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Page 1
How do I convert my CRT Non Responder into Responder?
Michael R Gold, MD, PhDMedical University of South Carolina
Charleston, SC
Disclosures:Clinical Trials and Consulting – Boston Scientific, Medtronic
6-Minute Hall Walk
250
300
350
Met
ers
Base-line
1 Month
3Months
6Months
P=0.033P=0.004P=0.032
CRTN=121
ControlN=116
MIRACLE
Page 2
Quality of LifeMinnesota Living With Heart Failure Score
30
40
50
60
70
Baseline 1 Month 3 Months 6 Months
Control N=114 CRT N=121
P=0.013P=0.051P=0.020
Total ScoreIm
prov
emen
t
MIRACLE
Echocardiographic ParametersLVEDD
6.50
6.75
7.00
7.25
7.50
ControlN=63
CRTN=61
Cen
tim
eter
s
Baseline 6-Months
P<0.001
LVEF
10
15
20
25
30
35
ControlN=81
CRTN=63
Per
cen
tag
e
Baseline 6-Months
P<0.001
MIRACLE
Page 3
COMPANION: Primary EndpointDeath or Any Hospitalization
CARE HF: All-Cause Mortality
571192321365404Medical Therapy
889213351376409CRT
Number at risk0 500 1000 1500
0.00
0.25
0.50
0.75
1.00
Eve
nt-
free
Su
rviv
al
Days
Medical Therapy
HR 0.64 (95% CI 0.48 to 0.85)
P = .0019CRT
Page 4
REVERSE: Clinical Composite Response
40% 39%
21%
54%
30%
16%
Improved Unchanged Worsened
CRT OFF (n=191) CRT ON (n=419)
P = 0.10
P = 0.004
MADIT-CRT: Kaplan-Meier Estimate of Heart-failure Free Survival Probability
N = 1820P<0.001Average FU = 2.4 yrs.
Page 5
9
RAFT: All Cause Mortality
0%
10%
20%
30%
40%
50%
0 12 24 36 48 60
Months Since Randomization
Mo
rtal
ity
Rat
e
Number 730 687 533 366 189 83 remaining 708 679 530 361 206 89
ICD
CRT -D
p = 0.006HR = 0.71 (0.56-0.91)
Tang et al, NEJM
Cardiac Resynchronization Therapy: Weight of Evidence
10,000 patients evaluated in randomized controlled trials of advanced heart failure Consistent improvement in quality of life,
functional status, and exercise capacity Strong evidence of changes in LV structure
– ↓ LV volumes and dimensions– LVEF– ↓ Mitral regurgitation
Reduction in HF and all-cause morbidity and mortality
Page 6
Nonresponders
• Most clinical studies report CRT non-responder rates of about 30%
• This percentage has remained stable over a decade of trials involving both severe and mild heart failure
• However, the non-response rate is very dependent on endpoint measured and time
• Defining appropriate definitions of CRT response remains challenging
How to Choose an Endpoint for CRT Response
• Duration of study
– Mortality cannot be assessed in short duration studies
– Remodeling and QOL changes occur within 6 months
• Study design
– Blinded vs open labelled – Placebo effect is very important
Page 7
Nonresponder Rates
NonrespondersMagnitude of response is Dependent
on Variable Measured
Birnie. Curr Opin Cardiol. 2006;21:20-26.
Page 8
What defines a responder vs. "non-responder"?
Steffel & Ruschitzka, Circulation 2015
Negative responders
Non-responder
"Non progressor"
Responder
Super-Responder
Time
Status CRTImplantation
REVERSE: Mortality Rate After LVESVi Change
16
Gold et al, 2015
Page 9
First Principles: Prevent non-responders by patient selection
• Clinical predictors of response rate
– Women
– Non-ischemic Cardiomyopathy
– QRS duration
– LBBB
• Clinical predictor of poor response
– Inotropic dependent
– Scar
– Apical LV lead position
Heart Failure (HF) Event or Death by QRS Pattern in MADIT-CRT Patients
LBBB Non-LBBB
Page 10
19
REVERSE: Clinical Composite Subgroup Analysis
0.01 0.1 1 10
All Patients
Ischemic
Non-ischemic
CRT-P
CRT-D
NYHA Class I
NYHA Class II
Male
Female
0.26
0.90
0.46
0.52
InteractionP-value
0.01 0.1 1 10
LBBB
RBBB
IVCD
Non-white
White
> 65 yrs
< 65 yrs0.75
0.60
0.01
Odds Ratio with 95% CI Odds Ratio with 95% CI
CRT ON Better
CRT OFF Better
CRT ON Better
CRT OFF Better
ll1
QRSd ≥150 msQRSd ≥150 ms
Stavrakis S, et al. J Cardiovasc Electrophysiol 2012;23:163-168.
Slide 19
ll1 left bundle vs non-left bundle?landbl1, 7/27/2011
Page 11
QRSd <150 msQRSd <150 ms
Stavrakis S, et al. J Cardiovasc Electrophysiol 2012;23:163-168.
Change in LVESVi by QRS Width
1.2
4.1
7.1
12.7
18.4
36.1
-0.4
-0.8
-10 -5 0 5 10 15 20 25 30 35 40
120-136(n=125)
137-151(n=118)
152-165(n=132)
166-230(n=128)
Bas
elin
e Q
RS
Wid
th (
ms)
Mean Improvement in LVESVi (ml/m2) at 12 Months
CRT ON(n=340)CRT OFF(n=163)
Gold et al, 2012
Page 12
Individual Patient Meta-analysis of CRT Trials
After adjusting for QRS duration
Prognostic Benefit of CRTNot modified by
• Sex• QRS Morphology• Etiology
Cleland et al Eur Heart J 2013
ECHO CRT: CRT in Narrow QRS
Ruschitzka et al. NEJM 2013
Page 13
BBB Morphology and Width after CRT-DOutcomes Among 24,169 Medicare BeneficiariesBBB Morphology and Width after CRT-D
Outcomes Among 24,169 Medicare Beneficiaries
Peterson et al. JAMA 2013.
All-Cause Mortality by QRS Morphology and Width
All-Cause Readmission by QRS Morphology and Width
Modifiable “Risk Factors”
• Heart Failure Medications
• Treating comorbidities
– COPD
– Sleep Apnea
– Renal Failure
– Diabetes
• LV lead position
• ? Device programming
Page 14
LV Lead Location: COMPANION
LV Lead Position & Clinical OutcomeDeath &/or Heart Failure
No difference amongst Anterior, Posterior and Lateral lead positions
Apical lead positions associated with a significantly worse clinical outcome
Differences maintained even after non-apical leads sub-stratified into mid-ventricular and basal
Anterior, posterior and lateral position Apical versus Non-apical position
Page 15
Ypemburg et al. J Am Coll Cardiol 2008; 52: 1402-9
Site-Specific Pacing:Targeting mechanical dyssynchrony
Murphy et al, Am J Cardiol, 2006;97:1615-21
Imaging Guided LV Lead PositioningTARGET & STARTER
• TARGET: Khan JACC 59:1509, 2012
– RCT of 220 CRT pts• Control: post-lat / lat CS branch
• Targeted: 2D echo speckle-tracking: latest activated segment
– LV pacing concordance• Control: 47%
• Targeted: 63%
• STARTER: Saba Circ HF 6:427, 2013
– RCT of 187 CRT pts
– Also used speckle-tracking ECHO
– LV pacing concordance• Control: 66%
• Targeted: 85%
Page 16
Physiologic Guided Lead Positioning:QLV Interval Measurement
Physiologic Guided Lead Positioning:QLV Interval Measurement
Q-LV Interval to Predict Acute Response
R = 0.74
-5
0
5
10
15
20
25
30
35
40
0 50 100 150 200
Q-LV (ms)
%L
V+
dP
/dT
max
R
NR
R = 0.74
-5
0
5
10
15
20
25
30
35
40
0 50 100 150 200
Q-LV (ms)
%L
V+
dP
/dT
max
R
NR
Gold et al, J Cardiovasc Electrophysiol 2014
Page 17
Impact of QLV on Reverse and QOL with CRTImpact of QLV on Reverse and QOL with CRT
Gold et al, Eur Heart J. 2011
LVESV Response by SubgroupUnivariate Logistic Regression ResultsLVESV Response by Subgroup
Univariate Logistic Regression Results
Page 18
Interventricular Electrical DelayInterventricular Electrical Delay
Association of RV-LV Time with LV Remodeling and QOL
Page 19
RV-LV Time and Clinical OutcomeRV-LV Time and Clinical Outcome
Assessment of Non-Responder in Clinical Practice
• Validated endpoint measures are rarely used in clinical practice
• Rather, non-responders are classified by subjective assessment
• This should be supplemented with some functional or structural evaluation, such as echo or walk test
Page 20
CRT Response Evaluation
Evaluation of Non-responder
• Assess for reversible and treatable causes– Lead dislodgement
– Loss of capture
– Atrial fibrillation
– Metabolic or medical issues exacerbating HF
• Consider interventions to improve CRT response– Optimize medical regimen
– Programming AV delays or rate
– Invasive lead reposition
Page 21
The Initial Evaluation
NON-RESPONDER
CXRDevice
InterrogationECG
Paced and Unpaced
• LV and RV capture• AF
• Lead Position
Lateral Wall (Mid-Ventricular) Dislodged into CS
Consider Reversible Causes
Non-responder
Atrial Fibrillation Volume StatusCardiac
Ischemia
• Rule out ischemia• Treat ischemia
• Maintain NSR• Rate control (AVN vs. MED)• Adjust upper pacing rate• Program VVIR/VS Response• Individualize strategy (LV)
Other Co-morbidities
• Depression• COPD• Arthritis• Anemia etc.
Page 22
CRT Follow-Up Clinic
Altman R / Singh JP et al, AHA 2011
Altman R / Singh JP et al, AHA 2011
Summary
• There are many definitions of CRT response with no consensus on the best choice
• In practice, non-responders are classified by subjective assessment. However, this should be supplemented with some objective criteria such as exercise or echo response
• Patient selection and optimal LV lead position based on electrical or mechanical delay is useful
• A systematic approach to the evaluation and treatment of nonresponders is vital, including device evaluation, HF Rx and noncardiaccontributing causes
Page 23
Iterative Method
Truncated E<A Fused
Too Short Optimal Too Long
EE
EA
A
A
Question:
Are echocardiographic experts able to identify optimal AV intervals?
Nijjer SS, .. Francis DP J Am Coll Cardiol Img 2012:5:1046-1065
Qualitative echo optimization
Page 24
Patient 1
… a total of 30 experienced echocardiographers choose an option for 20 sets of images …
Qualitative echo optimization
Patient 1
0
5
10
15
20
25
30
35
40
A B C D E F
1
56
11
6
1
Qualitative echo optimization
Page 25
But there were not 20 subjects!
There were only 10 sets of Doppler freeze frames pictures, each shown twice
So each observer examined each identical sets of Dopplers twice
Qualitative echo optimization
A
B
C
D
E
F
A
B
C
D
E
F
Patient 1
AV optimisation on first viewingAV optimisation on second viewing of identical data
2
5
5
9
6
2
5
8
4
9
4
0
“Patient 11”but really same Doppler as “1”
Page 26
Operators disagreed with each otherOperators disagreed with themselves
kappa=0.27
Disagreed just as much with themselves as with others:= Not a failure of “inexperienced readers”
But a failure of the method
“They did not know that they did not know”
Qualitative echo optimization
Rationale to LV Endocardial Pacing
• Access to all regions of the LV (theoretical)
• Electrophysiological advantages: faster activation and more homogeneous transmural activation/repolarization
• Mechanical response: greater and less site‐dependent
Purkinje Endo Epi
Myerburg et al., Circ. Res. 1978
Page 27
Spragg et al JACC 2010;56:774–81
Endo vs Epi Pacing
The Future CRT Device???
Page 28
SUMMARY
Traditionally, LV leads are placed on the lateral wall of the left ventricle via the coronary sinus
More recently, studies have shown the importance of physiologically guided lead placement, based on mechanical or electrical delay
Optimal LV lead position can reduce nonresponderrates
Ultimately LV endocardial leadless pacing may be the optimal CRT pacing configuration combined with subcutaneous defibrillation leads
FREEDOM Trial Results: Primary Endpoint HF Clinical Composite Score
(Intent-to-Treat Analysis)
Treatment Control
HF CCS n % n % p-value
Improved 551 67.52 559 67.51 0.5
Unchanged 76 9.31 86 10.39
Worsened 189 23.16 183 22.10
Total 816 100 828 100
No treatment differences in pre-specified ischemic and non-ischemic sub groups
Page 29
SMART AVSMART AV
ADAPTIVE CRT
Martin et al Heart Rhythm 2012
Page 30
Are We Thinking About AV Optimization Wrong?
We can not always turn lemons into lemonade! A nonresponder may be a nonresponder (narrow QRS, scar, lead position)
However, optimal pacing may maximize a positive response
Changes in LVESV as a function of QLV and AV optimization Changes in LVESV as a function of QLV and AV optimization
Page 31
Patients with Higher Percentage Synchronized LV Pacing in the aCRTArm had a lower rate of death and HF hospitalizations
Adaptive LV Pacing Analysis1
1. Birnie D. et al., Clinical Outcomes with Synchronized Left-Ventricular Pacing: Analysis of the Adaptive CRT Trial. Heart Rhythm 2013 ( doi: 10.1016/j.hrthm.2013.07.007).
LogrankP = 0.003
AdaptivCRT™ Arm Only
Pegasus: Clinical Composite Score
N=1342
Page 32
Pivotal RCTs of CRT
• NYHA II-IV
• LVEF < 35%
• QRS > 120-130 msec
• NRS (except RAFT)
No study was restricted to LBBB or even stratified randomization by BBB
RBBB in CRT Trials
Advanced HF– MIRACLE
– CONTAK CD
– COMPANION
– CARE HF
Mild HF– REVERSE
– MADIT-CRT
– RAFT
(28)
(33)(162)
(35)
(82)
(228)(161)
Page 33
COMPANION
Bristow, N Engl J Med. 2004;350:2140‐50.
Response Measures
Category Example Advantage Disadvantage
Outcome
Measures
Mortality
Cardiac Transplant
HF Hospitalization
Well defined measures
Easy to access
Objective
Less susceptible for bias
Need large number of patients
Need long term follow‐up
Need comparison group (best with randomized controlled trial)
Differences in outcomes could be attributable to other factors
than CRT
Remodeling
Measures
LV Volumes
LV Ejection
Fraction
Standardized measures
Objective
Related to CRT effect
Need less patients
Need short term follow‐
up
Susceptible to inter‐observer variability
Affected by incomplete data/loss of follow‐up
Can be affected by attrition and detection bias
Page 34
Response Measures
Category Example Advantage Disadvantage
Clinical
Measures
NYHA functional
Class
6‐Minute Walk Test
Peak VO2
Quality of Life
Patient Global Ass.
Easy to assess
Clinically relevant
Need less patients
Need short term follow‐up
Subjective
Can be affected by performance, attrition and detection bias
Susceptible to inter‐observer variability
Affected by incomplete data/loss of follow‐up
Clinical
Composite
Measures
Composite of
above categories
Include hard outcome,
remodeling and clinical
measures
Clinically relevant
Affected by the proportion of individual measures
QLV and Reduction in MR at 6 Months
Longer QLV associated with ↓ MR at 6 months
QLV ≥ 95 msec
QLV < 95 msecChatterjee, Gold, et al, Heart Rhythm 2016