It has been shown from meta-analysis of randomized clinical trials that patients with a pre-crt QRS duration (QRSD) >150 ms benefit

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Cardiac Resynchronization Therapy may be detrimental in patients with a Very Wide QRSD > 180 ms (VWQRSD) and Right Bundle Branch Block Morphology: Analysis From the Medicare ICD Registry Varun

1 Cardiac Resynchronization Therapy may be detrimental in patients with a Very Wide QRSD > 180 ms (VWQRSD) and Right Bundle Branch Block Morphology: Analysis From the Medicare ICD Registry Varun Sundaram MD, Kenneth C. Bilchick MD, Albert L. Waldo MD, PhD (Hon), Yogesh N. V. Reddy MD, Samuel J. Asirvatham MD, Judith A. Mackall MD, Anselma Intini MD, Brigid Wilson PhD, Daniel I. Simon MD, Jayakumar Sahadevan MD. Disclosures; None

2 Background It has been shown from meta-analysis of randomized clinical trials that patients with a pre-crt QRS duration (QRSD) >150 ms benefit more than QRSD of ms However, the benefits in the group of patients with a very wide QRSD 180 ms (VWQRSD) has not been well studied, as these patients were under-represented in CRT trials Sipahi I et al, Am Heart J 2012;163(2): Cleland JG et al, Eur Heart J 2013;32(46):

Causes of wide QRS complex Conduction block

Electrical uncoupling Isolated diffuse left

working myocardium alone produces a QRSD of

electrical uncoupling, the With true left

the range of 140 benefits +/- 16 ms, of and

branch slow and block dispersed (RBBB), the

Any further widening of the QRSD beyond 140

BBB and electrical uncoupling Potse M et al.

3 Causes of wide QRS complex Conduction block (LBBB, RBBB, IVCD) Combination of both Electrical uncoupling Isolated diffuse left ventricular electrical uncoupling of the working myocardium alone produces a QRSD of 120 +/- 10ms In the presence of significant electrical uncoupling, the With true left bundle branch block (LBBB), the QRSD is in the range of 140 benefits +/- 16 ms, of and CRT with may true be right negated bundle by branch slow and block dispersed (RBBB), the QRSD is even less conduction during pacing Any further widening of the QRSD beyond 140 ms +/- 16 ms is due to a combined effect of BBB and electrical uncoupling Potse M et al. Europace 2012;14: v33 v39 Potse M et al. J Cardiovasc Transl Res 2012;5:

4 Role of Cardiac Resynchronization Therapy (CRT) BBB like morphology? QRS < 130 ms QRS 140 ms +/- 16 ms QRS > 180 ms Electrical uncoupling True BBB Combination of both BBB and electrical uncoupling ECHO CRT trial. Frank Ruschitzka, et al, N Engl J Med 2013; 369:

$Methods Included patients with a left ventricular ejection fraction (LVEF) 35% and evidence of electrical dyssynchrony, defined by a QRSD 120 ms from the Medicare ICD$ and April 2006) Classified into 3 groups based on their QRS interval 120-149 ms 150-179 ms > 180 ms HYPOTHESIS When stratified by BBB morphology, patients with a VWQRSD

and April 2006) Classified into 3 groups based on their QRS interval 120-149 ms 150-179 ms > 180 ms HYPOTHESIS When stratified by BBB morphology, patients with a VWQRSD

5 Methods Included patients with a left ventricular ejection fraction (LVEF) 35% and evidence of electrical dyssynchrony, defined by a QRSD 120 ms from the Medicare ICD registry All patients included in the analysis survived at least three days after CRT-D implantation Final analysis N=14,902 patients (Received CRT-D between Jan 2005 and April 2006) Classified into 3 groups based on their QRS interval ms ms > 180 ms HYPOTHESIS When stratified by BBB morphology, patients with a VWQRSD ( 180 ms) had worse clinical outcomes than those with a QRSD of ms. Follow up of 6 years Outcomes 1. Death 2. Composite of death and heart failure hospitalization (HFH)

6 RESULTS: Table 1 Demographics by QRS group Variable Group 1 Group 2 Group 3 QRS ms QRS ms QRS >= 180 ms P value (n=6010) (n=5983) (n=2909) Age, mean +/SD yrs 72.4± ± ±10.4 < BBB Morphology LBBB n (%) 3,928 (65.3%) 4,383 (73.3%) 2,019 (69.4%) < RBBB n (%) 705 (11.7%) 708 (11.8%) 218 (7.5%) < IVCD n (%) 1,377 (22.9%) 892 (14.9%) 672 (23.1%) < LVEF mean +/-SD % 23.4± ± ±6.3 < SBP, mean +/- SD, mm Hg 126.7± ± ± DBP, mean +/- SD, mm Hg 70.4± ± ± Gender n (%) Male 4,316 (71.8%) 4,225 (70.6%) 2,287 (78.6%) <0.001 Female 1,694 (28.2%) 1,758 (29.4%) 622 (21.4%) <0.001 NYHA n (%) Class I 62 (1.03%) 76 (1.27%) 43 (1.48%) 0.5 Class II 667 (11.1%) 654 (10.9%) 317 (10.9%) 0.56 Class III 4,482 (74.6%) 4,426 (74.0%) 2,141 (73.6%) 0.56 Class IV 799 (13.3%) 827 (13.8%) 408 (14.0%) 0.56

7 RESULTS: Table 1 Demographics by QRS group Group 1 Group 2 Group 3 Variable QRS ms QRS ms QRS >= 180 ms P value (n=6010) (n=5983) (n=2909) Ischemic CM, n (%) 4288 (71.4%) 4056 (67.8%) 1965 (67.6%) < Atrial fibrillation, n (%) 1995 (33.2%) 1978 (33.1%) 1198 (41.2%) < Ventricular Tachycardia, n (%) 1196 (19.9%) 1144 (19.1%) 582 (20.0%) 0.46 Sudden Cardiac arrest, n (%) 95 (1.58%) 91 (1.52%) 69 (2.37%) Diabetes Mellitus, n (%) 2202 (36.6%) 2160 (36.1%) 960 (33.0%) Medications Beta Blockers 4727 (78.7%) 4748 (79.4%) 2283 (78.5%) 0.53 ACEI/ARB 4452 (74.1%) 4463 (74.6%) 2150 (73.9%) 0.72 Diuretic 4686 (78.0%) 4686 (78.3%) 2351 (80.8%) Amiodarone 694 (11.6%) 789 (13.2%) 540 (18.6%) < Digoxin 2391 (39.8%) 2472 (41.3%) 1349 (46.4%) < Coumadin 1811 (30.1%) 1811 (30.3%) 1119 (38.5%) <0.0001

8 Table 2 : Multivariable HRs for Early/Intermediate Time Points -- Death Outcome Adjusted HR for Mortality at 1 yr (95% CI) P value Adjusted HR for Mortality at 3 yrs (95%CI) P value Age (per year) ( ) < ( ) < Female Gender 0.89 ( ) ( ) < QRS ms LBBB (REF) 1.00 N/A 1.00 N/A RBBB 1.48 ( ) ( ) < IVCD 1.30 ( ) ( ) QRS ms LBBB 1.33 ( ) < ( ) < RBBB 1.65 ( ) < ( ) < IVCD 1.53 ( ) < ( ) < QRS >=180 ms LBBB 0.88 ( ) ( ) 0.63 RBBB 1.74 ( ) ( ) < IVCD 1.01 ( ) ( ) <0.0001

9 Table 2 : Multivariable HRs for Early/Intermediate Time Points -- Death Outcome Adjusted HR for Mortality at 1 yr (95% CI) P value Adjusted HR for Mortality at 3 yrs (95% CI) P value Ischemic CM 1.31 ( ) < ( ) < Atrial Fibrillation 1.24 ( ) < ( ) < Diabetes Mellitus 1.36 ( ) < ( ) < Ventricular Tachycardia 1.13( ) 00-Jan ( ) NYHA Class (REF=II) Class III 1.46 ( ) < ( ) < Class IV 2.64 ( ) < ( ) < LVEF (per 0.01) ( ) < ( ) < Systolic BP (per mm Hg) ( ) < ( ) < Diastolic BP (per mm Hg) ( ) 00-Jan ( ) Beta Blockers 0.89 ( ) 00-Jan ( ) < ACEI/ARB 0.65 ( ) < ( ) < Diuretic 1.13 ( ) 00-Jan ( ) < Amiodarone 1.34 ( ) < ( ) <

10 Table 3: Multivariable HRs for Early/Intermediate Time Points Death/HF hospitalization Outcome Adjusted HR for Death/HF at 1 Year (95% CI) P value Adjusted HR for Death/HF at 3 Years (95% CI) P value Age (per year) ( ) ( ) < Female Gender 1.04 ( ) ( ) 0.26 QRS ms LBBB (REF) 1.00 N/A 1.00 N/A RBBB 1.40 ( ) < ( ) < IVCD 1.10 ( ) ( ) 0.1 QRS ms LBBB 1.31 ( ) < ( ) < RBBB 1.43 ( ) < ( ) < IVCD 1.39 ( ) < ( ) < QRS >=180 ms LBBB 0.88 ( ) ( ) 0.67 RBBB 1.68 ( ) < ( ) < IVCD 1.02 ( ) ( ) 0.76

11 Figure1: Adjusted hazard ratios/95% confidence intervals for death at 6 years in a Cox Proportional Hazard model

12 Figure 2 (A, B, C): Kaplan Meyer 6 year survival plots for freedom from death (within each BBB group) Figure 2A: LBBB Figure 2B: RBBB Figure 2C: IVCD Freedom from death A (LBBB); 3 groups, p< for QRS ms v QRS ms, p= for QRS ms v QRS> 180 ms, p< for QRS ms v QRS> 180 ms, overall log-rank p < Time (yrs) B (RBBB); 3 groups, p=0.04 for QRS> 180 ms vs QRS ms, overall log-rank p = 0.07 C (IVCD); 3 groups, overall log-rank p =0.49

13 Figure 3 (A, B, C): Kaplan Meyer 6 year survival plots for freedom from death/hfh (within each BBB group) Figure 3A: LBBB Figure 3B: RBBB Figure 3C: IVCD Freedom from death / HFH p< for QRS ms v QRS ms, p< for QRS ms v QRS> 180 ms, p= for QRS ms v QRS> 180 ms, overall log-rank p < Time (yrs) p=0.10 for QRS> 180 ms v QRS ms, overall log-rank p = 0.15 p=0.08 for QRS ms v QRS ms, p=0.03 for QRS ms v QRS> 180 ms, overall log-rank p =0.08

14 Major findings In patients with RBBB, clinical outcomes with VWQRSD ( 180 ms) were worse when compared to a QRSD of ms and a QRSD of ms. There appears to be an incremental risk within this group that increases with patients in the higher end of this range (QRSD > ms). In patients with LBBB, clinical outcomes with VWQRSD ( 180 ms) were similar when compared to LBBB patients with QRSD of ms. 14

15 Limitations The Medicare ICD registry had a wide range of patient information, but certain important patient characteristics, such as biomarkers and right ventricular function, were missing No follow up ECGs or echocardiograms which are markers of the remodeling effects of CRT implantation 15

16 In Conclusion VWQRSD prior to CRT implantation has complex long-term effects on prognosis after resynchronization, with a dependency on BBB morphology. In patients with RBBB, a VWQRSD is possibly a marker of advanced electrical remodeling and suggests that CRT may be ineffective in restoring synchronous contraction. Outcomes were worst for the narrower QRSD group in LBBB, and the VWQRSD group in RBBB. 16

17 Thank you Veteran Affairs Medical Center, Cleveland 17

The Role of Ventricular Electrical Delay to Predict Left Ventricular Remodeling With Cardiac Resynchronization Therapy

The Role of Ventricular Electrical Delay to Predict Left Ventricular Remodeling With Cardiac Resynchronization Therapy Results from the SMART-AV Trial Michael R. Gold, MD, PhD, Ulrika Birgersdotter-Green,