Πρόληψη του ΑΚΘ σε ασθενείς με μη-ισχαιμική μυοκαρδιοπάθεια:

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1 Πρόληψη του ΑΚΘ σε ασθενείς με μη-ισχαιμική μυοκαρδιοπάθεια: Νεώτερα δεδομένα στη διαστρωμάτωση κινδύνου Εμμ. Μ. Κανουπάκης MD, PhD, FESC Πανεπιστημιακό Νοσοκομείο Ηρακλείου

2 NIDCM Presence of LV dilatation and LV systolic dysfunction Absence of abnormal loading conditions or CAD prevalence: 36-40/ individuals incidence: 5-8 cases/100000/year 5-year mortality from 70% in the early 1980s to approximately 20% nowadays Maron B et al, Circulation 2006;113:

3 Final common pathway of Infections viral, often producing myocarditis bacterial, fungal, rickettsial, mycobacterial parasitic (Chagas disease) Toxins alcohol, chemotherapeutic agents, metals Autoimmune and systemic disorders collagen vascular disorders Neuromuscular disorders dystrophies Mitochondrial, metabolic, endocrine and nutritional disorders Familial (~25%) incomplete and age-dependent penetrance Maron B et al, Circulation 2006;113:

4 SCD & NIDCM Why is NIDCM arrhythmogenic? How to prevent SCD in NIDCM? How to stratify the risk?

5 Pathology in NIDCM Diffuse presence of: reactive (interstitial) & reparative (replacement) fibrosis creating patchy areas. 60% in autopsy Myofiber disarray, with variable degrees of myocyte hypertrophy and atrophy. de Leeuw N et al, Traspl Int 2001;14:299

6 EP substrate in NIDCM Abnormal fractionated electrograms due to lines of activation block from fibrosis Wu et al, J Am Coll Cardiol 1998;32:187 96

7 EP substrate in NIDCM Generation of reentrant wavefronts de Bakker et al, JACC 1996;27:1071

8 VA mechanisms in NIDCM Soejima K et al, JACC 2004;43:

9 Ventricular arrhythmias in NIDCM Frequent ventricular ectopy: up to 87% Non-sustained ventricular tachycardia: 49-60% Sustained monomorphic VT: 3-4% per year Sudden Cardiac Death 10 15% of all SCDs are due to DCM SCD accounts for at least 30% of all deaths in DCM Eckhardt et al, ESC textbook 2009

10 SCD & NIDCM Why is NIDCM arrhythmogenic? How to prevent SCD in NIDCM? How to stratify the risk?

11 Evidence-based medicine Randomized controlled trials Consensus guidelines Clinical practice

12 CAT trial 104 pts recent-onset (<9mo) NIDCM, LVEF<30%, NYHA II & III ICD vs. medical therapy alone Only 3.8% of pts on β-blocker therapy The survival was excellent in both groups The trial was stopped for futility All-cause mortality was not different in either short-term or long-term follow-up Prognosis in NIDCM differs significantly from that of ICM Circulation 2002;105:

13 AMIOVERT 103 pts NIDCM and NSVT, LVEF <35% and NYHA I III ICD vs. amiodarone Prematurely stopped Inability to demonstrate that ICDs are better than amiodarone in reducing mortality Amiodarone was more cost effective and had a better arrhythmia-free survival rate at 3 years than ICDs Should amiodarone be the initial choice in patients with NIDCM, especially in those with NSVT? J Am Coll Cardiol 2003;41:

14 DEFINITE 458 pts NIDCM, EF<35% & NSVT and/or PVCs Optimal medical therapy ± ICD Only 5% on amiodarone Arrhythmic death was significantly reduced in the ICD group All-cause mortality benefit was not demonstrated Routine implantation of an ICD not recommended for all patients with NIDCM N Engl J Med 2004;350:

15 SCD-HeFT 1211 pts NYHA II or III LVEF <35% Amiodarone did not improve survival ICD therapy reduced mortality compared with placebo but not statistically significant Limited benefit of ICD therapy in NIDCM primary prevention N Engl J Med 2005;352:

16 RCT on ICD primary prevention in NIDCM ICD may reduce the risk of SD but total mortality is not significantly modified

17 ACCF/AHA/HRS Guidelines 2012 Class I, level of evidence B ICD is recommended for primary prevention, to reduce total mortality by reducing SCD in patients with: Non-ischaemic dilated cardiomyopathy LVEF 35 % NYHA class II III Optimal Medical Therapy (duration not defined) Contraindications: Life expectancy <1 year, important comorbidities Epstein et al. JACC 2013;61:e6 75

18 ACCF/HRS/AHA/ASE/HFSA/SCAI/SCCT/SCMR Appropriate use criteria 2013 Russo et al. JACC 2013;61:

19 Recent onset NIDCM & improvement 2/3 of pts with NIDCM and SCD-HeFT criteria at presentation did not maintain ICD indications 3 to 9 months later with optimal medical therapy. Am J Cardiol 2012;109: In a multicenter cohort of recent onset NIDCM the risk of SCD was low at 1% per year J Cardiac Fail 2012;18: Patients with new-onset systolic HF have both a good chance of LVEF recovery and low 6-month mortality. Am Heart J 2012;164: These data support delaying ICD implantation

20 How many primary prevention pts benefit from ICD? Only 5 7% of RCT participants with DCM received an appropriate shock per year. NNT: 25 to prevent 1 death at 2 years

21 LVEF limitations Odds ratio: 2.58 Sensitivity: 71.1% Specificity: 50.5% In order to achieve adequate risk stratification for clinical decision making with a high level of discrimination, odds ratios>15-20 are likely necessary. Goldberger J et al, JACC in press

22 EF sensitivity Maastricht Circulatory Arrest Registry The absolute number of SCD victims (who had EF measured before their arrest) was highest in the normal EF category Gorgels et al, Eur Heart J 2003; 24: Stecker et al, JACC 2006;47:1161-6

23 SCD & NIDCM Why is NIDCM arrhythmogenic? How to prevent SCD in NIDCM? How to stratify the risk?

24 From evidence-based to personalized medicine

25 Towards personalized medicine tailoring of medical treatment to the individual characteristics of each patient. doesn t mean the creation of drugs or medical devices that are unique to a patient BUT rather the ability to classify individuals into subpopulations that differ in their susceptibility to a particular disease or their response to a specific treatment.

26 Personalized medicine in NIDCM The combination of LVEF with other markers identifies high- and low-risk patients in a better manner. Especially, those at low risk for ventricular tachyarrhythmias despite low EFs.

27 Risk stratification tools extent of myocardial damage and scar formation LVEF slowed conduction QRS duration, SAECG heterogeneities in ventricular repolarization QT interval, QT dispersion, T-wave alternans imbalance in autonomic tone HRV, heart rate turbulence, baroreceptor sensitivity ventricular ectopy Holter, EP study Goldberger J et al, JACC 2008;52:

28 Risk markers...not promising Fragmented QRS prognostic power not confirmed in a recent prospective trial QT dispersion methodological problems in measurement HRV, BRS, HR turbulence not statistically significant predictors

29 NSVT in NIDCM After medical stabilization, NSVT did not increase the risk of major VA in patients with DCM and LVEF 0.35 Zecchin et al, PACE 2008; 31:

30 Reappraisal of the role of EPS Induction of VT/VF during EPS, in contrast to LVEF, was the only single independent prognostic factor for future ICD activation. Gatzoulis et al, Circ Arrhythm Electrophysiol. 2013;6:

31 T-wave alternans TWA is directly linked to cellular arrhythmia mechanisms arising from sympathetic nerve activity and abnormalities in calcium handling

32 T-wave alternans High negative predictive value BUT No randomized trial to confirm that TWA identify DCM pts at low risk of SD among those with LVEF 35%.

33 The killer is fibrosis detected by serum markers and imaging techniques

34 Serum markers of fibrosis in NIDCM J Am Coll Cardiol 2010;55: Am Heart J 2012;164:530-7

35 Serum markers of fibrosis in NIDCM Serum markers of collagen turnover could predict arrhythmic events in ICD recipients Kanoupakis et al, J Am Coll Cardiol 2010;55:2753 9

36 Analysis of delayed enhancement images

37 LGE-CMR differentiates cardiomyopathies Stirrat et al, Canadian Journal of Cardiology 2013;29:

38 MR assessment of scar in NIDCM Scar distribution can identify the substrate for inducible VT and may identify high-risk patients with NIDCM currently missed by EF criteria. Nazarian et al, Circulation 2005;112:

39 Incidence of midwall fibrosis in NIDCM In 101 pts affected by NIDCM midwall fibrosis was present in 35% of patients Assomull R et al, JACC 2006;48:

40 Midwall fibrosis & prognosis in NIDCM Pts with fibrosis had a significantly worse outcome of the primary end point, allcause death or cardiac hospitalization and a significantly greater incidence of the secondary end point of SCD/VT. Assomull R et al, JACC 2006;48:

41 Midwall fibrosis & prognosis in NIDCM The association between the extent of fibrosis and outcome was better than for established prognostic parameters such as LVESV, LVEDV and LVEF. Assomull R et al, JACC 2006;48:

42 Fibrosis & Events Midwall fibrosis provided independent prognostic information and reclassified patients as high or low risk Gulati et al, JAMA 2013;309:

43 LGE-CMR studies with arrhythmic endpoints High negative predictive value BUT No randomized trial to confirm that LGE-CMR identify DCM pts at low risk of SD among those with LVEF 35%.

44 Familial NIDCM: 25% of cases Heart Failure Society of American Practice Guidelines Useful to consider the more common disease genes and mutations which are associated with a well-known phenotype. LMNA mutations high arrhythmic risk Dystrophin mutations - high risk of end-stage HF LMNA genetic testing for all DCM patients Hershberger et al. J Card Fail 2009;15:83 97

45 ACCF/HRS/AHA/ASE/HFSA/SCAI/SCCT/SCMR Appropriate use criteria 2013 Russo et al. JACC 2013;61:

46 A decision-making algorithm

47 The dilemma The conflict between guideline-based medicine and personalized medicine Withhold a therapy that is recommended or supported by the guidelines but that may not be beneficial for an individual patient. Future expectation If a subpopulation may not benefit from the therapy, it is important to identify the subpopulation and verify this finding in an appropriate clinical trial.

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