How do I convert my CRT Non Responder into Responder?

Transcription

1 How do I convert my CRT Non Responder into Responder? Michael R Gold, MD, PhD Medical University of South Carolina Charleston, SC Disclosures: Clinical Trials and Consulting Boston Scientific, Medtronic MIRACLE 6-Minute Hall Walk P=0.032 P=0.004 P=0.033 Meters Control N=116 CRT N= Baseline 1 Month 3 Months 6 Months Page 1

2 Quality of Life Minnesota Living With Heart Failure Score MIRACLE Total Score 30 P=0.020 P=0.051 P=0.013 Improvement Baseline 1 Month 3 Months 6 Months Control N=114 CRT N=121 MIRACLE Echocardiographic Parameters LVEDD LVEF 7.50 P< P<0.001 Centimeters Control N=63 Baseline CRT N=61 6-Months Percentage Control N=81 Baseline CRT N=63 6-Months Page 2

3 COMPANION: Primary Endpoint Death or Any Hospitalization CARE HF: All-Cause Mortality 1.00 HR 0.64 (95% CI 0.48 to 0.85) Event-free Survival CRT P =.0019 Medical Therapy Number at risk CRT Medical Therapy Days Page 3

4 REVERSE: Clinical Composite Response P = % 40% 39% 30% P = % 16% Improved Unchanged Worsened CRT OFF (n=191) CRT ON (n=419) MADIT-CRT: Kaplan-Meier Estimate of Heart-failure Free Survival Probability N = 1820 P<0.001 Average FU = 2.4 yrs. Page 4

5 RAFT: All Cause Mortality Mortality Rate 50% 40% 30% 20% 10% p = HR = 0.71 ( ) ICD CRT -D 0% Months Since Randomization Number remaining Tang et al, NEJM 9 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 5

6 Nonresponders Most clinical studies report CRT nonresponder 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 6

7 Nonresponder Rates Nonresponders Magnitude of response is Dependent on Variable Measured Birnie. Curr Opin Cardiol. 2006;21: Page 7

8 What defines a responder vs. "non-responder"? Status CRT Implantation Super- Responder Responder "Non progressor" Negative responders Non-responder Time Steffel & Ruschitzka, Circulation 2015 REVERSE: Mortality Rate After LVESVi Change Gold et al, Page 8

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 9

10 REVERSE: Clinical Composite Subgroup Analysis ll1 Odds Ratio with 95% CI Odds Ratio with 95% CI All Patients Ischemic Non-ischemic Interaction P-value 0.26 < 65 yrs > 65 yrs 0.75 CRT-P CRT-D 0.52 Non-white White 0.60 NYHA Class I NYHA Class II Male Female LBBB RBBB IVCD CRT ON CRT OFF Better Better CRT ON CRT OFF Better Better 19 QRSd 150 ms Stavrakis S, et al. J Cardiovasc Electrophysiol 2012;23: Page 10

11 Slide 19 ll1 left bundle vs non-left bundle? landbl1, 7/27/2011

12 QRSd <150 ms Stavrakis S, et al. J Cardiovasc Electrophysiol 2012;23: Change in LVESVi by QRS Width Baseline QRS Width (ms) (n=128) (n=132) (n=118) (n=125) CRT ON (n=340) CRT OFF (n=163) 36.1 Gold et al, Mean Improvement in LVESVi (ml/m 2 ) at 12 Months Page 11

13 Individual Patient Meta-analysis of CRT Trials After adjusting for QRS duration Prognostic Benefit of CRT Not 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 12

14 BBB Morphology and Width after CRT-D Outcomes Among 24,169 Medicare Beneficiaries All-Cause Mortality by QRS Morphology and Width All-Cause Readmission by QRS Morphology and Width Peterson et al. JAMA Modifiable Risk Factors Heart Failure Medications Treating comorbidities COPD Sleep Apnea Renal Failure Diabetes LV lead position? Device programming Page 13

15 LV Lead Location: COMPANION LV Lead Position & Clinical Outcome Death &/or Heart Failure Anterior, posterior and lateral position Apical versus Non-apical position 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 midventricular and basal Page 14

16 Site-Specific Pacing: Targeting mechanical dyssynchrony Ypemburg et al. J Am Coll Cardiol 2008; 52: Murphy et al, Am J Cardiol, 2006;97: Imaging Guided LV Lead Positioning TARGET & 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 15

17 Physiologic Guided Lead Positioning: QLV Interval Measurement Q-LV Interval to Predict Acute Response R = 0.74 %LV+ dp/dtmax R NR Q-LV (ms) Gold et al, J Cardiovasc Electrophysiol 2014 Page 16

18 Impact of QLV on Reverse and QOL with CRT Gold et al, Eur Heart J LVESV Response by Subgroup Univariate Logistic Regression Results Page 17

19 Interventricular Electrical Delay Association of RV-LV Time with LV Remodeling and QOL Page 18

20 RV-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 19

21 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 20

22 The Initial Evaluation NON-RESPONDER CXR Lateral Wall (Mid-Ventricular) LV and RV capture AF Device Interrogation ECG Paced and Unpaced Dislodged into CS Lead Position Consider Reversible Causes Non-responder Atrial Fibrillation Volume Status Cardiac Ischemia Other Co-morbidities Maintain NSR Rate control (AVN vs. MED) Adjust upper pacing rate Program VVIR/VS Response Individualize strategy (LV) Rule out ischemia Treat ischemia Depression COPD Arthritis Anemia etc. Page 21

23 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 noncardiac contributing causes Page 22

24 Iterative Method Too Short Optimal Too Long E A E A E A Truncated E<A Fused Qualitative echo optimization Question: Are echocardiographic experts able to identify optimal AV intervals? Nijjer SS,.. Francis DP J Am Coll Cardiol Img 2012:5: Page 23

25 Qualitative echo optimization Patient 1 a total of 30 experienced echocardiographers choose an option for 20 sets of images Qualitative echo optimization Patient A B C D E F Page 24

26 Qualitative echo optimization 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 Patient 1 2 A Patient 11 but really same Doppler as 1 A 5 5 B B 8 5 C C 4 9 D D 9 6 E E 4 2 F AV optimisation on first viewing F 0 AV optimisation on second viewing of identical data Page 25

27 Qualitative echo optimization Operators disagreed with each other Operators 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 Purkinje Endo Epi Myerburg et al., Circ. Res Mechanical response: greater and less site dependent Page 26

28 Endo vs Epi Pacing Spragg et al JACC 2010;56: The Future CRT Device??? Page 27

29 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 nonresponder rates 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 Unchanged Worsened Total No treatment differences in pre-specified ischemic and non-ischemic sub groups Page 28

30 SMART AV ADAPTIVE CRT Martin et al Heart Rhythm 2012 Page 29

31 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 Page 30

32 Adaptive LV Pacing Analysis 1 Patients with Higher Percentage Synchronized LV Pacing in the acrt Arm had a lower rate of death and HF hospitalizations AdaptivCRT Arm Only Logrank P = Birnie D. et al., Clinical Outcomes with Synchronized Left-Ventricular Pacing: Analysis of the Adaptive CRT Trial. Heart Rhythm 2013 ( doi: /j.hrthm ). Pegasus: Clinical Composite Score N=1342 Page 31

33 Pivotal RCTs of CRT NYHA II-IV LVEF < 35% QRS > msec NRS (except RAFT) No study was restricted to LBBB or even stratified randomization by BBB RBBB in CRT Trials Advanced HF MIRACLE (28) CONTAK CD (33) COMPANION (162) CARE HF (35) Mild HF REVERSE (82) MADIT-CRT (228) RAFT (161) Page 32

34 COMPANION Bristow, N Engl J Med. 2004;350: Response Measures Category Example Advantage Disadvantage Outcome Mortality Well defined measures Need large number of patients Measures Cardiac Transplant Easy to access Need long term follow up HF Hospitalization Objective Need comparison group (best with randomized controlled trial) Less susceptible for bias Differences in outcomes could be attributable to other factors than CRT Remodeling LV Volumes Standardized measures Susceptible to inter observer variability Measures LV Ejection Objective Affected by incomplete data/loss of follow up Fraction Related to CRT effect Can be affected by attrition and detection bias Need less patients Need short term followup Page 33

35 Response Measures Category Example Advantage Disadvantage Clinical NYHA functional Easy to assess Subjective Measures Class Clinically relevant Can be affected by performance, attrition and detection bias 6 Minute Walk Test Need less patients Susceptible to inter observer variability Peak VO2 Need short term follow up Affected by incomplete data/loss of follow up Quality of Life Patient Global Ass. Clinical Composite of Include hard outcome, Affected by the proportion of individual measures Composite above categories remodeling and clinical Measures measures Clinically relevant QLV and Reduction in MR at 6 Months Longer QLV associated with MR at 6 months QLV 95 msec QLV < 95 msec Chatterjee, Gold, et al, Heart Rhythm 2016 Page 34