Cardiac Resynchronization Therapy: Current Indications and Future Prospects. Saverio Iacopino, MD, FACC, FESC

Transcription

1 Cardiac Resynchronization Therapy: Current Indications and Future Prospects Saverio Iacopino, MD, FACC, FESC

2 CHF Population in Europe 6.5 Million CHF Population Incidence = (9.0%) Mortality = (4.6%)

3 Hospital Discharges for CHF American Heart Association. Heart Disease and Stroke Statistics Update.

4 CHF Patients Survival Results American Heart Association. Heart Disease and Stroke Statistics Update.

5 HF and/or Decreased LV Function ü About one-half of all deaths in HF patients are characterized as sudden due to arrhythmias ü The risk of SCD increases as left ventricular function deteriorates (low LVEF) Myerburg RJ. Heart Disease, A Textbook of Cardiovascular Medicine. 5 th ed, Vol 1. Philadelphia: WB Saunders Co; 1997:ch 24. Middlekauf HR. J Am Coll Cardiol. 1993;21: Stevenson WE. Circulation. 1993;88:

6 Incidence of SCD in Specific Populations and Annual SCD Numbers General adult population Multiple risk subgroups Patients with any previous coronary event Patients with ejection fraction <35% or CHF Cardiac arrest, VT/VF survivors High-risk post-mi subgroups Incidence of Sudden Death (% of group) , ,000 Incidence of Sudden Deaths Per Year (number) 300,000 Adapted from: Myerburg RJ. Sudden Cardiac Death: Exploring the Limits of Our Knowledge. J Cardiovasc Electrophysiol Vol. 12, pp , March 2001.

7 Risk of Sudden Death: GISSI-2 Trial p log-rank Survival Survival p log-rank A Days 0.88 B Days Patients without LV Dysfunction (LVEF >35%) No PVBs 1-10 PVBs/h > 10 PVBs/h Patients with LV Dysfunction (LVEF < 35%) Maggioni AP. Circulation. 1993;87:

8 Severity of Heart Failure Modes of Death NYHA II 12% NYHA III 26% 64% 24% CHF Other Sudden Death Deaths = % CHF Other Sudden Death Deaths = 232 NYHA IV 15% 33% 56% CHF Other Sudden Death Deaths = 27 11% MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). LANCET. 1999;353: The greatest opportunity for SCD prevention is in patients that have mild to moderate CHF.

9 Hospitalization/NYHA Class in HF 100 Survival 10 Annual survival (%) Hospitalization 1 Hospitalizations/year 0 I II III IV 0.1 NYHA CLASS

10 Quality of Life for HF patients Overall perception of health General population Depression Angina AF symptomatic Valve disease symptomatic Chronic Bronchitis Heart Failure NYHA Class II Heart Failure NYHA Class III Heart Failure NYHA Class IV Hobbs FDR, et al. Eur Heart J 2002

11 SCD in Heart Failure ü Despite improvements in medical therapy, symptomatic HF still confers a 20-25% risk of pre-mature death in the first 2.5 yrs after diagnosis. ü 50% of these premature deaths are SCD (VT/VF) ü The role of device therapy? 1 Bardy G. The Sudden Cardiac Deatth-Heart Failure Trial (SCD-HeFT) in Woosley RL, Singh S, Arrhythmia Treatment and Therapy, Copyright 2000 by Marcel Dekker, Inc., pp , 2 Sweeney MO PACE 2001;24:

12 Reductions in Mortality with ICD Therapy % Mortality Reduction w/ ICD Rx % 75% 55% 76% Overall Death Arrhythmic Death 31% 61% MADIT MUSTT 2 MADIT-II 1 3, 4 27 months 39 months 20 months ICD mortality reductions in primary prevention trials are equal to or greater than those in secondary prevention trials. % Mortality Reduction w/ ICD Rx % 56% 28% 59% Overall Death Arrhythmic Death 20% 6 AVID CASH CIDS Years 3 Years 3 Years 33% 1 Moss AJ. N Engl J Med. 1996;335: Buxton AE. N Engl J Med. 1999;341: Moss AJ. N Engl J Med. 2002;346: Moss AJ. Presented before ACC 51st Annual Scientific Sessions, Late Breaking Clinical Trials, March 19, The AVID Investigators. N Engl J Med. 1997;337: Kuck K. Circ. 2000;102: Connolly S. Circ. 2000:101:

13 SCD-HeFT Mortality Rate Overall Results 0.4 Hazard Ratio (97.5% Cl) P-Value Amiodarone vs. Placebo 1.06 ( ) 0.53 ICD vs. Placebo 0.77 ( ) Mortality Rate No. at Risk Months of Follow-Up Amiodarone Placebo ICD Bardy GH. N Engl J Med. 2005;352: Amiodarone Placebo ICD 48 60

14 SCD-HeFT Overall Mortality Results Hazard Ratio (97.5% CI) P-Value Amiodarone vs. Placebo 1.06 ( ) 0.53 ICD vs. Placebo 0.77 ( ) ICDs reduce mortality by 23% Bardy GH. N Engl J Med. 2005;352:

15 CHF Population in Europe 6.5 Million CHF Population Incidence = (9.0%) Mortality = (4.6%) Wide QRS (10-30%) 1.95 Million NYHA III + IV (30-35%)

16 Prevalence of Inter- or Intraventricular Conduction Delay General HF Population 1,2 Moderate to Severe HF Population 3,4,5 IVCD 15% IVCD >30% 1 Havranek E, Masoudi F, Westfall K, et al. Am Heart J 2002;143: Shenkman H, McKinnon J, Khandelwal A, et al. Circulation 2000;102(18 Suppl II): abstract Schoeller R, Andresen D, Buttner P, et al. Am J Cardiol. 1993;71: Aaronson K, Schwartz J, Chen T, et al. Circulation 1997;95: Farwell D, Patel N, Hall A, et al. Eur Heart J 2000;21:

17 Prevalence and Prognosis of Ventricular Dysynchrony LBBB More Prevalent with Impaired LV Systolic Function Increased All-Cause Mortality with Wide QRS at 45 Months (3) Preserved LVSF (1) 8% P < % Impaired LVSF (1) 24% 34% Mod/Sev HF (2) 38% QRS < 120 ms QRS > 120 ms 1. Masoudi, et al. JACC 2003;41: Aaronson, et al. Circ 1997;95: Iuliano et al. AHJ 2002;143: Ventricular dysynchrony impairs diastolic and systolic function 4-6 : Reduced LV filling time; Increased mitral regurgitation; Depressed dp/dt 4. Grines, et al. Circulation 1989;79: Xiao, et al. Br Heart J 1991;66: Xiao et al. Br Heart J 1992;68:403-7

18 Wide QRS Proportional Mortality Increase Vesnarinone Study 1 (VEST study analysis) 100% QRS Duration (msec) ü NYHA Class II-IV patients ü 3,654 ECGs digitally scanned ü Age, creatinine, LVEF, heart rate, and QRS duration found to be independent predictors of mortality ü Relative risk of widest QRS group 5x greater than narrowest Cumulative Survival 90% 80% 70% 60% < >220 Days in Trial 1 Gottipaty V, Krelis S, Lu F, et al. JACC 1999;33(2): 145 [Abstr 847-4].

19 Desincronia Ventricolare ü Elettrica: Ritardo di conduzione intraventricolare (BBsn) ü Strutturale: disgregazione della matrice di collagene cardiaca che danneggia efficienza meccanica e conduzione elettrica ü Meccanica: Anormalità nel movimento delle pareti con incrementato carico di lavoro e sforzo, compromettendo i meccanismi ventricolari Tavazzi L. Eur Heart J 2000;21:

20 R P L Durrer. Total Excitation of the Isolated Human heart Circulation 1970 A Scher:The sequence of Ventricular Excitation Am. J.Cardiol. 1964

21 Site and Length of the Line-of-Block Anterior Line of Block Septum >150 msec QRS Duration msec Septum Lateral Inferior Anterior Lateral Inferior Auricchio et al. Circulation 2004

22 Electromechanical Decoupling Electrical disturbance ü wide QRS ü LBBB Mechanical dysynchrony ü Impaired intra- and interventricular coordination Toussaint J-F, et al. PACE 2002;25:

23 Hemodynamic Consequences of Ventricular Dysynchrony Normal Effects of LBBB on LV Contraction and Relaxation (1) Start of QRS LBBB mc ao ac mo IVCT Ejection IVRT Filling ü Reduced LV filling time 1,2 ü Prolonged mitral regurgitation 1,2 ü Impaired systolic function (depressed dp/dt) 3,4 ü Abnormal septal wall motion 1 ü Mechanical and temporal dysynchrony 4 1. Grines C, et al. Circulation 1989;79: Xiao, et al. Br Heart J 1991;66: Xiao et al. Br Heart J 1992;68: Curry C, et al. Circulation 2000;101:e2

24 The Cardiac Conduction System and Biventricular Pacing Jarcho J. N Engl J Med 2006;355:

25 Baseline CRT

26 Proposed Mechanisms of Benefit Cardiac Resynchronization Intraventricular Synchrony Atrioventricular Synchrony Interventricular Synchrony dp/dt, EF, CO ( Pulse Pressure) MR LA Pressure LV Diastolic Filling RV Stroke Volume LVESV LVEDV Reversed Remodeling Yu C-M, et al. Circulation 2002;105:

27 Acute Studies Systolic Blood pressure Pulmonary Capillary Wedge Pressure p<.01 p< mm Hg p<.01 p< BAS RVA RVO LV BV 0 BAS RVA RVO LV BV 23 pts mean ± SD Blanc et al., Circulation 1997

28 Acute Studies 120 RV Apex 120 RV Septum LV Pressure (mm Hg) LV Freewall Biventricular Intrinsic Paced LV Pressure (mm Hg) LV Volume (ml) LV Volume (ml) Kass et al, Circulation 99

29 Over 8,000 Patients Studied in Clinical Trials MADIT CRT REVERSE

30 MUSTIC Trial CRT Improve Quality of Life (MLHFQ) S.Cazeau et al NEJM 2001;344:873-80

31 MUSTIC Trial 225 LVESV and LVEDV 40 Pacing MR area No pacing Left ventricular volume (ml) * * * * * * * * Mitral regurgitation (%) * * * * * N = 25 Baseline 1wk 1mo 3mo off-immed off-1wk off-4wk 10 Baseline 1wk 1mo 3mo off-immed off-1wk off-4wk S.Cazeau et al NEJM 2001;344:873-80

32 MIRACLE Time to Death or Worsening HF requiring Hospitalization Event Free Survival (%) 100% 95% 90% 85% 80% 75% 70% Patients At Risk P = Relative risk = 0.60; 95% CI (0.37, 0.96) Months After Randomization CRT Control Control CRT MIRACLE: Circulation 2003;107:

33 COMPANION Composite of Death or Hospitalization for Any Cause Results Event-Free Survival (%) OPT CRT CRT-D (CRT vs. OPT) P = (CRT-D vs. OPT) P = Days after Randomization No. at Risk OPT CRT CRT-D Bristow M. N Engl J Med. 2004;350:

34 COMPANION All-Cause Death Results Event-Free Survival (%) OPT CRT CRT-D (CRT vs. OPT) P = (CRT-D vs. OPT) P = Days from Randomization No. at Risk OPT CRT CRT-D Bristow M. N Engl J Med. 2004;350:

35 CARE-HF - Death or Unplanned Hospitalization for CV Event Results % Patients Free of Death from Any Cause or Unplanned Hospitalization for a Major CV Event P < CRT HR 0.63 (95% CI 0.51 to 0.77) 37% Relative Risk Reduction Medical Therapy No. at Risk Days CRT Medical Therapy Cleland JGF. N Engl J Med. 2005;352:

36 CARE-HF Death from Any Cause Results 100 % Patients Free of Death from Any Cause HR 0.64 (95% CI 0.48 to 0.85) 36% Relative Risk Reduction P < CRT Medical Therapy No. at Risk Days CRT Medical Therapy Cleland JGF. N Engl J Med. 2005;352:

37 ICD and CRT Which Patient? ICD: ü Mild to moderate HF NYHA Class I-III ü LV ejection fraction 35% ü Post-MI ( 40 days); post-cabg ( 3 months) ü Optimal medical therapy ü Survival > 1 yr CRT: ü Moderate to severe HF (NYHA Class III/IV) patients ü Symptomatic despite optimal, medical therapy ü QRS 120 msec ü LVEF 35 ü Sinus rhythm CRT plus ICD: ü Same as above with ICD indication

38 CMS ICD Coverage Reference Guide History of MI Yes LVEF 30% MADIT-II No LVEF 35% No No Yes Yes NIDCM > 9 months NYHA Class II or III heart failure and LVEF 35% SCD-HeFT non-ischemic Yes NYHA Class II or III HF SCD-HeFT ischemic Yes No Not eligible for defibrillator No History of inherited conditions with high risk of VT Yes Yes CAD, inducible sustained VT or VF at EPS MADIT No No History of cardiac arrest due to VF No Sustained VT, spontaneous or induced by EPS No Not eligible for defibrillator Yes Yes NYHA Class IV Cardiogenic shock or hypotension CABG or PTCA within past 3 months MI within past 40 days Candidate for coronary revascularization Irreversible brain damage from preexisting cerebral disease Other disease with survival < 1 year Yes No Eligible for defibrillator

39 CMS CRT/CRT-D Coverage Reference Guide Symptomatic HF despite stable, optimal medical therapy Yes No No Prolonged QRS and LVEF 35% Yes NYHA Class IV heart failure Yes No NYHA Class III heart failure Yes No Meets coverage criteria for the implantation of an ICD Yes Not eligible for CRT device Eligible for CRT pacemaker (CRT-P) Eligible for CRT defibrillator (CRT-D) Reference CMS Local Coverage Decision and Bulletins for any specific coverage requirements specific to your region or state. Some local policies require a QRS duration > 130 ms.

40 AIAC Guidelines ICD - PRIMARY PREVENTION IN CARDIOMYOPATHY CLASS I Ischemic Cardiomyopathy, Reduced EF ( 40%) Non Sustained VT and Sustained Inducible VT (Level B) Ischemic & Non-Ischemic Cardiomyopathy (for Ischemic at least 40 days after AMI) Reduced EF ( 30%), NYHA II/III, Optimal Medical Treatment (Level A) CLASS II Ischemic (at least 40 days after IMA) & Non-Ischemic Cardiomyopathy 31% EF 35%, NYHA II/III Optimal Medical Treatment (Level B) Ischemic Cardiomyopathy (at least 40 days after IMA) Reduced EF ( 30%), NYHA I, Optimal Medical Treatment (Level B)

41 AIAC Guidelines CARDIAC RESYNCHRONISATION THERAPY CLASS I Synus Rhythm, Reduced EF ( 35%) Ventricular Dyssynchrony (QRS > 120ms) NYHA III-IV despite Optimal Medical Therapy CLASS II Pts In Atrial Fibrillation, Reduced EF ( 35%) Ventricular Dyssynchrony (QRS > 120ms) NYHA III-IV despite Optimal Medical Therapy Reduced EF ( 35%), QRS 120 ms Ventricular Dyssynchrony (Echo assessment) NYHA III-IV despite Optimal Mdical Therapy Synus Rhythm, Reduced EF ( 35%) Ventricular Dyssynchrony (QRS > 120ms) Symptomatic (NYHA II) and with pacing indication or Primary Prevention ICD Chronic Right Ventricular Stimulation, Reduced EF ( 35%) Severe Ventricular Dyssynchrony NYHA III-IV despite Optimal Medical Therapy (Upgrade) RECOMMENDATIONS FOR CRT-D USE The use of ICD in addition of CRT (CRT-D) should be based on recommendations for ICD use in primary or secondary prevention of sudden cardiac death

42 Indications of CRT New Guidelines of ESC CRT using BIV pacing can be considered in patients with reduced EF and ventricular dyssynchrony (QRS widht > 120 msec), who remain symptomatic (NYHA III-IV) despite optimal medical therapy to improve: ü Symptoms (Class I, level A) ü Hospitalizations (Class I, level A) ü Mortality (Class I, level B) WCC, Barcellona 2-6 September 2006

43 Therapy OFF Therapy ON QRS=160 ms QRS=120 ms

44 Cardiac Resynchronization Therapy: Creating Realistic Patient Expectations ü Approximately two-third of patients should experience improvement (responders vs. non-responders) 1 ü Some patients may not experience immediate improvement CRT is adjunctive and is not intended to replace medical therapy. Patients will continue to be followed by HF Specialist and Physician managing implantable devices. 1 Abraham, WT, et. Al. Cardiac Resynchronization in Chronic Heart Failure. N Engl J Med 2002;346:

45 Patient Selection for CRT Reasons for Low (or no) Response to CRT ü Inappropriate patient selection ü Inappropriate lead positioning ü Inappropriate AV delay tuning ü Inappropriate CRT delivery (PM functioning) ü Inappropriate drug treatment ü Spontaneous or PM mediated arrhythmias

46 Definition of Responder/Non Responder RESPONDER ü Survival + at least 1 NYHA class down + 10% increase in peak VO2, for at least 6 months. Alonso. AJC 1999 ü Improvement > 1 NYHA class. Oguz. Eur J H Fail 2002 ü LVESV decreased by > 15%. Stellbrink. J ACC 2001 ü Persistent decrease of > 1 NYHA class, irrespective of the changes of others parameters. NON RESPONDER: ü No decrease in NYHA class + no decrease in the QOL score. Reuter. AJC 2002 ü Therapy considered as neutral or not beneficial (same NYHA class or decline of status; need for heart transplant; death due to progressive, drug-refractory pump failure). Lunati. J CE 2002

47 Reasons for low (or no) response to CRT 1. Inappropriate patient selection ü No Ventricular asynchrony +++ ü CRT may create ventricular asynchrony!! ü End stage cardiomyopathy ü Severe RV dysfunction, High pulmonary hypertension ü Additional indications for Heart Surgery ü Valve replacement, CABG

48 Reasons for low (or no) response to CRT 2. Inappropriate lead positioning ü LV lead placed in the Great Cardiac Vein ü RV lead close to the apex ü High lat RA lead in inter atrial conduction block ü Short AVD: good BiV capture + poor LA contraction ü Long AVD: poor BiV capture + good LA contraction

49 Possible Venous Tributaries of the CS CS venous anatomy allowing LV lead tip should usually be positioned in a basal/mid-basal lateral (region C) or basal/mid-basal postero-lateral (region D) location

50 Varying Patient Anatomy

51 Reasons for low (or no) response to CRT 3. Inapproriate setting of AV delay Long AV Delay 160 ms: Opt A Short AV Delay 50 ms: opt E Optimized AV Delay 100 ms: opt E + A Importance of AV delay optimization

52 Reasons for low (or no) response to CRT 4. Inappropriate CRT delivery: Up to 20%! PVC AS AS AS AR AR AR AR PVARP PVARP PVARP PVARP PVARP PVARP PVARP VP VP VP VS VR VS VR VS VR VS VR VS VR SAV SAV SAV iav iav iav iav IVCD IVCD IVCD IVCD IVCD

53 Reasons for low (or no) response to CRT 5. Inappropriate drug treatment ü ACE inhibitors: ü increase in dosage, re-introduction ü Diuretics: ü decrease in dosage +++ ü Beta-Blockers: ü Introduction ü increase in dosage ü Combination: Amiodarone and beta-blockers

54 CRT Procedure and Device Related Risks Procedure Related Complications in 571 Patients Attempted; Proportion (n) Unsuccessful implant 7.5% (43) CS Dissection or Perforation Bradycardia 0.3% (2) Death 0.3% (2) 6% (35; all recovered w/o sequela) Device Related Complications in 6 months in 528 Patients Successfully Implanted ; Proportion (n) LV Lead Revision 5.7% (30; all replaced or repositioned) Reduced Procedure Time with Increased Experience Implant Time (minutes) Up to first 5 P < Next 6 to 10 Next 11 more Center-based experience Unpublished data. MIRACLE study. PM Pocket/ RV Lead Infection 1.3% (7; 4 of 7 re-implanted) Abraham WT, et al. NEJM 2002;346: (MIRACLE)

55 3 4 CS dissection 1 2

56 When to Consider Epicardial Approach for LV Pacing ü Failure to implant LV lead: 0 to 10 % ü LV lead in mid or great cardiac vein: 0 to 10 % ü Interest of endocardial versus epicardial pacing 100% 88% 90% 92% 93% 96% 70% InSync InSync It Mustic Miracle Med OTW

57 LV pacing using epicardial approach

58 Incremental Cost-Effectiveness Cardiovascular Interventions Incremental Cost per Life-Year Saved $ $ $ $ $ $ $ $ $ $ $0 $8,461 PTCA (chronic CAD, severe angina 1 VD) $17,701 CABG (chronic CAD mild angina, 3 VD) $40,750 Hypertension Therapy (diastolic mmhg) $67,000 End Stage Renal Disease Treatment $120,000 Exercise SPECT (atypical angina who can walk on treadmill) Moss AJ. Satellite Symposium, Cost-Effectiveness of Device Therapy in the Heart Failure Population", September 23, Kupersmith J. Progress in Cardiovascular Diseases. 1995;Vol XXXVII, No. 5: Stanton M. Circulation. 2000;101: $135,000 Lovastatin (chol. = 290 mg/dl, 50 yrs old, male, no risk factors) $150,000 Carotid Disease Screening (65 yrs old, male, no symptoms) $1,000,000 Routine Coronary Angiography (35-84 yrs old, low risk MI, has CHF) Economically Unattractive Expensive Borderline Cost-Effective Cost-Effective Highly Cost-Effective

59 Incremental Cost-Effectiveness ICD, CRT, and CRT-D Therapies Incremental Cost per Life-Year Saved $ $ $ $ $ $ $ $ $ $ $0 $28,000 $33,000 $38,200 COMPANION CRT 1 SCD-HeFT ICD 2 COMPANION CRT-D 1 $50,000 MADIT-II ICD 3 $67,000 AVID ICD 4 Economically Unattractive Expensive Borderline Cost-Effective Cost-Effective Highly Cost-Effective 1 Feldman AM. ACC News. March 16, Mark DB. AHA News. November 11, Ak-Khatib S. Ann Intern Med. 2005;142: Larsen G. Circulation. 2002;105:

60 Actual Key Questions ü QRS<120ms or QTc dispersion? ü Which implication in patients with unstable haemodinamic profile? ü CRT in Right Bundle Branch Block? ü Up-grading in RVA pacing? ü CRT in chronic Atrial Fibrillation?

61 Over 8,000 Patients Studied in Clinical Trials Prevalence of AF in moderate-to-severe CHF varies between 25% and 50% MADIT CRT 2% REVERSE

62 The interaction between AF and HF means that neither can be treated optimally without treating both HF promotes aggravates AF

63 Does early intervention with CRT-D slow the progression of HF in high-risk patients with mild HF (NYHA I II) when compared to ICD only therapy? MADIT-CRT Question

64 MADIT-CRT Hypothesis: in minimally symptomatic high-risk pts with IHD (NYHA I or II) or NIHD (NYHA II), wide QRS (.13s), and low EF (.30), CRT will slow or prevent the development of heart failure ü CRT-D vs ICD-only ü 1820 pts: 110 enrolling centers in US & Europe ü Endpoint: HF or death, whichever comes first ü Enrollment complete, in f/up phase

65 Kaplan-Meyer Curves for Death and for HF/Death Both Rx Arms (CRT-D vs. ICD) Note: Of 1820 enrolled patients, 300 have experienced a 1 st end-point event.

66 LAO LV Sequential Pacing

67 Triple-site biventricular pacing SR RV LV(lv) LV(pl) LV(lvpl) BIV (RV+lv) Triple Site BIV (RV+2 left)

68 Multi-site Pacing