Cardiac resynchronization therapy for heart failure: state of the art

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1 Cardiac resynchronization therapy for heart failure: state of the art Béla Merkely MD, PhD, DSc, FESC, FACC Vice president of the European Society of Cardiology Honorary president of the Hungarian Society of Cardiology 70 YEARS OF CARDIOLOGY, ATHENS, 2017

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3 Ventricular dyssynchrony in heart failure Prevalence of LBBB in CHF Relative risk is 5 times higher with widest QRS 8% 100% QRS, ms CHF, preserved EF 90% <90 24% CHF, impaired EF Survival. 80% 70% >220 38% Moderate-severe CHF 60% Days JACC 2003;41: Circ 1997;95: ACC 1999 [Abstr];847-4.

4 Cardiac Dyssynchrony Interventricular Intraventricular Atrioventricular

5 Dyssynchrony demonstrated by cardiac MRI

6 Cardiac Resynchronization Therapy Goal: Mitigate dyssynchrony through atrial synchronous biventricular pacing Transvenous approach for left ventricular lead via coronary sinus Back-up epicardial approach

7 V Kutyifa, OA Breithardt. How to assess the nonresponder to cardiac resynchronization therapy-a comprehensive stepwise approach. REVISTA ESPANOLA DE CARDIOLOGIA 65:(6) pp (2012), Review. 7

8 Cardiac resynchronization therapy (CRT) Is an established therapy for improving heart failure patients especially with LBBB Symptoms Exercise capacity Quality of life Echo parameters Need for hospitalization Mortality Native QRS With CRT 8

9 The Varying Degrees of CRT Response In a study (n=302), 22% of CRT patients could be classified as negative-responders and 21 % as a non-responders or by LVESV after 6 months 1 1. Ypenburg C et al. J Am Coll Cardiol. 2009;53(6):

10 QRS as a patient selection tool Easy to measure, reproducible Pathophysiological plausibility for CRT Normal QRS LBBB IVCD PACE 2004;27(8):1105

11 Questions with QRS Factors that may affect the ability of QRS to measure dyssynchrony amenable to CRT AV delay Atrial fibrillation Scar Electromechanical uncoupling Rate dependent changes Diastolic inflow changes with CRT <100% CRT Irreversible dyssynchrony Variable baseline dyssyncrony Intermittent pacing Other factors...

12 MADIT-CRT QRS morphology LBBB was defined as QRS duration 130 ms; QS or rs in lead V1; broad (frequently notched or slurred) R waves in leads I, avl, V5, or V6; and absent q waves in leads V5 and V6. Non-LBBB 534, 30% IVCD; 306; 17% Nonspecific IVCD was defined as QRS 130 ms without typical features RBBB; 228; 12% LBBB; 1281; 71% Zareba et al, Circulation, 2011 RBBB required QRS duration 130 ms; rsr, rsr, rsr, or qr in leads V1 or V2; and occasionally, a wide and notched R wave and wide S waves in leads I, V5, and V6.

13 Who benefits from CRT? LBBB Zareba W. Circulation 2011;123:

14 Long term survival with CRT MADIT CRT Phase 2 CRT-D superior vs. ICD in LBBB with mild HF symptoms Goldenberg et al. N Engl J Med 2014; 370:

15 Long term survival with CRT MADIT CRT Phase 2 CRT-D not superior vs. ICD in non- LBBB Goldenberg et al. N Engl J Med 2014; 370:

16 MADIT-CRT long-term follow-up: QRS morphology or duration LBBB Goldenberg et al, NEJM, 2014

17 MADIT-CRT long-term follow-up: QRS morphology or duration non-lbbb Goldenberg et al, NEJM, 2014

18 Is there a specific population within non-lbbb that may benefit from implantation of a CRT-D?

19 Patients with prolonged PR-interval In patients with HF, longer PR interval has been shown to be associated with unfavorable clinical outcome, probably by altered AV mechanical sequence leading to impaired left ventricular diastolic filling and increased MI

20 CRT-D in non-lbbb: role of PR intervall MADIT CRT Pts with non-lbbb and prolonged PR did have benefit from CRT PR >=230 ms: CRT-D superior vs. ICD (n=96 22%) 73% and 81% RRR Kutyifa et al. Circ Arrh EP. 2014; 7:

21 CRT-D in non-lbbb: role of 1AVB MADIT CRT Pts with normal PR - increased incidence of HF/death with CRT-D PR <230 ms: CRT-D has worse mortality than ICD Kutyifa et al. Circ Arrh EP. 2014; 7:

22 QRS width QRS>150 msec QRS<150 msec Stavrakis, Lazzara et al. JCE 2012

23 The role of echocardiography in the assessment of dyssynhrony 809 patients with systolic heart failure NYHA III-IV st. <QRS 130 ms Assessement of dyssynchrony: core lab TDI and speckle tracking radialis strain Despite of dyssynchony demonstrated by echo, use of CRT associated with higher mortality in patients with narrow QRS 2013, NEJM Ruschitzka et al.

24 Measure QRS and determine morphology LBBB QRS< 130 msec NCDR LBBB Non-LBBB EchoCRT P< Peterson et al, JAMA 2013 Ruschiztka et al, NEJM 2013

25 Central role of QRS assessment in patient selection Benefits from CRT European Heart Journal (2013) 34,

26 The role of QRS morphology and duration 26

27 No. of pts treated with CRT in each country ( ) compared to the estimated range of incidence regarding actual guidelines R. Hatala et al: Ann Noninvasive Electrocardiol 2015; 20: 43-52

28 Rate of Cardiac Resynchronization in Europe The EHRA White Book 2017

29 Availabilty of CRT therapy in the four European ESC regions trends over 10 years Raatikainen, Arnar, Merkely, Nielsen, Hindricks, Heidbuchel, Camm. Europace,

30 Activation pattern in pts with LBBB is similar to right ventricular pacing RV pacing causes dyssynchrony J Am Coll Cardiol Img 2010;3:461 71

31 Background: Chronic RV pacing MOST trial DDD VVI Sweeney et al. Circulation. 2003;107:

32 Background: Chronic RV pacing DAVID trial Dual chamber vs. Ventricular backup pacing in patients with ICD Inclusion: 256 VVI- vs. 250 DDDR ICD, EF<40%, NYHA I-IV, Sinus Rhythm Primary endpoints: HF hospitalization or death Wilkoff et al. JAMA Dec 25;288(24):

33 BLOCK HF trial Inclusion NYHA I-III st. EF < 50% (mean EF 40.0±8.3%) Sinus or Permanent AF with AV block FU: 37 months Randomization After CRT-P/D implantation randomized to RV or Biv pacing Primary outcome: Composite endpoint of time to death form any cause or HF event or more than 15% increase in ESVi Curtis et Al. N Engl J Med 2013;368:1585-

34 Studies with AV-block: BLOCK HF RV: HR 0.74 (95% CI, ) RV: HR 0.73 (95% CI, ) CRT was superior to RV pacing in patients with AV-block and mild LV systolic dysfunction with NYHA class I, II, or III heart failure Curtis et Al. N Engl J Med 2013;368:

35 Background: BiV upgrade - RAFT trial ICD (904 patients) vs. CRT-D (894 patients) 96 cross-overs NYHA II-III. Class, EF 30%, QRS>120ms Primary endpoint: all-cause mortality or HF hospitalization No mortality or morbidity benefit was found in subgroup analysis Tang AS et Al. N Engl J Med 2010;363:

36 CRT Upgrade : Lack of evidences! Class IIb B ESC Guidelines AHA/ACC Guidelines

37 CRT Upgrade BUDAPeST Upgrade CRT study EFFECT OF BIVENTRICULAR UPGRADE ON LEFT VENTRICULAR REVERSE REMODELING AND CLINICAL OUTCOMES IN PATIENTS WITH LEFT VENTRICULAR DYSFUNCTION AND INTERMITTENT OR PERMANENT APICAL/SEPTAL RIGHT VENTRICULAR PACING First international, multicenter, randomized, controlled trial for upgrade Principal Investigator: Prof. Bela Merkely MD, PhD, DSc, MSc

38 Scope of the Budapest CRT-study To investigate the clinical effects of upgrade from chronic RV pacing to a CRT-D device compared to continued therapy with a single or dual chamber ICD Echocardiographic response at 12-month or HF event or death are investigated as endpoints In the following patient population: left ventricular dysfunction (LVEF 35%), symptomatic heart failure (NYHA II, III, IV-a), intermittent or permanent right ventricular pacing with paced QRS complex 150 ms (20-100%) International, multicenter, randomized, controlled trial 30 centers from Europe and Israel Randomization - CRT-D : ICD = 3:2,sample size: 360

39 Q Q Q Q Q Q Q Q Q Q Q Q3 Series T I M E

40 ICD or CRT-P or CRT-D? in Heart Failure No direct comparison (metaanalysis) Br Med J doi: /bmj be

41 CRT-D is superior in patients with ischaemic etiology compared to CRT-P regarding all-cause mortality, but no difference in NICM Non-ischaemic Ischaemic HR: 0.98; 95%CI ; p=0.894 HR: 0.70; 95%CI: ; p=0.032 Kutyifa et al Eur J Heart Fail Dec;16(12):

42 Heart failure patients (NYHA II-Iva) LVEF<35% NT-proBNP > 200 pg/ml Non-ischaemic etiology Optimal medical treatment Kober et al., NEJM 2016

43 The risk of sudden cardiac death was lower in the ICD group Kober et al., NEJM 2016

44 Younger patients may have a survival benefit in association with ICD implantation Kober et al., NEJM 2016

45 Cardiac resynchronization therapy CRT-P CRT-D Countries with middle income can utilise CRT-P, CRT-D is widespread mostly in high-income countries Raatikainen, Arnar, Merkely, Nielsen, Hindricks, Heidbuchel, Camm. Europace,

46 Conclusion (I) In average 10% of HF patients are indicated for implantation Procedure rates were 3 6 times higher in Western and Northern European than in the Eastern and non- European ESC countries Considerable heterogenity in the access to ICD/CRT use still exists across the ESC area, caused by underuse (East-South) and overuse (West-North) of the device The White Book data will form a steady backbone for future strategic initiatives to harmonise device therapy for HF - Building Bridges in the ESC area

47 Conclusion (II) CRT is recommended to reduce all-cause mortality and HF events in mild to symptomatic heart failure (NYHA II-IVa) patients with a QRS duration 130 ms, with an LVEF 35% and with LBBB CRT is recommended to reduce all-cause mortality and HF events in mild to symptomatic heart failure (NYHA II-IVa) patients with a QRS duration 150 ms, with an LVEF 35% and with Non- LBBB and prolonged PR CRT-D is only superior to CRT-P in ischaemic heart failure pts Activation pattern in pts with LBBB is similar to RV pacing which causes dyssynchrony. Lack of evidence for demonstrating efficacy of CRT upgrade: large randomized study is necessary to prove this hypothesis. Raatikainen, Arnar, Merkely, Nielsen, Hindricks, Heidbuchel, Camm. Europace,

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