprogramming. One patient (marked with an asterisk) developed atrial tachycardia at the test with pre-existing pacemaker settings.

28 Treating CI not necessarily beneficial Figure 3. Comparison between systemic (right) ventricular total isovolumic time (t-ivt), total filling time (t-ft) and aortic velocity time integral (VTI) at 3 different heart rates (HR). Non-parametric Wilcoxon tests (paired samples) were used to compare data.

29 Treating CI not necessarily beneficial ECG Phono FT Circulation Nov 7;102(19 Suppl 3):III Failure of stroke volume augmentation during exercise and dobutamine stress is unrelated to load-independent indexes of right ventricular performance after the Mustard operation. Derrick GP, Narang I, White PA, Kelleher A, Bush A, Penny DJ, Redington AN. HR 68 bpm HR 110 bpm HR 140 bpm t-ivt 17.1 s/min t-ivt 27.0 s/min t-ivt 28.0 s/min t-ft 24.8 s/min t-ft 15.6 s/min t-ft 13.9 s/min VTI 10.7 cm VTI 5.3 cm VTI 4.2 cm

30 Symptoms Hypothyroidism, Anaemia, Lung function, PHT Life style Extracardiac problems Haemodynamic problems Arrhythmias Surgey / Interventions Asynchrony, SCD EP? weak evidence Medical therapy CRT/CRT-D Transplantation Assist devices Supportive care

31 Conclusion Heart failure is a common problem in adults with CHD Associated with considerable morbidity and mortality Extrapolating from data in patients with (acquired) left heart disease is not straightforward Commonly a preload problem / diastolic dysfunction Assess indication for surgery/intervention for residual haemodynamic lesions Assess pts. as part of multidisciplinary team ACHD cardiologists/ EP/ Surgeons

32 Thank you.