How do I convert my CRT Non Responder into Responder? · 7/27/2011 · CRT -D p = 0.006 HR = 0.71...

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

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

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

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.

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

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

Nonresponder Rates

NonrespondersMagnitude of response is Dependent

on Variable Measured

Birnie. Curr Opin Cardiol. 2006;21:20-26.

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

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

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.

ll1 left bundle vs non-left bundle?landbl1, 7/27/2011

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

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

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

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

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%

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

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

Interventricular Electrical DelayInterventricular Electrical Delay

Association of RV-LV Time with LV Remodeling and QOL

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

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

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.

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

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

Patient 1

… a total of 30 experienced echocardiographers choose an option for 20 sets of images …


Patient 1

0

5

10

15

20

25

30

35

40

A B C D E F

1

56

11

6

1


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


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”

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”


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

Spragg et al JACC 2010;56:774–81

Endo vs Epi Pacing

The Future CRT Device???

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

SMART AVSMART AV

ADAPTIVE CRT

Martin et al Heart Rhythm 2012

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

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

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)

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

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

How do I convert my CRT Non Responder into Responder? · 7/27/2011 · CRT -D p = 0.006 HR = 0.71...

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Transcript of How do I convert my CRT Non Responder into Responder? · 7/27/2011 · CRT -D p = 0.006 HR = 0.71...