How to Use Echocardiography for. Cardiac Resynchronization Therapy WHY TRY TO IMPROVE PATIENT SELECTION FOR CRT? PROSPECT: CRT Response at 6 Months

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1 2/6/12 How to Use Echocardiography for Cardiac Resynchronization Therapy John Gorcsan, MD University of Pittsburgh, Pittsburgh, PA Disclosures: Research Grant Support: Biotronik, GE, Medtronic, St. Jude, Toshiba AHA/ACC/ESC Guidelines for Cardiac Resynchronization Therapy Patients with: NYHA class III or IV symptoms LVEF < 35% QRS > 1 msec (Class I indication. Level of Evidence: A) HOW FAR HAVE WE COME WITH CRT? CLINICAL COMPOSITE SCORE 2 1 Score (%) Clinical Composite MIRACLE TRIAL (n = 266) FREEDOM TRIAL (n = 1,525) 67% 67.5% Responders Responders 33% Non- Responders Abraham WT et al, N Eng J Med 2;24: % Non- Responders Abraham WT et al. HRS 1 WHY TRY TO IMPROVE PATIENT SELECTION FOR CRT? NonResponders 33% 67% Responders Avoid Risk of Unnecessary Complications Coronary Sinus Dissection Perforation - Tamponade Death Cost Savings $1-15, extra per CRT-D Implant Abraham W. et al Circulation 7 n = PROSPECT: CRT Response at 6 Months Dyssynchrony Clinical Composite Score % Responders 1 58% Responders p =.2 9 p <.5 8 p =.2 p =.4 7 M-Mode Pulsed TDI 2-Site No Dyssynchrony End-Systolic Volume M-Mode IVMD TDI 2-Site DYSSYNCHRONY-CRT LONG-TERM SURVIVAL STUDY n = 229 Consecutive Patients Routine CRT Indications NYHA: III (89%), IV (11%) QRS (ms) 16 ± 28, EF (%) 25 ± 7, 58% Ischemic Primary Events (4 yrs) 49 Deaths 9 Heart Transplants 6 Left Ventricular Assist Devices TRANSPLANT LVAD Gorcsan et al. Circulation 1;112 (Nov.9) 1

2 2/6/12 DYSSYNCHRONY-CRT LONG-TERM SURVIVAL STUDY Feasibility n = 229 Radial TDI Opposing TDI Speckle IVMD Wall Delay Yu Index Tracking 1 9%92% 92% 9% 89% 9 88% PROSPECT % 6 PROSPECT 5 5% 4 PROSPECT 3 1 Routine Pulsed Doppler INTERVENTRICULAR MECHANICAL DELAY Time to Pulmonic Flow Time to Aortic Flow Gorcsan et al. Circulation 1;112 (Nov.9) INTERVENTRICULAR MECHANICAL DELAY PREDICTS LONG TERM SURVIVAL from Transplant ular Assist Device Survival Free or Left Ventricu n = ms < 4ms p= (n) IVMD 4ms (n) IVMD < 4ms Gorcsan et al. Circulation 1;112 (Nov.9) TISSUE DOPPLER LONGITUDINAL VELOCITY OPPOSING WALL DELAY PREDICTS PROGNOSIS Death or Hospitalization For Heart Failure n = 85 1% 9% 8% 7% 6% 5% 4% 3% % 1% % Event Free Su urvival Dyssynchrony + CRT (> 65 ms) No Dyssynchrony + CRT (< 65 ms) p < Months After CRT Bax et al. J Am Col Cardiol;November 2, 4;44:1834 ree from Transplant ricular Assist Device Survival Fr or Left Vent n = TISSUE DOPPLER OPPOSING WALL DELAY PREDICTS LONG TERM SURVIVAL > 65 ms > 8 ms 65ms < 65ms p= ree from Transplant ricular Assist Device Survival Fr or Left Vent n = ms < 8ms p= (n) OWD 65ms (n) OWD 8ms (n) OWD < 65ms (n) OWD < 8ms Gorcsan et al. Circulation 1;112 (Nov.9) rom Transplant ar Assist Device Survival Free fr or Left Ventricula TISSUE DOPPLER YU INDEX PREDICTS LONG TERM SURVIVAL Yu Index: 12 Site Time Velocity S.D. n = ms < 32ms p= (n) Yu Index 32ms (n) Yu Index < 32ms Gorcsan et al. Circulation 1;112 (Nov.9) 2

3 2/6/12 SPECKLE TRACKING RADIAL STRAIN Normal Subject LBBB Dyssynchrony Suffoletto M Gorcsan et al. Circulation 6 (Feb 21) SPECKLE TRACKING RADIAL STRAIN PREDICTS LONG TERM SURVIVAL Anteroseptal to Posterior Wall Delay rom Transplant lar Assist Device Survival Free f or Left Ventricu n = ms 4 < 13ms p= (n) Radial Dyssynchrony 13ms (n) Radial Dyssynchrony < 13ms Gorcsan et al. Circulation 1;112 (Nov.9) Speckle Tracking And Resynchronization (STAR) Study 132 CRT pts. were prospective enrolled in the multicenter international STAR Study : University of Linz, Linz Austria University Hospital Essen, Essen Germany University of Pittsburgh, Pittsburgh, PA USA Age 66±13 years; 39% female All were NYHA class III or IV EF 24 ± 7 %, all 35% QRS duration 158 ± 26 ms, all 1ms Tanaka Gorcsan et al. European Heart Journal June 8, 1 FAST TRACK Death, Transplant ar Assist Device Freedom from or Ventricula 8 6 LONG-TERM OUTCOME AFTER CRT Radial Dyssynchrony vs. No-Dyssynchorny n= ms (n=79) 4 Radial Stra in (%) ECG Anterior Septum Posterior < 13ms (n=31) p =.19 vs. No-Dyssynchrony (n) Dyssynchrony 13ms (n) No-Dyssynchrony < 13ms Tanaka Gorcsan et al. European Heart Journal June 8, 1 FAST TRACK e from Transplant ar Assist Device Survival Free or Ventricula LONG-TERM OUTCOME AFTER CRT Transverse Dyssynchrony vs. No-Dyssynchorny n= ms (n=73) Transverse Strain (%) Septum Lateral < 13ms (n=35) p =.13 vs. No-Dyssynchrony (n) Dyssynchrony 13ms (n) No-Dyssynchrony < 13ms Tanaka Gorcsan et al. European Heart Journal June 8, 1 FAST TRACK Absence of Dyssynchrony is Associated with Serious Clinical Events After CRT th Adverse Events plant or LVAD) % of Patients Wit (Death, Trans n=11; 3.5 years Dyssynchrony No Dyssynchrony Radial Circumferential Transverse Longitudinal Combined Radial & Transverse p<.1 vs. patients with dyssynchrony p<.5 vs. circumferential and longitudinal 3

4 2/6/12 n = 397 Ischemic Disease Association of Dyssynchrony with Outcome Following CRT HF Hospitalization or Death MADIT CRT Trial 1,8 patients NYHA Class I or II Wide QRS > 13 ms, EF < 3% 34% Reduction Delgado Bax et al., Circulation 11;123:7 Moss et al. N Engl J Med. 9;361(14): MADIT-CRT Longitudinal Dyssynchrony Associated with Lower Event Rate Before CRT n = 177 After CRT Knappe D Solomon SD et al. Circ Heart Fail 11;4:433. MADIT-CRT: QRS Morphology Benefits Seen in LBBB Patients LBBB Non-LBBB September 16, 1 WASHINGTON FDA expands approval of implants for heart failure The Food and Drug Administration approved 3 implantable heart devices (cardiac resynchronization therapy defibrillators) from Boston Scientific Corp. for a new use in treating heart failure patients. The devices are implanted in the upper chest and use electrical signals to shock the heart and correct irregular beats and then coordinate its pumping action. RBBB IVCD The FDA approved the products for: A new indication in patients with mild or asymptomatic heart failure with left bundle branch block. Copyright 11 American Heart Association Zareba, W. et al. Circulation 11;123: That condition reduces the heart's pumping ability by delaying the electrical activation of its left ventricle. This means portions of the left ventricle contract later than the rest of the heart muscle. Previously the devices were only approved to treat patients with more severe heart failure. Boston Scientific said in a separate statement that the approval makes its devices the only ones approved by the FDA for all four classes of heart failure, as categorized by the New York Heart Association. The FDA based its approval on an 1,8-patient study that followed patients with left bundle branch block for three years. Patients implanted with a combination resynchronization-defibrillator had a 57 percent lower rate of death and heart failure than patients who only received a defibrillator. 4

5 2/6/12 MY REALITY CHECK Class III-IV HF Wide QRS > 15 ms or LBBB Echo Dyssynchrony is Unlikely to Change Clinical Practice in the Near Future QRS Width as a Surrogate for Dyssynchrony 1 ms 15 ms Narrow Wide LBBB Probability of Response to CRT Probability of Mechanical Dyssynchrony MADIT-CRT: LBBB vs. Non-LBBB LBBB RBBB Patient who had CRT Radial Strain (%) Posterior Wall Non-LBBB Septum Radial Dyssynchrony 293ms Zareba, W. et al. Circulation 11;123: Copyright 11 American Heart Association RBBB: Significant Radial Dyssynchrony; Long-term survivor 3 years; EF improved from 17% to 4% after CRT. QRS Morphology, Radial Dyssynchrony And Survival After CRT 1 n = 248 QRS Morphology, Interventricular Mechanical Delay And Survival After CRT rom Transplant ar Assist Device Survival Free fr or Left Ventricul p=.1 vs. LBBB or + Dyssynchrony LBBB Hara H Gorcsan J et al. ACC 11 Non-LBBB + Radial Dyssynchrony Non-LBBB No Radial Dyssynchrony ath, Transplant or r Assist Device Freedom from Dea Left Ventricular p<.1 vs. LBBB, p<.1 vs. Non-LBBB +IVMD LBBB (n=124) Non-LBBB +IVMD (n=31) Non-LBBB IVMD (n=79) Non-LBBB + IVMD (n=31) LBBB (n = 124) Non-LBBB - IVMD (n=79) Hara H Gorcsan J et al. ACC 11 5

6 2/6/12 The Benefit of CRT in QRS Duration <15 ms A Meta Analysis Stavrakis S et al. Journal of Cardiovascular Electrophysiology 11 Vol 1: 1-9 CARE-HF Required Dyssynchrony for Narrower QRS l Cause Mortality Al Cleland JGF N Eng J Med April 17 5 n = Years CRT Medical Therapy 36% Reduction p <.2 QRS 1-15 ms (2 of 3): IVMD > 4 ms Preejection Delay > 14 ms M-mode Posterior Lateral Wall Delay BORDERLINE QRS PATIENTS n = 187 Heart Failure Patients Referred for CRT Borderline QRS Wide QRS 1-13ms >13ms (n = 72) (n = 115) Age (years) 6 ± ± 11 Female 15 (32%) 37 (34%) NYHA III - IV III - IV Ischemic CM 55% 58% EF (%) 24 ± 5 24 ± 6 QRS (ms) 115 ±8 168 ±26 p<.1 vs. wide QRS Oyenuga O Gorcsan J et al. JACC imaging 1, Feb. RADIAL DYSSYNCHRONY PREDICTS REVERSE REMODELING IN BORDERLINE QRS PATIENTS n = 72 End-Systolic Volum me (ml) Radial No Radial Dyssynchrony Dyssynchrony (n=36) (n=35) Before After CRT Before After CRT p<.1 Oyenuga O Gorcsan J et al. JACC imaging 1, Feb. RethinQ Results Primary End-Point Peak O 2 Consumption n=43 n=47 n=42 n=4 Beshai et al. NEJM Nov. 6, 7 6

7 2/6/12 RETHINQ RANDOMIZED TRIAL EFFECTS ON NYHA CLASS 6 month Follow-Up n = 156 p < Improved Unchanged Worsened CRT Off CRT On Beshai et al. N Eng J Med 7; 357: Heart Failure Events In RethinQ After 6 Months Heart Failure Events (16%) n = 14 patients p = NS 41 Heart Failure Events (22%) n = 19 patients CRT Control (n= 87) (n= 85) Beshai et al. N Eng J Med 7; 357: There were 24 heart-failure events requiring intravenous therapy in 14 patients in the CRT group (16.1%) and 41 events in 19 patients in the control group (22.3%), but the difference was not significant. RETHINQ RANDOMIZED TRIAL Narrow QRS and Dyssynchrony n = 156 with Echo Dyssynchrony QRS 1-13 ms Beshai et al. NEJM Nov. 6, 7 QRS < 1 ms Randomized (1:1), prospective, doubleblinded, multi-center, international trial. NYHA Class III-IV, EF < 35%, QRS < 13 ms Tissue Doppler OW Delay > 8ms OR Narrow QRS Trial Speckle Tracking Radial Strain AS-P Delay > 13ms Primary Endpoint Evaluate the effect of CRT=ON versus CRT=OFF in time to event of a combined endpoint of death or first hospitalization for worsening HF. GOAL: Randomize ~125 pts worldwide; 11 with 2 yr. follow-up Echocardiography for Cardiac Resynchronization Therapy: Recommendations for Performance and Reporting A Report from the American Society of Echocardiography Dyssynchrony Writing Group Endorsed by the Heart Rhythm Society John Gorcsan, Theodore Abraham, Deborah A. Agler, Jeroen J. Bax, Genevieve Derumeaux, Richard A. Grimm, Randy Martin, Jonathan S. Steinberg, Martin St. John Sutton, Cheuk-Man Yu JASE 8 Volume 21, (March 8) pages E A Arrange for AV Programming if: E A Truncated A Wave AV Too Short or E Absent A Wave AV Much Too Short AV Optimization or E A A E Merged E and A AV Too Long Check: MV Inflow 1 ms 1 ms 14 ms Program 16 ms AV Delays: 18 ms ms From J. Gorcsan 2 ms 7

8 2/6/12 FREEDOM TRIAL 1,58 patients, 178 Sites, 16 Countries FREEDOM TRIAL 1,525 CRT patients with complete data Frequent AV & VV Control Group q 3 months Standard Care (n = 781) (n=744) Clinical Improvement % 66.5% 3 1 Abraham WT et al. Am Heart J 1;159: Abraham WT et al. HRS 1 SMART AV DELAY Randomized Trial: Empiric vs. Echo-Guided vs. Device-Based n = 16 enrolled, n = 98 Randomized. Enrollment and Implant CRT-D with SmartDelay Program device to VVI-4-RV SMART AV Trial Primary Endpoint LVESV Post-Implant Visit (1 to 14 days post-implant) 1:1:1 Randomization, Programmed to DDD(R)6 SmartDelay Echo (Iterative) Fixed: Empiric AV 1ms/ VV ms 3- month Visit 3- month Visit 3- month Visit 6- month Visit 6- month Visit 6- month Visit Ellenbogen et al. Circulation 1;122: Ellenbogen et al. Circulation 1;122: SMART AV Trial Primary Endpoint LVESV: Gender Subgroup Females n = 277, Males = % 67% Treatment Effect by Gender Effect of Concordance of Site of Latest Activation with LV Lead Site of Delay Lat Site of Pacing Lat None n = 5 Poslat Pos Inf Ant/Sep Poslat Pos Inf Ant/Sep EF Response Concordant Lead Position % Before After Discordant Lead Position Before After Ellenbogen et al. Circulation 1;122: Grimm R. et al. 8

9 2/6/12 Speckle Tracking Strain Localization of Site of Latest Mechanical Activation Echo-Fluoro Alignment LAO View Great Cardiac Vein Site of Latest Activation 12: Anterior Lateral 3: Lateral Posterior Lateral Miske G, Gorcsan and Saba et al. 6: Middle Cardiac Vein Posterior Saba S, Gorcsan J, et al. EXACT CONCORDANCE OF LV LEAD POSITION ACUTE IMPROVEMENTS IN LV SYNCHRONY BASELINE DAY AFTER CRT Inf 3D STRAIN MAPPING SITE OF LATEST ACTIVATION Patient A Apex Base Lat Patient B Apex Inf Base Lat Inferior Septum (n = 5) Anterior Septum Anterior Lead Placement Exact Match with Site of Latest Mechanical Activation Miske G, Gorcsan and Saba et al. ACC 1 Tanaka, H Gorcsan J et al. Am J Cardiol 9 4% 7% %18% 7% Inferior 29% Lateral 24% Posterior n = 397 LV Lead Position and Site of Latest Mechanical Activation HF Hospitalization or Death Delgado Bax et al., Circulation 11;123:7 TARGET STUDY 2 CRT patients Randomized LV Lead: Speckle Tracking Site of latest activation >1% thickening Routine Control Primary end-point: 15% Reduction in LV end systolic volume at 6 months Khan et al. ACC 11 9

10 2/6/12 TARGET Primary End-Point Results Khan et al. ACC 11 TARGET ESV response rate >15%: 7% vs. 55% in control (p=.3) TARGET Clinical response rate > 1 NYHA Class: 83% vs. 65% in control (p=.3) TARGET: Secondary End-Point HF Hospitalization or Death % Heart Failure Hospit alization or Death n = TARGET Control Time from CRT (days) Khan et al. ACC 11 Log rank p=.3 The Future? Wireless Endocardial Electrode 9 mm Wireless Endocardial Electrode Ultrasound Triggered Electrical Stimulation.5cc Electrode Delivery Catheter Epicardial border Endocardial border LV Lead (epicardial) Courtesy Faletra and Aurrichio 11 Courtesy Faletra and Aurrichio 11 TAKE HOME MESSAGES 1. There is an abundance of evidence that dyssynchrony by echo is associated with long term outcome after CRT. 2. Opportunities for Dyssynchrony by Echo to Influence Patient Care for CRT: Non-LBBB Borderline QRS Width ( ms) Narrow QRS Width (< 13 ms) Randomized Clinical Trials are Underway 3. Imaging Site of Latest Activation to Assist in Guiding Optimal LV Lead Position. 4. Future Applications for Echo in CRT Will Continue to Emerge 1