CARE-HF CArdiac REsynchronization in Heart Failure Clinical Study

1
CARE-HF CArdiac REsynchronization in Heart
Failure Clinical Study

• Independent trial by Clinical Community
• Sponsored by Medtronic

2
Electromechanical AssociationsEP HF
Specialties Progressively More EntwinedRogers JG
Cain MENEJM 20043502193-95

• 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
Prevalence and Prognosis of Ventricular
dyssynchrony
LBBB More Prevalent with
Increased All-Cause Mortality with
Impaired LV Systolic Function
Wide QRS at 45 Months (3)
P lt 0.001
Preserved
49
8
LVSF (1)
34
Impaired
24
LVSF (1)
QRS
QRS
Mod/Sev
lt 120 ms
120 ms
38
HF (2)
3. Iuliano, et al. AHJ. 20021431085-1091.
1. Masoudi, et al. JACC. 200341217-223.
2. Aaronson, et al. Circulation.
1997952660-2667.
4
Cardiac Resynchronization Proposed Mechanisms
Yu C-M, Chau E, Sanderson J, et al. Circulation
2002105438-445
5
Cumulative Benefit of ACE-I and Beta Blockers
P lt 0.01
P lt 0.05
Exner DV et al. JACC 1999 33 916-23
6
Total Mortality Benefit for an ICD Trial (AVID)
and a Statin Trial (WOSCOP)
4.1
3.2
25
18

• 27 Relative Risk Reduction
• 7 Absolute Risk Reduction
• 18 Residual Risk

• 22 Relative Risk Reduction
• 0.9 Absolute Risk reduction
• 3.2 Residual Risk

7
Residual Risk of SCD in Treatment Arms of
CHF-Beta Blocker Trials
Sudden Death of Total Death
54
31
54
n 696
No. Pts in Treatment Arm
n 1327
n 1990
Average Follow Up
12 months
16 months
6.5 months

1. CIBIS-II Investigators. Lancet 1999 353
   9-13. 3. Packer, M, et al. N Engl J Med 1996
   334 1349-55.
2. MERIT-HF Study Group. Lancet. 1999 353 2001-07.

8
MADIT II Hospitalization for Heart Failure
P 0.009
Moss AJ et al. NEJM 2002 346 877-83
9
Pharmacologic and Device Therapy Across the
Continuum
MADIT, MUSTT (ICD)
SCD-HeFT, MADIT-II (ICD)
MIRACLE, COMPANION, MUSTIC (CRT /- ICD) CARE-HF
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
CRT Improves Quality of Life and NYHA Functional
Class
P lt 0.05
Abraham et al., 2003
12
CRT Improves Exercise Capacity
P lt 0.05
Abraham et al., 2003
13
CRT Benefits Sustained Through 2 YearsMIRACLE
Study Program
Abraham et al., AHA 2003
14
Comparison with Drug Trials Digoxin, ACE-I and
Beta-blocker Therapies
P?.05 P?.01 P?.001
4 Am J Cardiol 1993711106-1107 (SOLVD
Treatment) 5 J Cardiac Failure 19973173-179 6
NEJM 20023461845-53 (MIRACLE)
1 NEJM 19933291-7 (RADIANCE) 2 Circulation
1996942793-2799 (PRECISE) 3 JAMA
1988259539-544
15
Systematic Review of 9 clinical trials CRT
reduces all-cause mortality by 21 (RR 0.79 Ci
0.66-0.96 NNTB 24 McAlister FA et al. Ann
Intern Med 2004 141381-90
CRT does not significantly reduce all-cause
mortality Calvert M, Freemantle N and Cleland
JGF Ann Intern Med 2005 142 305-7
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
Limitations of Previous Trials/Analyses or Why
Was CARE-HF Needed (contd)

• COMPANION had unbalanced 3-arm design (OMT, CRT,
  CRTICD)
• Inclusion of all 3 arms of COMPANION in
  meta-analyses inappropriately credits CRT with
  the mortality reduction due to the ICD

18
The CARE-HF StudyCArdiac 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
CARE-HFIntent

• 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
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
CARE-HF Communication
DSMB
22
CARE-HF

• Study Overview

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
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
Study Design
Patient screening- consent
Randomization
Optimal medical therapy cardiac
resynchronization
Optimal medical therapy
Follow-up (min 1.5 year)
Follow-up (min 1.5 year)
Primary outcome Secondary outcomes Mechanistic
health economic outcomes
26
Intervention

• InSync or InSync III -gt 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
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
Main Inclusion Criteria (contd)

• QRS ?120 ms
• Dyssynchrony confirmed by echo if
• QRS 120-149 ms
• Aortic pre-ejection delay gt140ms
• Inter-ventricular mechanical delay gt40 ms
• Delayed activation of postero-lateral LV wall

Main Exclusion Criteria

• Patients with chronic AF or requiring pacing
  excluded

29
Population Baseline Characteristics

• 813 pts predominantly class III (94)
• Mean age 65 (IQR 59-72)
• 34 aged gt 70 years
• 27 woman
• 38 Ischaemic Heart Disease, 46 Dilated CM
• Mean HR adequately controlled at 70 BPM
• 88 QRS gt 150 msec.
• Supine systolic BP 117 (IQR 105-130)
• 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
Population Baseline Characteristics (contd)

• 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
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 / ARBs 383 (95) 387 (95)
Beta blockers 298 (73) 288 (71)
Furosemide Eq ? 80 mg/day 177 (44) 175 (43)
Digitalis 181 (45) 165 (40)
Spironolactone 238 (59) 219 (54)
32
Baseline Characteristics (contd)
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) 110 (100 to 125)
Diastolic BP mm Hg 70 (60 to 80) 70 (60 to 79)
QRS interval ms 160 (152 to 180) 160 (152 to 180)
IVMD ms 50 (30 to 66) 49 (32 to 67)
Ejection fraction 25 (22 to 29) 25 (21 to 29)
ESV index 117 (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
MIRACLE, COMPANION, CARE-HF Similarities and
Differences
MIRACLE
COMPANION
CARE-HF
C CRT C CRT CRTICD C CRT
Age (yrs.) 65 64 68 67 66 66 67
Ischemic HD () 58 50 59 54 55 36 40
NYHA III () 91 90 82 87 86 93 94
QRS Duration 165 167 158 160 160 160 160
EF () 22 22 22 20 22 25 25
ACEI 90 93 87 89 90 95 95
BB 55 62 66 68 68 70 74
Spironolactone - - 55 53 55 59 54
F/U (mos.) 6 6 12 16 16 29 29
1 yr mortality () (Control Arm )
12.6
19
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 55-59 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
  gt90 of patients had EF lt 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
CARE-HF

• Results

36
1-14 Patients/Center gt14 Patients/Center

• Recruitment
• 813 patients (Jan 2001 - Mar 2003)
• 82 centers in 12 countries
• Austria, Belgium, Denmark, Finland, France,
  Germany, Italy, Netherlands, Spain, Sweden,
  Switzerland,
• and UK

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 -gt6 pts reached
  primary objective

38
Conduct of the Study

• Follow-up time
• Minimum 18 month -gt last patient Sep 2004
• Average (Mean) Follow up 29.4 month accounting
• Cut-off data (30 Sept. 2004 Randomization date)
• Maximum 44.7 months 3years 8 months
• At completion (30th September 2004)
• lt5 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
Primary Endpoint(All-cause Mortality or
Unplanned Hosp. for Major CVS Event)
1.00
0.75
0.50
Event-free Survival
Medical Therapy
0.25
0.00
0
500
1000
1500
Days
Number at risk
7
68
166
273
323
409
CRT
3
48
118
232
292
404
Medical Therapy
40
Primary Endpoint(All-cause Mortality or
Unplanned Hosp. for Major CVS Event)
CRT 159 pts (39)
41
All-Cause Mortality
1.00
0.75
0.50
Event-free Survival
Medical Therapy
0.25
0.00
0
500
1000
1500
Days
Number at risk
8
89
213
351
376
409
CRT
5
71
192
321
365
404
Medical Therapy
42
All-Cause Mortality
1.00
HR 0.64 (95 CI 0.48 to 0.85)
0.75
CRT 82pts (20)
P .0019
0.50
Event-free Survival
Medical 120 pts Therapy (30)
0.25
0.00
0
500
1000
1500
Days
Number at risk
8
89
213
351
376
409
CRT
5
71
192
321
365
404
Medical Therapy
43
PrimaryEndpoint
44
Symptoms Quality of Life at 90 days
Outcome Medical Therapy Mean (SD) CRT Group Mean (SD) Difference in means(95 CI P value)
NYHA class 2.7 (0.9) 2.1 (1.0) 0.6 (0.4 to 0.7 P lt 0.0001)
MLWHF score 40.0 (21.7) 31.1 (21.6) -10.1 (-8 to -12 P lt 0.0001)
Euroqol EQ5D 0.626 (0.289) 0.700 (0.284) 0.076 (0.037 to 0.115 P 0.0001)
45
Mechanistic Outcomes
Outcome Mean difference Mean difference
Outcome at 3 mo at 18 mo
Systolic BP (mm Hg) 5.8(P lt 0.0001) 6.3(P lt 0.0001)
Inter-ventricular mechanical delay (ms) -21(P lt 0.0001) -21(P lt 0.0001)
Ejection fraction () 3.7(P lt 0.0001) 6.9(P lt 0.0001)
Left ventricular end-systolic volume (mL) -18.2(P lt 0.0001) -26.0(P lt 0.0001)
Mitral regurgitation ( of LA Area) -5.1(P lt 0.0001) -4.2(P 0.003)
NT Pro-BNP pg mL-1 -225(P 0.36) -1,122(P 0.0016)
Positive values indicate higher value with CRT
compared to control
46
Serious Adverse Events
SAE Groupings Control CRT P value
Patients with Procedure or device related Adverse Event (Assessed by Independent Expert) Patients with Procedure or device related Adverse Event (Assessed by Independent Expert) Patients with Procedure or device related Adverse Event (Assessed by Independent Expert) Patients with Procedure or device related Adverse Event (Assessed by Independent Expert)
Procedure related death 1 1 P 0.99
Lead problems 6 27 P lt 0.001
Coronary sinus dissection 0 12 P lt 0.001
Pocket complications 1 9 P 0.012
Patients with Other Serious Adverse Events (Investigator Reported) Patients with Other Serious Adverse Events (Investigator Reported) Patients with Other Serious Adverse Events (Investigator Reported) Patients with Other Serious Adverse Events (Investigator Reported)
Myocardial Isch MI 84 70 P 0.21
Worsening HF 263 191 P lt 0.0001
Atrial arrhythmia 41 64 P 0.02
Ventricular arrhythmia 54 58 P 0.74
Respiratory infection 101 85 P 0.15
AVB or bradycardia 27 17 P 0.12
47
Cardiac Resynchronization TherapyPatient
Selection February 2005

• ? 18 years of age
• NYHA Functional Class III or IV despite
  stable/optimal drug regimen
• QRS duration ? 120-130 msec
• LVEF ? 35 LVEDD ? 55 millimeters
• With or without indication for ICD

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 (gt 30 days)
• Non-ischemics must have CHF of at least 3 (?9)
  months duration

49
Device Indications

• Stage C heart failure
• LVEF ? 35
• Optimal medical therapy

NYHA Functional Class NYHA Functional Class NYHA Functional Class
II III IV
QRS Duration ??? 120 ms ICD2 CRT1 ICD2 CRT1
QRS Duration lt 120 ms ICD2 ICD2
1. Abraham WT, Fisher WG, Smith AL, et al.
Cardiac resynchronization in chronic heart
failure. N Engl J Med 20023461845-1853 2.
Bardy GH, Lee KL, Mark DB, et al. Amiodarone or
an implanatble cardioverter-defibrillator for
congestive heart failure. N Engl J Med
2005352225-37
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
  (lt 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
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
CARE-HF

• Additional Resources

53
Additional Resources

• Slides presented at ACC are available at
• http//www.CARE-HF.org/
•  
• Clinicians can ask questions by emailing
• care.hf_at_medtronic.com
•  
• ACC Webcast of the Late Breaking Clinical Trials
• (March 7, 2005) http//www.acc05online.acc.org/hi
  ghlights/KeySessions.aspx?date7

54
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 20013481-489.
• 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. 20053521539-49.
• http//content.nejm.org/cgi/content/abstract/NEJM
  oa050496

55
CARE-HF Results

• Additional Information

56
Mechanistic Outcomes

• At 18 months, compared to the control group,
  patients randomized to CRT had
• Shorter Interventricular Mechanical delay P lt
  0.0001
• Higher LVEF (by about 7) P lt 0.0001
• Less mitral regurgitation P 0.003
• Lower ventricular volumes P lt 0.0001
• Higher systolic blood pressure P lt 0.0001
• Lower NT-pro-BNP P lt 0.0016

57
CARE-HF Baseline QOL
Calvert M et al. The impact of Chronic HF on
Health Related QOL CARE-HF baseline EJHF
20057(2) in press
58
Baseline EQ-5D CARE-HF population vs. Other
Diseases



General population
0.86 (0.85, 0.87)



General population age 65
-
74
0.78 (0.76, 0.80)

CARE
-
HF
0.60 (0.58, 0.62
)


Type II diabetes
0.77 (0.76, 0.78)


Mild motor neurone disease
0.63 (0.49, 0.77)


Moderate motor neurone disease
0.56 (0.43, 0.69)

Parkinson's disease
0.59 (0.54, 0.64)

Hospitalised after ischemic stroke
0.31 (0.24, 0.38)


3 month assessment post stroke
0.61 (0.55, 0.67)

Non
-
small Cell Lung Cancer
0.58 (0.51, 0.65)
0.2
0.0
0.4
0.6
0.8
1.0
Calvert M et al. The impact of Chronic HF on
Health Related QOL CARE-HF baseline EJHF
20057(2) in press
59
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.

60
Supplemental Slides
61
CRT Background
62
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 gt 120 msec)1-2.

1 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
2002143412-417 2 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 2000102(18 Suppl
II)
63
Achieving Cardiac Resynchronization
Goal Atrial synchronous biventricular
pacing Transvenous approach for left ventricular
lead via coronary sinus Back-up epicardial
approach
64
CRT Studies Over 90 NYHA III
Status at Enrollment
65
Early Steps to Answer remaining Questions about
CRT
66
Roles of Echocardiography to Guide Cardiac
Resynchronization Therapy
Patient Selection
LV RV Lead Positioning
Device Timing Optimization
67
Intra-ventricular Dyssynchrony Tissue Doppler
Imaging
Velocity6 segments
Strain rate6 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
  200291684688
• 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 200240723730

Uses tissue velocity data to calculate
regional deformation rates. May be less
influenced by translational motion or tethering.
68
One Study Assessed Whether Pacing at Site of
Latest Activation Had an Effect
Comparative changes in selected parameters with CRT Comparative changes in selected parameters with CRT Comparative changes in selected parameters with CRT Comparative changes in selected parameters with CRT

Paced at most delayed site? Paced at most delayed site?
Parameter Yes No P-Value
LVESV (mL) -28.4 -9.2 0.04
LVEF () 9 2 0.04
6 min walk distance (m) 31 8 0.19

• 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

13 of 31 paced at most delayed site 18 of 31
paced at other site
Ansalone, et al. JACC 200239489-99
69
CRT Device Optimization with EchoPotential
Targets
Stroke Volume (Aortic VTI)
Trans-mitral Flow
Intra- Ventricular Synchrony
70
Should AV Delays be Optimized?
Optimal AV Delays Vary by Patient and by Target
Optimization Measure
Chronic study of biventricular pacing. Optimal AV
delay determined via trans-mitral flow. Delurgio,
et al. PACE 200124pt 2651 abstr. 452
Acute study results of 27 patients with
biventricular pacing. Mean std. dev. Pulse
pressure (PP). Auricchio, et al. Circulation
1999992993-3001
71
Does Interventricular (VV) Delay Optimization
Make A Difference?

• Both studies
• Single center study of consecutive patients with
  NYHA III/IV HF, QRS gt 130 ms
• Trans-mitral flow optimized with AV delay post
  implant
• Rosanio, et al. Circ. 2003108IV-345
• N22
• VV delay of 0 for first 2 months.
• Echo based optimization of VV delay (OPT) at 2
  months.
• Sogaard, et al. Circ. 20021062078-84
• N20
• Optimal VV delay based on TDI
• Acute data shown. After 3 mo., LVEF further
  improved to 38.6. (Plt0.01)

Plt0.01 CRT with AV Opt versus Baseline
Plt0.01 VV Opt versus CRT with AV Opt
72
Do Wider QRS Respond Better to CRT?

• Positive Findings
• ? QOL and exercise tolerance only if QRS gt 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
• MIRACLE 166
• MUSTIC 176
• InSync ICD 165
• Contak CD 158
• COMPANION 160

• Negative Findings
• Achillis 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 2117-24)

73
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
  1417-21)
• 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 1567-73)
• 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
  27 308-13)

74
CRT RBBB vs. LBBB
Contak Insync ICD Miracle MUSTIC
QRS 158 165 166 176
LBBB 271 (54) 382 (69) 426 (80) 58 (87)
Bradley DJ JAMA 2003 289 733-40
Patients with RBBB benefit from CRT if there is
evidence of mechanical dyssynchrony
Bristow MR NEJM 2004 350 2140 Garrigue S. AJC
2001 88 1436-41 Higgins JACC 2003 42 1454-1459
75

• CRT and AF All Trials Show Improvement
• MUSTIC
• Leclerq AJC 2000 55 1154
• Etienne AJC 1999 83 1138

PAVE Trial
PAVE Changes in Peak VO2
Plt 0.01

• Inclusion
• Ablate and pace
• RV vs BiV
• NYHA I/II/III
• Chronic AF gt 1 mos
• Walk lt 450 meters in 6 minutes
• Endpoint
• 1 6 minute walk
• 2 CPX V02
• QOL

PAVE Changes in LVEF
76
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
  86231-33 Higgins JACC 2003 42 1454-1459)

• Negative Findings
• Epicardial LV leads cause repolarization
  abnormalities and prolongation of QT interval
  that may trigger ventricular arrhythmias
• (Medina-Ravell VA Circ. 2003 107 740-46)