CRTD Effectiveness by QRS Duration and Morphology in

CRT-D Effectiveness by QRS Duration and Morphology in the MADIT-CRT Patients Wojciech Zareba, MD, Ph. D, Helmut Klein, MD, Iwona Cygankiewicz, MD, Ph. D, W. Jackson Hall, Ph. D, Jeffrey Goldberger, MD, James P. Daubert, MD, Michael R. Gold, MD, Mayer Rashtian, MD, Sami Viskin, MD, Wlodzimierz Kargul, MD, Heinz Pitschner, MD, Scott Mc. Nitt, MS and Arthur J. Moss, MD. University of Rochester, NY, Northestern University, Chicago, IL, Duke University, Durham, NC, Medical University of South Carolina, Charlston, SC, Foothill Cardiology/California Heart Medical Group, Pasadena, CA, Tel Aviv Sourasky Medical Center, Tela Aviv, Israel, Silesian Medical University, Katowice, Poland, Kerckhoff Medical University, Ban Neuheim, Germany

Author Disclosure Information: W. Zareba - Boston Scientific Corp. , S, I; H. Klein - LIFECOR, M, A; Boston Scientific Corp. , S, I; I. Cygankiewicz - None; W. Hall - None; J. Goldberger - None; J. P. Daubert - Boston Scientific Corp. , M, A; Medtronic, Corp. , M, A; CV Therapeutics, Inc. , M, A; Biosense Webster, Inc. , M, A; S, I; St. Jude Medical, S, I; Biotronik, S, J; M. R. Gold - None; M. Rashtian - None; S. Viskin - None; W. Kargul - None; H. Pitschner - None; S. Mc. Nitt - None; A. J. Moss - Boston Scientific Corp. , S, I.

Multicenter Automatic Defibrillator Implantation Trial – Cardiac Resynchronization Therapy (MADIT-CRT) Moss et al. N Engl J Med 2009; 361: 1329 -1338

Entry Criteria: n Ischemic NYHA I-II or non-ischemic NYHA class II n EF<0. 30 n QRS >0. 13 sec n Sinus Rhythm n Optimal pharmacologic therapy: B-b (>3 mo. ); ACE/ARB (>1 mo. ); statins in IHD MADIT-CRT ICM NYHA I/II and NICM NYHA II EF < 0. 30; QRS >0. 13 sec Randomization N=1, 820 Exclusions: n NYHA III-IV <90 days PTE n Acute MI, CABG, PCI <3 months n Existing ICD or CRT device n AF; PR>250 ms; 2 nd or 3 rd degree HB n BUN >70 mg/dl or creatinine >3. 0 mg/dl ICD only CRT-D N=731 N=1, 089

MADIT-CRT: Baseline Clinical Characteristics Variable ICD (N = 731) Age (yrs) 64+11 Males 553 (76%) Ischemic heart disease NYHA class I 113 (16%) NYHA class II 288 (39%) Nonischemic heart disease NYHA class II 330 (45%) EF 24+5 Moss AJ et al. N Engl J Med 2009; 361: 1329 -1338 CRT-ICD (N = 1089) 65+11 814 (75%) 152 (14%) 446 (41%) 491 (45%) 24+5

Kaplan-Meier Estimates of the Probability of Survival Free of Heart Failure Moss AJ et al. N Engl J Med 2009; 361: 1329 -1338

Hazard Ratio for CRT-D vs. ICD only in MADIT-CRT HR (95% CI) P Value Heart failure or Death 0. 66 (0. 52– 0. 84) 0. 001 Heart failure only 0. 59 (0. 47– 0. 74) <0. 001 Death at any time 1. 00 (0. 69– 1. 44) 0. 99

Changes in Mean Echocardiographic Left Ventricular Volumes and Ejection Fraction between Baseline and 1 -Year Follow-up Moss AJ et al. N Engl J Med 2009; 361: 1329 -1338

Effects of CRT-D by QRS Morphology in MADIT-CRT Non-LBBB 534, 30%

Baseline Clinical Characteristics of MADIT-CRT Patients by QRS Morphology Clinical Characteristics LBBB n=1, 281 Non-LBBB n=536 RBBB n=228 IVCD n=308 Age (yrs) 64± 11 65± 10 66± 10* 64± 10 Females 394 (31%) 59 (11%)† 18 (8%)† 41 (13%)† Ischemic NYHA class I 143 (11%) 120 (22%)† 47 (21%)† 73 (24%)† Ischemic NYHA class II 420 (33%) 314 (58%)† 150 (66%)† 164 (53%)† Nonischemic NYHA class II 718 (56%) 102 (19%)† 31 (14%)† 71 (23%)† Prior hospitalization 563 (45%) 274 (52%) 112 (50%) 162 (53%) EF (%) 23. 5± 5. 3 24. 5± 5. 0† 25. 2± 5. 0† 23. 9± 5. 2† QRS (ms) 163± 19 146± 15† 153± 15† 142± 14† 21± 9 22± 9 21± 9 1. 14± 0. 32 1. 23± 0. 46† 1. 28± 0. 53 1. 18± 0. 40† BUN (mg/dl) Creatinine (mg/dl) * P<0. 05; † P<0. 01 when comparing with LBBB patients

Baseline Clinical Characteristics of MADIT-CRT Patients by QRS Morphology Clinical Characteristics LBBB n=1, 281 Non-LBBB n=536 RBBB n=228 IVCD n=308 Echo Parameters LVEDV (ml) 251± 66 242± 52* 231± 45† 250± 54* LVESV (ml) 180± 53 171± 41† 162± 35† 177± 43† LAV (ml) 94± 22 93± 21 92± 22 94± 20 ACE Inhibitors 982 (77%) 418 (78%) 177 (78%) 241 (78%) Ang. Rec. Blockers 278 (22%) 98 (18%) 42 (18%) 56 (18%) Beta-blockers 1204 (94%) 490 (91%)* 202 (89%)† 288 (94%) Diuretics 873 (68%) 353 (66%) 206 (67%) Medication: 147 (64%) * P<0. 05; † P<0. 01 when comparing with LBBB patients

Cumulative Probability of Heart Failure (HF) Event or Death by Treatment (CRT-D vs. ICD only) in patients with LBBB and Non. LBBB QRS Pattern in MADIT-CRT Patients LBBB Non-LBBB

Cumulative Probability of Heart Failure (HF) Event or Death by Treatment (CRT-D vs. ICD only) in patients with RBBB and IVCD QRS Pattern in MADIT-CRT Patients RBBB IVCD

Cumulative Probability of VT/VF or Death by Treatment (CRT-D vs. ICD only) in patients with LBBB and Non-LBBB QRS Pattern in MADIT-CRT Patients LBBB Non-LBBB

Cumulative Probability of Death by Treatment (CRT-D vs. ICD only) in patients with LBBB and Non-LBBB QRS Pattern in MADIT-CRT Patients LBBB Non-LBBB

Hazard Ratios for Clinical Endpoints by QRS Morphology Endpoint Heart Failure Event or Death Heart Failure Event Death LBBB n=1, 281 Non-LBBB n=536 P value for Interaction HR 95% CI P value 0. 47 0. 37, 0. 61 <0. 001 1. 24 0. 85, 1. 81 0. 257 <0. 001 HR 95% CI P value 0. 41 0. 31, 0. 54 <0. 001 1. 23 0. 76, 1. 68 0. 559 <0. 001 HR 95% CI P value 0. 75 0. 49, 1. 16 0. 196 1. 79 0. 90, 3. 57 0. 097 0. 037 * The model adjusted for sex, ischemic or nonischemic cardiomyopathy, prior hospitalizations for heart failure, ejection fraction, QRS>150, left ventricular ejection fraction, left ventricular end-systolic volume.

Hazard Ratios for Clinical Endpoints by QRS Morphology Endpoint VT/VF HR 95% CI P value 0. 67 0. 52, 0. 87 0. 002 Non-LBBB P value for n=536 Interaction 1. 11 0. 77, 1. 60 0. 574 0. 028 VF HR 95% CI P value 0. 54 0. 33, 0. 87 0. 011 1. 24 0. 58, 2. 66 0. 585 0. 070 HR 95% CI P value 0. 69 0. 55, 0. 87 0. 002 1. 21 0. 87, 1. 69 0. 254 0. 006 VT/VF/Death LBBB n=1, 281 * The model adjusted for sex, ischemic or nonischemic cardiomyopathy, prior hospitalizations for heart failure, ejection fraction, QRS>150, left ventricular ejection fraction, left ventricular end-systolic volume.

Hazard Ratios for Primary and Secondary Endpoints by QRS Morphology in MADIT-CRT * * *p<0. 05

Hazard Ratios for Primary Endpoint by QRS Morphology and Duration by Gender Males n P value Females n HR P value QRS Duration <140 ms 140 -159 ms 160 -179 ms ≥ 180 ms 240 465 417 242 1. 69 0. 77 0. 51 0. 50 0. 063 0. 164 0. 003 0. 019 61 178 153 61 0. 20 0. 31 0. 42 0. 33 0. 008 0. 001 0. 036 0. 100 QRS Morphology LBBB* Non-LBBB RBBB IVCD 887 477 210 267 0. 56 1. 25 0. 94 1. 49 <0. 001 0. 273 0. 841 0. 133 394 59 18 41 0. 25 1. 55 NA 1. 31 <0. 001 0. 516 0. 701 * p=0. 006 for interaction comparing HR = 0. 56 in males vs. HR = 0. 25 in females

Mean Change in Echocardiographic Parameters from Enrollment to 12 months in CRT-D Patients * * p<0. 001 when comparing LBBB and Non-LBBB patients (all changes within subgroups were significant)

Conclusions 1. Heart failure patients with NYHA class I or II and ejection fraction ≤ 30% who present with LBBB derive substantial benefit from CRT-D: reduction in heart failure progression and reduction in the risk of ventricular tachyarrhythmias. 2. No evidence of CRT-D benefit was observed in patients with Non-LBBB QRS pattern: RBBB or IVCD regardless of their QRS duration. 3. Beneficial effect of CRT-D in LBBB patients was observed in all studied subjects: males and females, ischemic and non-ischemic, QRS>150 and QRS<150 ms.