La stimulation biventriculaire (Traitement par Resynchronisation Cardiaque) Indications et Résultats. Daniel Gras, DIU, Paris 2007

Transcription

1 La stimulation biventriculaire (Traitement par Resynchronisation Cardiaque) Indications et Résultats, DIU, Paris 2007

2 CRT: Results and indications Background Results of CRT Studies Today s classical CRT indications Potential Role of ICD during CRT Particular Indications for CRT

3 The evolving perspective of HF HF Prevalence Will Double in 30 Years HF Prevalence in Western Europe (Millions) Ageing population CAD management Source: New Medicine Reports 1997 ; 1999 Heart and Stroke Statistical Update, AHA

4 HF patients die primarily from CV death (mortality by cause in control groups of selected HF trials*) non CV death 18.5% Consensus, Solvd T, Solvd P, Save, Aire, Trace, Rales, Ephesus, Cibis, US Carvedilol, Merit HF, Cibis II, Best, Capricorn, Copernicus, Comet all-cause mortality: 81.5% CV death Publications reporting all-cause mortality, CV death, SCD, death by progression of HF (N= pts, control groups, 16 studies)

5 Care-HF pts also die primarily from CV death non CV death 46/255 (18.1%) Unclassifiable 12/255 (4.7%) CV Death: 197/255 (77.2%)

6 SCD is the leading cause of CV death (mortality by cause in control groups of selected HF trials*) Other CV death Consensus, Solvd T, Solvd P, Save, Aire, Trace, Rales, Ephesus, Cibis, US Carvedilol, Merit HF, Cibis II, Best, Capricorn, Copernicus, Comet HF Progression 36% Sudden Cardiac Death 42% Publications reporting all-cause mortality, CV death, SCD, death by progression of HF (N= pts, control groups, 16 studies)

7 Functional abnormalities in isolated LBBB LBBB Normal Radionuclide images showing the onset of RV and LV contraction Grines, Circulation 1989

8 Functional abnormalities in Isolated LBBB IVCT IVRT Grines, Circulation 1989

9 Rationale for CRT: Abnormal LV segmental contraction

10

11 CRT system implantation

12 CRT-D System Implantation (Right Side) AP view LAO view

13 Mechanisms of benefit during CRT Systolic function ( increase in CO) Coordination in LV contraction Shorter LV contraction duration Diastolic function Longer LV filling duration Decrease in Mitral regurgitation Effects on neurohormones, Remodelling...

14 CRT Improves LV Function Without Oxidative Stress MVO2/HR (Relative Units) 0,24 0,22 0,20 0,18 0,16 0,14 P<0.05 Dobutamine LV Pacing dp/dt max (mm/hg/s) Nelson et al. Circulation 2000 n=7 Nowak. JACC 2003

15 Mechanisms of CRT Decrease in Mitral Regurgitation

16 CRT: Results and indications Background Results of CRT Studies Today s classical CRT indications Potential Role of ICD during CRT Particular indications for CRT

17 What we know from morbi-mortality trials Cumulative Enrollment in CRT Trials Cumulative Patients Open Studies CARE HF MIRACLE ICD MIRACLE MUSTIC AF MIRACLE ICD II MUSTIC SR COMPANION PATH CHF PATH CHF II CONTAK CD Results Presented

18 Outcomes and Follow-up of CRT patients Randomized Controlled Trials on CRT Study (n randomized) MIRACLE (453) MUSTIC SR (58) MUSTIC AF (43) PATH CHF (41) MIRACLE ICD (369) CONTAK CD (490) COMPANION (1520) PATH CHF II (89) MIRACLE ICD II (186) CARE HF (814) NYHA III, IV III, IV 120 Normal No Published + Exercise III, IV 130 Capacity: Normal 6 Yes MW, Published Peak VO2 + LV II-IVfunction: 120 Normal EF, MR Yes Published + Reverse III, IV 120 remodeling: Normal NoLV Published EDV, ESV + III, IV 120 Normal Both Published + III, IV QRS 130 III >150 Normal NYHA III >200* Class, AF 120 Sinus CRT Improves: Normal Normal Normal ICD? No No No Yes No Status Published Published Published Quality of life score (MLWHF), Hospitalization, II 130 Mortality Published Published Results LVEF 35% for all trials * RV paced QRS

19 CRT Improves Exercise Capacity Average Change in 6 Minute Walk Distance Average Change in Peak VO 2 m MIRACLE * MUSTIC SR * CONTAK CD * MIRACLE ICD ml/kg/min MIRACLE * MUSTIC SR * CONTAK CD * * 0 MIRACLE ICD Control CRT Control CRT Abraham et al., 2003 * P < 0.05

20 6 Min. WT: + 13/20% QoL (MLWHF): + 30% NYHA: - 0.5/0.8 NO CRT CRT Miracle ICD

21 Comparison with Drug Trials: Digoxin, ACE-I and Beta-blocker Therapies Change from baseline in 6 minute walk distance Change from baseline in CPX Duration Change from baseline in QoL (MLWHF) Score * 5 meters Dig (1) * BB (2) CRT (6) seconds * Dig (1) Control ACE (3) CRT (6) Treatment Improvement score ACE (4) NS BB (5) CRT (6) * P.05 P.01 P NEJM 1993;329:1-7 (RADIANCE) 2 Circulation 1996;94: (PRECISE) 3 JAMA 1988;259: Am J Cardiol 1993;71: (SOLVD Treatment) 5 J Cardiac Failure 1997;3: NEJM 2002;346: (MIRACLE)

22 Effects of CRT on Hospitalization Rate MUSTIC Monthly rate of hospitalisations for CHF (Randomisation to M 12) MIRACLE Total Days Hospitalized for Heart Failure 0,14 0,12 0,10 0,08 0,06 0,04 0,02 0 / 7 CR - CR Control N=225 77% p = CRT N=228

23 Euro Karolinska Study Hospital costs per patient before implant Differenz: after implant Costs for CRT: 8.019/Patient. Costs for the device balance the saved money within one year. Braunschweig F. Eur J Heart Failure 2: (2000)

24 COMPANION: Primary Endpoint All cause Mortality + Hospitalization Bristow et al. NEJM. 2004; 350: Companion reinforces previous results of CRT trials

25 COMPANION : Mortality and HF hospitalization Death: 24% Hosp: 76%

26 Cardiac Resynchronisation in Heart Failure: CARE-HF Baseline Evaluation Randomization (1:1) OMT CRT (CRT+OMT) Minimum 18 Month Follow-up 813 patients, 82 centers,12 countries, FU: 29.4 M NYHA class III/IV, LVSD: EF 35%; EDD > 30mm/hm QRS 150 ms or Echo if QRS ms Primary composite endpoint: All-cause mortality or unplanned hosp. for a major CVS event (time to first event analysis, Hosp adjudicated by a blinded EP committee)

27 Care-HF: Baseline Characteristics Age [yr] - median (IQR) Male (%) NYHA IV (%) Ischaemic heart disease (%) Treatment (%) ACEIs / ARBs Beta blockers Furosemide Eq 80 mg/day Digitalis Spironolactone Control n = (59 to 72) 293 (73%) 27 (6.7%) 142 (35%) 383 (95%) 298 (73%) 177 (44%) 181 (45%) 238 (59%) CRT n = (60 to 73) 304 (74%) 23 (5.6%) 167 (41%) 387 (95%) 288 (71%) 175 (43%) 165 (40%) 219 (54%)

28 SAE Groupings Care-HF: Serious Adverse Events Patients with Procedure or device related Adverse Event (Assessed by Independent Expert) Procedure related death Lead problems Coronary sinus dissection Pocket complications Patients with Other Serious Adverse Events (Investigator Reported) Myocardial Isch & MI Worsening HF Atrial arrhythmia Ventricular arrhythmia Respiratory infection AVB or bradycardia Control CRT P value P = 0.99 P < P < P = P = 0.21 P < P = 0.02 P = 0.74 P = 0.15 P = 0.12

29 CARE-HF: Improved NYHA, QoL, LVEF Euro Qualit of Life Score NYHA Class 0,8 0,70 0,6 0,4 0,2 Daniel 0,0 Gras NYHA Class at 90 days p< ,0 2,5 2,1 2,0 1,5 1,0 0,5 0,0 2,7 Euro QoL Score at 90 days p< ,63 CRT Control 0,35 0,3 0,25 0,2 0,15 0,1 0,05 0 Mean LVEF at 18 Months p< ,9% CRT 25,0% Control Patients in the CRT group had a lower NYHA class and a higher Euro Quality of Life score at 90 days. Mean LV ejection fraction was higher on average in the CRT group compared with the medical therapy alone group. Cleland et al. New England Journal of Medicine. 2005; 352:

30 Care-HF: Changes in LVES volume & LVEF Volume (ml) Ejection Fraction (%) Baseline 3 months P< months P< months P< Baseline 3 months P< months P< months P< Control Group CRT Group Control Group CRT Group LV End-Systolic Volumes LV ejection Fraction

31 Changes in IVMD (ms) and MRI in Care HF Time (ms) LA area index (%) Baseline 3 months P< months P< months P< Baseline 3 months P< months P= months P=0.015 Control Group CRT Group Control Group CRT Group Interventricular Mechanical Delay Mitral Regurgitation index

32 CARE-HF: Primary endpoint All-cause Mortality or Unplanned Hosp. for Major CVS Event Event-free Survival No statistical significant heterogeneity in subgroups HR 0.63 (95% CI 0.51 to 0.77) Death : 20% Hospitalizations : 80% CRT P <.0001 Medical Tx 0.00 Number at risk CRT Medical Tx Days Cleland. N Engl J Med. 2005;352

33 Care-HF: All-Cause Mortality Event-free Survival HR 0.64 (95% CI 0.48 to 0.85) CRT (20%) P =.0019 Medical Therapy (29.7%) 0.00 Number at risk CRT Medical Therapy Days

34 CRT impacts on Mortality & Hospitalization rates 100 Survival 10 Annual survival (%) CRT Hospitalization 1 Hospitalizations / year 0 I II III IV NYHA CLASS.1

35 Care-HF extension phase Cross Over Control Group (n= 404) Main Study 19 prior to Primary EP (5%) 50 in total (12.4%) Extension Phase 45 (11.1%) One lost to follow-up Total 95 (23.5%) Implant Failures CRT Group (n = 409) Main Study 19 (4.6%) Extension Phase None Total 19 (4.6%)

36 CARE-HF Extension Study Effect of CRT on All-Cause Mortality 1.00 Hazard Ratio 0.60 (95% CI 0.47 to 0.77; P<0.0001) 0.75 CRT Survival 0.50 Mean Follow-up Medical Therapy Number at risk 0.25 CRT Medical therapy Mean Follow-up 36.4 months (range 26.1 to 52.6) CRT Deaths = 101 (24.7%) Medical Therapy Deaths = 154 (38.1%) Time (days)

37 CARE-HF Extension Study Time to Death from Worsening Heart Failure 1.00 Survival Hazard Ratio 0.55 (95% CI 0.37 to 0.82; P=0.003) CRT Medical Therapy CRT = 38 HF deaths (9.3%) Medical Therapy = 64 HF deaths (15.8%) Time (days)

38 CARE-HF Extension Study Time to Sudden Death 1.00 CRT Survival Hazard Ratio 0.54 (95% CI 0.35 to 0.84; P=0.006) Medical Therapy CRT = 32 sudden deaths (7.8%) Medical Therapy = 54 sudden deaths (13.4%) Time (days)

39 CRT: Results and indications Background Results of CRT Studies Today s classical CRT indications Potential Role of ICD during CRT Particular indications for CRT

40 CRT in Clinical Practice ACC/AHA; HFSA; CCS; ESC Guidelines 2005 CRT: Indication Class I, Level A

41 Impact of CRT on PCWP Start pacing Stop pacing pcw Hemodynamics of CRT: beat-to-beat reduction of pcw and v-wave

42 Acute hemodynamic evaluation is not necessary Acute hemodynamic changes do not correlate with long term effect of CRT Mitral regurgitation (%) MR LVEF LV volumes Ejection fraction (%) Yu Circulation 2002 Baseline 1 w k 1 mo 3 mo off-imm 20 off-1w k off-4w k 80 Left ventricular volume (m baseline 1 wk 1mo 3 mo off-imm off-1wk off-4wk Immediate effect Delayed effect baseline 1 w k 1 mo 3 mo off-imm off-1w k off-4w k

43 CRT provides LV reverse remodeling effect Sogaard P, et al; J Am Coll Cardiol 2002

44 Today s classical CRT indications 1. Cardiomyopathy (Ischemic or not): EF<35%, EDD>55 mm 2. NYHA functional class III/IV 3. OMT (6 weeks) : ACEI, Diur., Bb., Spiron. 4. Ventricular Asynchrony QRS > 150 ms QRS < 150 ms: Echo criteria (Care-HF) 1. Aortic Pre-ejection delay > 140 ms 2. Interventricular mechanical delay > 40 ms 3. LV segmental post systolic contraction + 4. Intra LV asynchrony + 5. AV asynchrony

45 Patient selection for CRT Echo parameters consideration (Q to Pulmonary Ejection = 120 ms) (Q to Aortic Ejection = 230 ms) ( 1 ) Prolonged aortic pre-ejection delay ( 2 ) Interventricular Mechanical Delay = 110 ms

46 Patient selection for CRT Echo Parameters Under Consideration QRS-LLW: 590 ms QRS-E: 530 ms OVERLAP (3) LV late systolic contraction

47 Echocardiographic criteria to select pts for CRT S E S A Just prove it!! DESIRE and PROSPECT trials E A Courtesy of G Habib

48 Mr Seg, 63 years, DCM, NYHA Class III

49 Me Seg, 63 ans, CMD

50 1. AV Dyssynchrony : LVFT < 40% Cardiac Cycle DFT at Baseline: 280 ms DFT during CRT: 400 ms

51 Clinical Case: LVEF: 25%, SR, LBBB (QRS 160 ms), NYHA III/OMT

52 Complex forms of ventricular asynchrony Advanced CRT: RV septal, Dual-site LV pacing

53 CRT & reduced RV function: Interaction at 18 M 0 LVESV Control CRT 302/40 291/53 LVEF P= from baseline (cm 3 ) ,4-52,1-76,4-41,7 2,1 4,9 10,3 4, from baseline (%) -100 TAPSE >14 mm P=0.002 TAPSE 14 mm 302/40 291/53 Control CRT 0 TAPSE: Tricuspid Annular plane systolic excursion

54 Dual site RV Pacing to optimize CRT

55 Typical non responder to CRT: 84 Yo, ICM, NYHA IV, RV dysfunction

56 CRT: Results and indications Background Results of CRT Studies Today s classical CRT indications Potential Role of ICD during CRT Particular indications for CRT

57 ESC Guidelines Indications for ICD in HF Previous Cardiac Arrest, SVT: I, A ICM, LVEF < 30-35%, after 40 days of MI: I, A NYHA III-IV, LVEF < 35%, QRS > 120 ms: IIa, B 1.European Heart Journal 2005;26: Madit 1 & 2: Moss NEJM 1996, Definite: Kadish NEJM Salukhe Circulation Desai Jama SCDHefT: Bardy NEJM 2005

58 MADIT II Survival Results ICM + LVEF < 30% 1.0 Probability of Survival P = Conventional Defibrillator No. At Risk Year Defibrillator (0.91) 274 (0.94) 110 (0.78) 9 Conventional (0.90) 170 (0.78) 65 (0.69) 3 Moss AJ. N Engl J Med. 2002;346:

59 International Perspective of the evolving Role of CRT Sudden Cardiac Death despite CRT COMPANION CRT-P arm CARE-HF Sudden death as % of total mortality Sudden deaths account for ~35% of mortality in CRT-P

60 Time to SCD in Care HF and Companion 1.00 CRT Survival Hazard Ratio 0.54 (95% CI 0.35 to 0.84; P=0.006) Medical Therapy CRT = 32 sudden deaths (7.8%) Medical Therapy = 54 sudden deaths (13.4%) Time (days)

61 CARE-HF, COMPANION, SCD-HeFT: Mode of Death OPT CRT-P CRT-D ICD CARE-HF (29.4mth) COMPANION (16.6mth) SCD-HeFT (45.5mth) Mortality 16,0% 14,0% 12,0% 10,0% 8,0% 6,0% 4,0% 2,0% 0,0% 9,4% 7,1% SCD 13,9% 8,1% 7,8% PUMP FAILURE 5,8% 2,9% SCD 11,0% 8,6% 8,7% PUMP FAILURE 11,6% SCD 4,6% 7,8% 8,7% PUMP FAILURE Cause of death JM Cleland JGF. N Engl J Med. 2005;352: Bristow MR. N Engl J Med. 2004;350: Bardy GH. N Engl J Med. 2005;352: Packer DL. Heart Rhythm May;2 (1suppl):AB20-2.

62 Strategy to reduce mortality in HF pts treated by CRT 1 Year Mortality ACE-I, Beta-blockade, ACE-I Spironolactone & Beta Blockade Reduce Mortality 16% 12% 8% 4% 0% Reduce mortality 15,6% 12,4% 11,5% 7,8% SOLVD-T MERIT-HF + CIBIS II Placebo Adapted from McMurray JJV; Heart 1999 Treatment Further reduction expected from CRT/ICD in selected HF patients Further Reduction with CRT + ICD for Higher Risk Patients HF Mortality Sudden Cardiac Death CRT ICD Care-HF Madit, Companion, SCD-HeFT With respect to «clinical» contra indication to ICD

63 «Clinical» Contra-Indication to ICD in HF Pts Physiological: Age > 80-85, Psychological pbs... Class IV + other disease Advanced RV dysfunction, High PVR Comorbidities Renal dysfunction: creatinine clearance < 30 ml/mn Severe liver impairment Advanced other disease (diabetes )

64 Effect of Starting Age and Device Longevity on Cost per QALY Base case Incremental Cost Per QALY Gained 80,000 70,000 5 Years 60,000 50,000 40,000 8 Years 30,000 20,000 10, Age at Starting Treatment 7 Years CRT-D vs CRT-P CRT-D vs MT CRT-P vs MT Freemantle, ESC 2006 CRT+MT vs MT CRT+ICD+MT vs CRT + MT CRT+ICD+MT vs MT

65 CRT: Results and indications Background Results of CRT Studies Today s classical CRT indications Potential Role of ICD during CRT Particular indications for CRT

66 Patient selection for CRT: particular cases 1. Origin of the DCM: impact in clinical outcome? 2. NYHA class II: candidates for CRT? 3. Is long QRS duration required for CRT? 4. RBBB versus LBBB outcome? 5. Do patients with Chronic AF benefit from CRT? 6. Role of CRT in candidates for cardiac pacing?

67 Patient selection for CRT: particular cases 1. Origin of the DCM: impact in clinical outcome? YES ml 0 Left Ventricular End Diastolic Volume 2,5-16,6 6,6 0 0,5 1 1,5 2 2,5 P=0.016 Ischemic P<0.001 P<0.001 Non-Ischemic Control CRT ,7 Impact of CRT in ischemic versus non ischemic pts

68 Interaction Between CRT & Ischemic Etiology from baseline (cm 3 ) Control LVESV CRT -6,9-26,4-49,0-84,4 P=0.01 LVEF P= ,2 6,0 2,9 1,5 Control CRT from baseline (%) Non-ischemic etiology Ischemic etiology

69 Possible Reasons for Failure of CRT: ICM CRT-D combined to optimal revascularization

70 MIRACLE ICD II Study 6 Min Walk, QoL, NYHA (Circulation 2004) m Distance Walked in 6 Minutes Base P= Mo Quality of Life Score (MLWHF) Base P= Mo Proportion of Patients NYHA Class at 6 Months 70% P= % 50% 40% 30% 20% 10% 0% I II III IV Control (n=96) CRT (n=81) Control (n=98) CRT (n=82)

71 MIRACLE ICD II Study Improvements in Cardiac Volumes and Dimension suggest that CRT Improves Cardiac Function and Structure cm Left Ventricular End Diastolic Diameter P=0.04 cm Left Ventricular End Systolic Diameter P=0.01 % Left Ventricular Ejection Fraction P= Base 6 Mo 200 Base 6 Mo 20 Base 6 Mo Control (n=85) CRT (n=69) Abraham, Circulation 2004

72 Recommendations for CRT are based on the results of controlled trials: 158 < QRS < 176 Study (n) NYHA QRS Rhythm Results MUSTIC SR (58) III >150 Sinus + MUSTIC AF (43) III >200* AF + MIRACLE (453) III, IV 130 Sinus + PATH CHF (41) III, IV 120 Sinus + MIRACLE ICD (369) III-IV 130 Sinus + CONTAK CD (227) II-IV 120 Sinus + MIRACLE ICD II (186) II 130 Sinus + PATH CHF II (89) III, IV 120 Sinus + COMPANION (1520) III, IV 120 Sinus + CARE HF (814) III, IV 120 Sinus +

73 Patient selection for CRT: particular cases 4. RBBB versus LBBB LBBB aspect Common finding in DCM Conduction disturbances at distal Purkinje system RBBB aspect 1. and «hemifascicular LBBB» aspect (left axis deviation) 2. and severe RV dilatation/dysfunction

74 Patient selection for CRT 5. Role of CRT in AF Pts: Mustic trial ml/kg/min = % p = BiV-RV RV-BiV Baseline Rando CO1 CO2 Results Baseline 1 Year 2 Year Heart Rate 75±15 76 ± 7 71 ± 12 NYHA 3 ± ± ± 0.5 6MWT 325 ± ± ± 99 Peak VO2 13 ± 4 14 ± 3.5 NA QOL 45 ± ± ± 20 LVEF (%) 26 ± ± 8 NA

75 Patient Selection for CRT: Particular Cases LV Function Changes in MUSTIC AF Patients Rand n=67 BIV-CO n=48 BIV 9M n=45 BIV 12M n=43 LVEDD (mm) 74±10 69±11*** 68±10*** 67±12*** LVESD (mm) 63±10 58±12*** 56±11*** 57±12*** MR area (cm 2 ) 7.8± ± ±4.6** 4.3±4.0** DFT (ms) 375± ±137* 471±154** 425±129*

76 PAVE trial (Post AV nodal ablation Evaluation study) «Ablate and pace» for AF, NYHA I-III, 6min HWT<450m, Mean QRS ~ 100ms, LVEF ~ 45% m Change in 6-min HWT P=0.03 LVEF (%) Change in LVEF P= weeks 6 months 20 Preimplant 6 months RV (n= 106) BV (n=146) Doshi, ACC 2004

77 Impact of CRT in Patients with AF Gasparini JACC 2006

78 Patient selection for CRT: particular cases 6. CRT in candidates for cardiac pacing? On evaluation CRT in PM pts N QRS (ms) NYHA Peak VO2 (ml/min/kg) QOL LVEF (%) Leclercq 1 20 Leon 2 23 NA Bakker 3 60 NA 1. Compare 2. Prevent 3. Combat 4. Block-HF 5. X-Change HF 1- C. Leclercq. Am Heart J 2000;140: A. Leon. J Am Coll Cardiol 2002;39: C. Bakker. PACE 2002;25:

79 CRT: Results and indications (Conclusions) Cardiac asynchrony is deleterious on hemodynamics CRT improves: NYHA Class, QOL score, Exercise Capacity (6MW, Peak VO2), LV function (EF, MR), Reverse Remodeling, Hospitalization, Mortality Classical CRT indications: Drug refractory NYHA III-IV, SR, QRS > 120 ms CM (ischemic or not): EF < 35%, EDD > 55 mm Additional CRT indications Chronic AF, Classical PM indications (Biopace) Future: NYHA II (Predict, Raft, Madit CRT), Investigation of Asynchrony at Echo (Desire, Prospect)