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1 CARE-HF CArdiac REsynchronization in Heart Failure Clinical Study Independent trial by Clinical Community Sponsored by Medtronic.

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Presentation on theme: "1 CARE-HF CArdiac REsynchronization in Heart Failure Clinical Study Independent trial by Clinical Community Sponsored by Medtronic."— Presentation transcript:

1 1 CARE-HF CArdiac REsynchronization in Heart Failure Clinical Study Independent trial by Clinical Community Sponsored by Medtronic

2 2 “Electromechanical Associations” EP & HF Specialties Progressively More Entwined Rogers JG & Cain ME NEJM 2004;350: EP specialists understand that: –Drugs (ACEIs, BB, Aldo Antagonists) have a profound impact on HF progression and mortality –Drugs (BB and Aldo Antagonists) significantly decrease SCD HF specialists understand that: –50% of HF patients die from SCD –ICD decreases mortality –CRT decreases morbidity and mortality

3 3 Prevalence and Prognosis of Ventricular dyssynchrony LBBB More Prevalent with Impaired LV Systolic Function 38% 24% 8% Mod/Sev HF (2) Impaired LVSF (1) Preserved LVSF (1) 1. Masoudi, et al. JACC. 2003;41: Aaronson, et al. Circulation. 1997;95: Increased All-Cause Mortality with Wide QRS at 45 Months (3) 34% 49% QRS < 120 ms QRS ≥ 120 ms 3. Iuliano, et al. AHJ. 2002;143: P < 0.001

4 4 Cardiac Resynchronization: Proposed Mechanisms Yu C-M, Chau E, Sanderson J, et al. Circulation 2002;105: Yu C-M, Chau E, Sanderson J, et al. Circulation 2002;105: IntraventricularSynchronyAtrioventricularSynchronyInterventricularSynchrony  LA Pressure  LV Diastolic Filling  RV Stroke Volume  LVESV  LVEDV Reverse Remodeling Cardiac Resynchronization  MR  dP/dt,  EF,  CO (  Pulse Pressure)

5 5 Cumulative Benefit of ACE-I and Beta Blockers Exner DV et al. JACC; 1999; 33: P < 0.01 P < 0.05

6 6 25% 18% 4.1% 3.2% Total Mortality Benefit for an ICD Trial (AVID) and a Statin Trial (WOSCOP) 27% Relative Risk Reduction 27% Relative Risk Reduction 7% Absolute Risk Reduction 7% Absolute Risk Reduction 18% Residual Risk18% Residual Risk 22% Relative Risk Reduction22% Relative Risk Reduction 0.9% Absolute Risk reduction0.9% Absolute Risk reduction 3.2% Residual Risk3.2% Residual Risk

7 7 Residual Risk of SCD in Treatment Arms of CHF-Beta Blocker Trials 1.CIBIS-II Investigators. Lancet 1999; 353: Packer, M, et al. N Engl J Med 1996: 334: MERIT-HF Study Group. Lancet. 1999; 353: Average Follow Up: 54%31%54% n = months16 months No. Pts in Treatment Arm:n= 1327n= months Sudden Death % of Total Death

8 8 Moss AJ et al. NEJM 2002; 346: P= MADIT II: Hospitalization for Heart Failure

9 9 Moderate CHF Severe CHF Mild CHF Post-MI LV dysfunction Pharmacologic and Device Therapy Across the Continuum SOLVD Treatment (enalapril) CONSENSUS (enalapril) AIRE/SAVE (ramipril/captopril) US Carvedilol/MERIT (carvedilol/metoprolol) COPERNICUS (carvedilol) CAPRICORN (carvedilol) RALES (spironolactone) EPHESUS (eplerenone) CHARM/Val-HeFT (candesartan/valsartan) MADIT, MUSTT (ICD) SCD-HeFT, MADIT-II (ICD) MIRACLE, COMPANION, MUSTIC (CRT +/- ICD) CARE-HF

10 10 CRT Background CRT has been shown to be consistently associated with: –Reductions in LV size and volume –Increased Stroke Volume –Increased Ejection Fraction –Reduced Mitral Regurgitation –Improved exercise capacity –Improved QOL and functional capacity Effects of CRT on hospitalisation and mortality remain uncertain

11 11 CRT Improves Quality of Life and NYHA Functional Class * P < 0.05 Abraham et al., 2003

12 12 CRT Improves Exercise Capacity * P < 0.05 Abraham et al., 2003

13 13 CRT Benefits Sustained Through 2 Years MIRACLE Study Program Abraham et al., AHA 2003 Baseline Follow-up Paired Data Displayed Mean distance walked in 6 minutes (m) P<0.001 P= (N=1124)12 (N=693)18 (N=320)24 (N=68) Months of Active CRT Mean QoL Score P< Mean NYHA Functional Class P<0.001

14 14 ‡ * * NS ‡ ‡ Improvement * P .05 † P .01 ‡ P .001 * † † 1 NEJM 1993;329:1-7 (RADIANCE) 2 Circulation 1996;94: (PRECISE) 3 JAMA 1988;259: Comparison with Drug Trials: Digoxin, ACE-I and Beta-blocker Therapies 4 Am J Cardiol 1993;71: (SOLVD Treatment) 5 J Cardiac Failure 1997;3: NEJM 2002;346: (MIRACLE)

15 15 Systematic Review of 9 clinical trials CRT reduces all-cause mortality by 21% (RR 0.79 [Ci ] NNT B 24 McAlister FA et al. Ann Intern Med 2004; 141: CRT does not significantly reduce all-cause mortality Calvert M, Freemantle N and Cleland JGF Ann Intern Med 2005; 142 :305-7

16 16 Limitations of Previous Trials/Analyses or Why Was CARE-HF Needed No individual clinical trial found a statistically significant reduction in all-cause mortality 8/9 trials required successful device implantation before pts. were randomly assigned to CRT on or off [omission of implant failures (10%) and procedural deaths (0.4%) and exposure of controls to the effects of implanted device] CRT combined with ICD in some but not all studies (difficult to isolate effect of CRT alone on mortality)

17 17 Limitations of Previous Trials/Analyses or Why Was CARE-HF Needed (cont’d) COMPANION had unbalanced 3-arm design (OMT, CRT, CRT+ICD) Inclusion of all 3 arms of COMPANION in meta-analyses inappropriately credits CRT with the mortality reduction due to the ICD

18 18 The CARE-HF Study CArdiac REsynchronisation in Heart Failure John GF Cleland - Kingston-upon-Hull. UK Jean-Claude Daubert – Rennes. France Erland Erdmann – Cologne. Germany Nick Freemantle – Birmingham. UK Daniel Gras – Nantes. France Lukas Kappenberger – Lausanne. Switzerland Werner Klein – Graz. Austria Luigi Tavazzi – Pavia. Italy on behalf of the CARE-HF Study Investigators

19 19 CARE-HF Intent To assess the effect on morbidity and mortality of adding CRT to optimised pharmacological therapy in patients with moderate and severe HF due to LVSD complicated by cardiac dyssynchrony To investigate the mechanisms underlying the observed effect to identify markers predicting success or failure of CRT To define long term effects and Health Economics.

20 20 CARE-HF Committees Steering Committee (8) Data Safety and Monitoring Board (4) Ryden, Poole-Wilson, Wellens, Wedel Blinded Endpoint Adjudication Committee (2) Uretsky, Thygesen Independent device-related adverse event assessor (1) (Bocker)

21 21 CARE-HF Communication DSMB BRC FCM/ Monitors Core-labs Steering Committee Steering Committee Sites - Investigators - Coordinators Sites - Investigators - Coordinators USA Tolochenaz Quintiles - SS&R - DM - CEVA Quintiles - SS&R - DM - CEVA EPC

22 22 CARE-HF Study Overview

23 23 Primary & Main Secondary Endpoints Primary Composite Endpoint All-cause mortality or unplanned hosp. for a major CVS event (time to first event analysis) –Hospitalisations adjudicated by a blinded EP committee Main Secondary Endpoint All-cause mortality

24 24 Statistical Methods Assumptions for Death or Unplanned CV hospitalization –Event rate in the control group: 40% –Absolute reduction in risk: 5.7% 80% power with 300 primary outcome events Censoring data within first 10 post randomization for Hospitalization endpoint. (No influence on results when analyzed without 10 days)

25 25 Study Design Patient screening- consent Randomization Optimal medical therapy & cardiac resynchronization Primary outcome Secondary outcomes Mechanistic & health economic outcomes Follow-up (min 1.5 year) Optimal medical therapy

26 26 Intervention InSync® or InSync® III -> CRT-alone Atrial-based, biventricular stimulation –RV: from apex using a standard pacing lead –LV: from lateral or postero-lateral free wall via the coronary sinus and veins using an Attain™ lead Echo guided optimization of AV delay

27 27 Main Inclusion Criteria Heart failure for at least 6 weeks requiring loop diuretics Currently in NYHA class III/IV A high standard of pharmacological therapy LV systolic dysfunction and dilation –EF  35%; EDD  30mm/height in metres

28 28 Main Inclusion Criteria (cont’d) QRS  120 ms –Dyssynchrony confirmed by echo if QRS = ms Aortic pre-ejection delay >140ms Inter-ventricular mechanical delay >40 ms Delayed activation of postero-lateral LV wall Main Exclusion Criteria Patients with chronic AF or requiring pacing excluded

29 29 Population – Baseline Characteristics 813 pts predominantly class III (94%) Mean age 65 (IQR 59-72) –34% aged > 70 years –27 % woman 38 % Ischaemic Heart Disease, 46% Dilated CM Mean HR adequately controlled at 70 BPM 88% QRS > 150 msec. Supine systolic BP : 117 (IQR ) 94 % diuretic, 95 % Ace or ARB, 72 % b-Blocker, 56% Spironolactone Baseline Characteristics of Patients Recruited into the CARE-HF Study; With Courtesy : JGF Cleland et al. Submitted to EJHF

30 30 LV EF 26% LVEDD 72 mm 2D and Doppler date suggest that few patients had end-stage disease characterized by pulmonary hypertension and right ventricular dysfunction Co-Morbidities: –Diabetes 21%, history Atrial Arrhythmias 21%, Pulmonary disease 19%, renal dysfunction 18% Baseline Echo Cardiographic Characteristics of HF Patients enrolled in a large European Multicenter trial (Cardiac Resynchronization in Heart Failure) With Courtesy : S. Ghio et al. Submitted to EJHF. Baseline Characteristics of Patients Recruited into the CARE-HF Study; With Courtesy : JGF Cleland et al. Submitted to EJHF Population – Baseline Characteristics (cont’d)

31 31 Baseline Characteristics Control n = 404 CRT n = 409 Age [yr] - median (IQR)66 (59 to 72)67 (60 to 73) Male (%)293 (73%)304 (74%) NYHA IV (%)27 (6.7%)23 (5.6%) Ischaemic heart disease (%)142 (35%)167 (41%) Treatment (%) ACEIs / ARBs383 (95%)387 (95%) Beta blockers298 (73%)288 (71%) Furosemide Eq  80 mg/day 177 (44%)175 (43%) Digitalis181 (45%)165 (40%) Spironolactone238 (59%)219 (54%)

32 32 Baseline Characteristics (cont’d) Parameter (median [IQR]) Control n = 404 CRT n = 409 Heart rate [bpm]70 (61 to 78)69 (60 to 78) Systolic BP [mm Hg]110 (100 to 125) Diastolic BP [mm Hg]70 (60 to 80)70 (60 to 79) QRS interval [ms]160 (152 to 180) IVMD [ms]50 (30 to 66)49 (32 to 67) Ejection fraction25 (22 to 29)25 (21 to 29) ESV index117 (94 to 147)121 (92 to 151) MR [% of LA area]23 (11 to 34)21 (12 to 33) GFR [mL min -1 ]61 (46 to 73)60 (46 to 73) NT proBNP [pg mL -1 ]1,806 (719 to 3,949)1,920 (744 to 4,288)

33 33 MIRACLE, COMPANION, CARE-HF: Similarities and Differences CCRTC CRT+ICDCCRT Age (yrs.) Ischemic HD (%) NYHA III (%) QRS Duration EF (%) ACEI BB Spironolactone F/U (mos.) MIRACLECOMPANIONCARE-HF 1 yr mortality (%) (Control Arm )

34 34 CARE-HF vs. other CRT Trial Populations CARE-HF patients did not need a hospitalization within the year preceding enrollment, as requested in the COMPANION trial. Diabetes co-morbidity in COMPANION was 40-45% vs. 21% in CARE-HF. Ischaemic population % vs. 38% in CARE-HF. One-year mortality in Control group : COMPANION 19% / CARE-HF 12.6%. Average patient in CARE-HF appear to be less symptomatic than in MIRACLE, as CARE-HF included over 94% NYHA Class III. However, in CARE-HF >90% of patients had EF < 30 %. Since CRT proved effective in CARE-HF, this may provide evidence of benefit in a broader symptomatic group than previously studied. Quote from Baseline Characteristics of Patients Recruited into the CARE-HF Study; With Courtesy : JGF Cleland et al. Submitted to EJHF

35 35 CARE-HF Results

36 Patients/Center >14 Patients/Center Recruitment 813 patients (Jan Mar 2003) 82 centers in 12 countries Austria, Belgium, Denmark, Finland, France, Germany, Italy, Netherlands, Spain, Sweden, Switzerland, and UK

37 37 CRT Arm - Implantation 409 Patients Randomized to CRT Arm –1 Death –4 No implant attempt 404 Implant Attempts –390 pts CRT implanted –96% with 3 attempts, 86% at first attempt Time randomization to implant : 4 days [2,8] Implant success rate 96% Before activation of CRT therapy ->6 pts reached primary objective

38 38 Conduct of the Study Follow-up time –Minimum 18 month -> last patient Sep 2004 –Average (Mean) Follow up : 29.4 month accounting Cut-off data (30 Sept – Randomization date) –Maximum 44.7 months: 3years 8 months At completion (30 th September 2004) –<5% cross-over before primary endpoint –Survival status ascertained on all patients 202/ 813 pts (25% reached secondary endpoint) 383/813 pts (45% reached primary endpoint) All Adverse Events were adjudicated into Major, Minor, Planned hospitalization and for mode, cause, place

39 39 Primary Endpoint (All-cause Mortality or Unplanned Hosp. for Major CVS Event) Medical Therapy CRT Number at risk Event-free Survival Days Medical Therapy

40 40 Primary Endpoint (All-cause Mortality or Unplanned Hosp. for Major CVS Event) CRT : 159 pts (39%) Medical Therapy CRT Number at risk HR 0.63 (95% CI 0.51 to 0.77) Event-free Survival Days P <.0001 Medical : 224 pts Therapy (55 %)

41 41 All-Cause Mortality Medical Therapy CRT Number at risk Event-free Survival Days Medical Therapy

42 42 All-Cause Mortality Medical Therapy CRT Number at risk Event-free Survival Days Medical 120 pts Therapy (30%) HR 0.64 (95% CI 0.48 to 0.85) P =.0019 CRT : 82pts (20%)

43 43 Primary Endpoint

44 44 Outcome Medical Therapy Mean (SD) CRT Group Mean (SD) Difference in means (95% CI; P value) NYHA class2.7 (0.9)2.1 (1.0) 0.6 (0.4 to 0.7; P < ) MLWHF score40.0 (21.7)31.1 (21.6) (-8 to -12; P < ) Euroqol EQ5D (0.289) (0.284) (0.037 to 0.115; P = ) Symptoms & Quality of Life at 90 days

45 45 Mechanistic Outcomes Outcome Mean difference at 3 mo*at 18 mo* Systolic BP (mm Hg) +5.8 (P < ) +6.3 (P < ) Inter-ventricular mechanical delay (ms) -21 (P < ) Ejection fraction (%) +3.7 (P < ) +6.9 (P < ) Left ventricular end- systolic volume (mL) (P < ) (P < ) Mitral regurgitation (% of LA Area) -5.1 (P < ) -4.2 (P = 0.003) NT Pro-BNP [pg mL -1 ] -225 (P = 0.36) -1,122 (P = ) * Positive values indicate higher value with CRT compared to control

46 46 Serious Adverse Events SAE GroupingsControlCRTP value Patients with Procedure or device related Adverse Event (Assessed by Independent Expert) Procedure related death11 P = 0.99 Lead problems627 P < Coronary sinus dissection012 P < Pocket complications19 P = Patients with Other Serious Adverse Events (Investigator Reported) Myocardial Isch & MI8470 P = 0.21 Worsening HF P < Atrial arrhythmia4164 P = 0.02 Ventricular arrhythmia5458 P = 0.74 Respiratory infection10185 P = 0.15 AVB or bradycardia2717 P = 0.12

47 47 Cardiac Resynchronization Therapy: Patient Selection February 2005  18 years of age NYHA Functional Class III or IV despite stable/optimal drug regimen QRS duration  msec LVEF  35%; LVEDD  55 millimeters With or without indication for ICD

48 48 ICDs: Patient Selection February 2005  18 years of age NYHA Functional Class II or III despite stable/optimal drug regimen LVEF  35% Ischemics must have “ remote ” MI (> 30 days) Non-ischemics must have CHF of at least 3 (?9) months duration

49 49 Device Indications Stage C heart failure LVEF  35% Optimal medical therapy NYHA Functional Class IIIIIIV QRS Duration  120 ms ICD 2 CRT 1 & ICD 2 CRT 1 < 120 msICD 2 1. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346: Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implanatble cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225-37

50 50 Remaining Questions About CRT Effects of CRT in pts. with EF ≤ 35%, but NYHA class I or II ( MADIT-CRT, REVERSE) Effects of CRT in pts. with NYHA class IV HF (< 5% of population in CRT trials) Effects of CRT in pts. with narrow QRS but evidence of mechanical dyssynchrony Effects of CRT in pts. with atrial fibrillation (excluded from CRT trials) Predictors of response to CRT (PROSPECT trial) Cost effectiveness of CRT

51 51 Conclusions Conclusive results from CARE-HF demonstrate that CRT should be considered as part of routine therapy for patients with moderate to severe HF due to LVSD with evidence (ECG supported by Echo) of cardiac dyssynchrony to*: –Improve cardiac function and efficiency –Improve symptoms and QoL –Reduce morbidity –Prolong survival These benefits are in addition to those of pharmacological therapy On-going promising research to solve remaining questions about CRT

52 52 CARE-HF Additional Resources

53 53 Additional Resources Publications: Baseline: The CARE-HF study: rationale, design and end-points Cleland JGF, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Klein W, Tavazzi L, on behalf of The CARE-HF study Steering Committee and Investigators. Eur J Heart Fail 2001;3: Results The effect of cardiac resynchronization on morbidity and mortality in heart failure. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L; Cardiac Resynchronization-Heart Failure (CARE- HF) Study Investigators. N Engl J Med. 2005;352:

54 54 CARE-HF Results Additional Information

55 55 Mechanistic Outcomes At 18 months, compared to the control group, patients randomized to CRT had: Shorter Interventricular Mechanical delay P < Higher LVEF (by about 7%) P < Less mitral regurgitationP = Lower ventricular volumesP < Higher systolic blood pressure P < Lower NT-pro-BNPP <

56 56 CARE-HF Baseline QOL Problem Total #pts/ % EQ-5D dimension Moderate Problem Extreme Problem Any Mobility483 (64.6)9 (1.2)492 (65.8) Self Care168 (22.5)8 (1.1)176 (23.6) Usual activities 455 (61.0)111 (14.9)566 (75.9) Pain/Discomfort449 (60.2)56 (7.5)505 (67.7) Anxiety/Depress ion 322 (43.1)52 (7.0)374 (50.1) Calvert M et al. The impact of Chronic HF on Health Related QOL – CARE-HF baseline EJHF 2005;7(2) in press

57 57 Baseline EQ-5D : CARE-HF population vs. Other Diseases Non-small Cell Lung Cancer 0.58 (0.51, 0.65) 3 month assessment post stroke 0.61 (0.55, 0.67) Hospitalised after ischemic stroke 0.31 (0.24, 0.38) Parkinson's disease 0.59 (0.54, 0.64) Moderate motor neurone disease* 0.56 (0.43, 0.69) Mild motor neurone disease* 0.63 (0.49, 0.77) Type II diabetes 0.77 (0.76, 0.78) CARE-HF 0.60 (0.58, 0.62 ) General population age (0.76, 0.80) General population 0.86 (0.85, 0.87) Calvert M et al. The impact of Chronic HF on Health Related QOL – CARE-HF baseline EJHF 2005;7(2) in press

58 58 Investigators Steering Committee – J.G.F. Cleland (Chairman), J-C. Daubert, E. Erdmann, D. Gras, L. Kappenberger, W. Klein, L. Tavazzi; Data and Safety Monitoring Committee – P.A. Poole-Wilson, L. Rydén (Chairman), H. Wedel, H.J.J. Wellens; Endpoints Committee – B. Uretsky, K. Thygesen; Independent Device Related Adverse Event Assessor – D. Böcker; Study Management – M.M.H. Marijianowski; Statistical Analysis Group – N. Freemantle, M.J. Calvert; Pharmacovigilance and Data Management – Quintiles; CARE-HF investigators – Austria – G. Christ, F. Fruhwald, R. Hofmann, A. Kypta, F. Leisch, R. Pacher, F. Rauscha; Belgium – R. Tavernier; Denmark – P.E. Bloch Thomsen, S. Boesgaard, H. Eiskjær, G.T. Espersen, J. Haarbo, A. Hagemann, E. Korup, M. Møller, P. Mortensen, P. Søgaard, T. Vesterlund; Finland – H. Huikuri, K.I. Niemelä, L. Toivonen; France – F. Bauer, A. Cohen-Solal, C. Crocq, P. Djiane, J.L. Dubois-Rande, P. de Groote, Y. Juilliere, G. Kirkorian, M. Komajda, T. Laperche, H. Le Marec, C. Leclercq, C. Tribouilloy; Germany – F. Er, E. Fleck, U.C. Hoppe, F.X. Kleber, B. Maisch, J. Neuzner, C. Reithmann, T. Remp, C. Schmitt, C. Stahl, R.H. Strasser; Italy – M.C. Albanese, A. Bartoloni, M. Bocchiardo, A. Capucci, A. Carboni, A. Circo, M. Disertori, R. del Medico, T. Forzani, M. Frigerio, A. Gavazzi, M. Landolina, M. Lunati, S. Mangiameli, M. Piacenti, A. Pitì, P.A. Ravazzi, A. Raviele, M. Santini, A. Serio, G.P. Trevi, M. Volterrani, M. Zardini; Netherlands – F.A.L.E. Bracke, C.C. de Cock, A. Meijer, R. Tukkie; Spain – J. Casares Mediavilla, M. Concha, J.F. Delgado, A. González-García, R. Muñoz-Aguilera, J. Martínez Ferrer, F. Ridocci; Sweden – B. Andren, J. Brandt, P. Blomström, M. Edner, K. Hellström, S. Jensen, F. Maru, S.J. Moller, F. Rönn, P. Smedgård, G. Wikström; Switzerland – J. Fuhrer, G. Girod; UK – G.H. Broomes, S. Chalil, H. Dargie, W. Davies, A. Delaney, P. Elliott, G.K. Goode, G. Haywood, G.C. Kaye, A.S. Kurbaan, R. Lane, T. Levy, F. Leyva, H. Marshall, S. Muhyaldeen, N. Nikitin, M.J.D. Roberts, J.D. Skehan, W.D. Toff, D.J. Wright; Corelabs – Echocardiography (Pavia, Italy) – C. Bassi, S. Ghio, E. Ghizzardi, G. Magrini, M. Pasotti, V. Pierota, E. Tellaroli, A. Serio, L. Scelsi; Neuro-endocrine (Graz, Austria) – A. Fahrleitner, G. Leb, H. Wenisch; Therapy Delivery (Kingston-upon-Hull, UK) – A. Bennett, M. Cooklin, J. Ghosh, S. Hurren, G.C. Kaye, N.K. Khan.

59 59 Supplemental Slides

60 60 CRT Background

61 61 Prevalence and Prognosis of Ventricular dyssynchrony Cardiac dyssynchrony is common in patients with HF due to LVSD. Approximately 15% of all heart failure patients have an inter- or intra-ventricular conduction delay (QRS > 120 msec) Havranek EP, Masoudi FA, Westfall KA, Wolfe P, Ordin DL, Krumholz HM. Spectrum of heart failure in older patients: Results from the National Heart Failure Project. Am Heart J 2002;143: Shenkman HJ, McKinnon JE, Khandelwal AK, et al. Determinants of QRS Prolongation in a Generalized Heart Failure Population: Findings from the Conquest Study [Abstract 2993]. Circulation 2000;102(18 Suppl II)

62 62 Achieving Cardiac Resynchronization Goal: Atrial synchronous biventricular pacing Transvenous approach for left ventricular lead via coronary sinus Back-up epicardial approach Right Atrial Lead Right Ventricular Lead Left Ventricular Lead

63 63 CRT Studies: Over 90% NYHA III Status at Enrollment

64 64 Early Steps to Answer remaining Questions about CRT

65 Roles of Echocardiography to Guide Cardiac Resynchronization Therapy Patient Selection LV & RV Lead Positioning Device Timing Optimization

66 Intra-ventricular Dyssynchrony Tissue Doppler Imaging Velocity—6 segmentsStrain rate—6 segments, same pt. A standard deviation of 32.6 ms in differences in time to peak systolic contraction (velocity) between 12 LV segments predicted response (LVESV) to CRT in 30 pts. Yu CM et al. Am J Cardiol 2002;91:684–688 % of 6 basal LV segments with contraction after aortic valve closure measured using strain rate* predicted change in LVEF with CRT in 20 pts. Søgaard P, et al. JACC 2002;40:723–730 * Uses tissue velocity data to calculate regional deformation rates. May be less influenced by translational motion or tethering.

67 One Study Assessed Whether Pacing at Site of Latest Activation Had an Effect 31 nonischemic HF patients with LBBB TDI used to assess basal region of greatest delayed activation Global improvement versus baseline in LVEDV, LVESV, LVEF, NYHA class, 6 min walk distance, LV filling time, isovolumic contraction time Ansalone, et al. JACC 2002;39: of 31 paced at most delayed site 18 of 31 paced at other site Comparative changes in selected parameters with CRT Paced at most delayed site? Parameter YesNoP-Value LVESV (mL) LVEF (%) min walk distance (m)

68 CRT Device Optimization with Echo Potential Targets Trans-mitral Flow Stroke Volume (Aortic VTI) Intra- Ventricular Synchrony

69 Should AV Delays be Optimized? Optimal AV Delays Vary by Patient and by Target Optimization Measure Acute study results of 27 patients with biventricular pacing. Mean ± std. dev. Pulse pressure (PP). Auricchio, et al. Circulation 1999;99: Chronic study of biventricular pacing. Optimal AV delay determined via trans-mitral flow. Delurgio, et al. PACE 2001;24[pt 2]:651 [abstr. 452]

70 Does Interventricular (VV) Delay Optimization Make A Difference? Both studies: –Single center study of consecutive patients with NYHA III/IV HF, QRS > 130 ms; –Trans-mitral flow optimized with AV delay post implant Rosanio, et al. Circ. 2003;108:IV-345 –N=22 –VV delay of 0 for first 2 months. –Echo based optimization of VV delay (OPT) at 2 months. Sogaard, et al. Circ. 2002;106: –N=20 –Optimal VV delay based on TDI –Acute data shown. After 3 mo., LVEF further improved to 38.6%. (P<0.01) * P<0.01 CRT with AV Opt versus Baseline # P<0.01 VV Opt versus CRT with AV Opt

71 71 Do Wider QRS Respond Better to CRT? Positive Findings –↑ QOL and exercise tolerance only if QRS > 150 msec. (Auricchio A. JACC 2003; 42: 2107) –Longest QRS greatest benefit (Bristow MR. NEJM 2004; 350: 2140) –Average QRS in trials showing CRT benefit MIRACLE166 MUSTIC176 InSync ICD165 Contak CD158 COMPANION160 Negative Findings –Achilli’s Study: CRT benefit (NYHA, 6 min walk, QRS reduction) equal in patients with wide and narrow QRS –Conclusion: patient selection for CRT should be based on evidence of mechanical rather than electrical dyssynchrony (Achilli C. JACC 2003; 42: )

72 72 Does Shortening of QRS Duration Indicate a Positive Response to CRT? Positive Findings –Positive response to CRT related to electrical resynchronization (Alonso C. AJC 1999; 84: ) –MIRACLE, InSync had significant decline in QRS duration Negative Findings –Changes in QRS with pacing did not predict CRT efficacy (Kass DA.Circ. 1999; 99: ) –Responders exhibit a significant reduction in QRS duration after CRT, but individual responses are highly variable and do not permit adequate selection of responders. (Molhoek SG Pace, 2004; 27: )

73 73 CRT – RBBB vs. LBBB ContakInsync ICDMiracleMUSTIC QRS LBBB271 (54)382 (69)426 (80)58 (87) Bradley DJ JAMA 2003; 289: Patients with RBBB benefit from CRT if there is evidence of mechanical dyssynchrony Bristow MR NEJM 2004: 350: 2140 Garrigue S. AJC; 2001; 88: Higgins JACC 2003; 42:

74 74 Inclusion –Ablate and pace –RV vs BiV –NYHA I/II/III –Chronic AF > 1 mos –Walk < 450 meters in 6 minutes Endpoint –1° 6 minute walk –2 ° CPX V02 QOL PAVE: Changes in LVEF PAVE: Changes in Peak VO 2 P< 0.01 CRT and AF: All Trials Show Improvement MUSTIC Leclerq AJC 2000; 55: 1154 Etienne AJC 1999; 83: 1138 PAVE Trial

75 75 CRT: Decrease in VT ? Positive Findings –Three studies show that CRT is associated with decreased ventricular arrhythmias (Higgins JACC 2000; 36: 842; Walker S AJC 2000; 86: ; Higgins JACC 2003; 42: ) Negative Findings –Epicardial LV leads cause repolarization abnormalities and prolongation of QT interval that may trigger ventricular arrhythmias (Medina-Ravell VA Circ. 2003; 107: )

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