CRT-D Effectiveness by QRS Duration and Morphology in the MADIT-CRT Patients

Wojciech Zareba, MD, PhD, Helmut Klein, MD, Iwona Cygankiewicz, MD, PhD, W. Jackson Hall, PhD, Jeffrey

Goldberger, MD, James P. Daubert, MD, Michael R. Gold, MD, Mayer Rashtian, MD, Sami Viskin, MD, Wlodzimierz Kargul, MD, Heinz Pitschner, MD, Scott McNitt, MS and Arthur J. Moss, MD.

University of Rochester, 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:Author Disclosure Information:      

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

Moss et al. N Engl J Med 2009;361:1329-1338

Multicenter Automatic Defibrillator Implantation Multicenter Automatic Defibrillator Implantation Trial – Cardiac Resynchronization TherapyTrial – Cardiac Resynchronization Therapy

(MADIT-CRT)(MADIT-CRT)

MADIT-CRTMADIT-CRTEntry Criteria:Entry Criteria: Ischemic NYHA I-IIIschemic NYHA I-II

or non-ischemic NYHA class II or non-ischemic NYHA class II EFEF<<0.300.30 QRS QRS >>0.13sec0.13sec Sinus RhythmSinus Rhythm Optimal pharmacologic therapy: Optimal pharmacologic therapy:

B-b (>3 mo.); ACE/ARB (>1 mo.); statins in IHDB-b (>3 mo.); ACE/ARB (>1 mo.); statins in IHD

Exclusions:Exclusions: NYHA III-IV <90 days PTENYHA III-IV <90 days PTE Acute MI, CABG, PCI <3 monthsAcute MI, CABG, PCI <3 months Existing ICD or CRT deviceExisting ICD or CRT device AF; PRAF; PR>>250ms; 2250ms; 2ndnd or 3 or 3rdrd degree HB degree HB BUN >70mg/dl or creatinine >3.0mg/dlBUN >70mg/dl or creatinine >3.0mg/dl

RandomizationRandomizationN=1,820N=1,820

CRT-DCRT-DN=1,089 N=1,089

ICM NYHA I/II and ICM NYHA I/II and NICM NYHA II NICM NYHA II EF EF << 0.30; QRS 0.30; QRS

>>0.13sec0.13sec

ICD onlyICD onlyN=731 N=731

MADIT-CRT: Baseline Clinical Characteristics

Moss AJ et al. N Engl J Med 2009;361:1329-1338

Variable ICD CRT-ICD(N = 731) (N = 1089)

Age (yrs) 64+11 65+11Males 553 (76%) 814 (75%)Ischemic heart diseaseNYHA class I 113 (16%) 152 (14%)NYHA class II 288 (39%) 446 (41%)Nonischemic heart diseaseNYHA class II 330 (45%) 491 (45%)EF 24+5 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

HRHR (95% CI) (95% CI) P ValueP Value

Heart failure or DeathHeart failure or Death 0.66 0.66 (0.52–0.84)(0.52–0.84) 0.0010.001

Heart failure onlyHeart failure only 0.59 0.59 (0.47–0.74) (0.47–0.74) <0.001<0.001

Death at any timeDeath at any time 1.00 1.00 (0.69–1.44) (0.69–1.44) 0.990.99

Hazard Ratio for CRT-D vs. ICD only in MADIT-CRTHazard Ratio for CRT-D vs. ICD only in MADIT-CRT

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 Effects of CRT-D by QRS Morphology in MADIT-CRTMorphology in MADIT-CRT

LBBB, 1281, 70%

RBBB, 228, 13%

IVCD, 306, 17%Non-LBBBNon-LBBB

534, 30%534, 30%

Clinical Characteristics LBBBn=1,281

Non-LBBBn=536

RBBBn=228

IVCDn=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†

BUN (mg/dl) 21±9 22±9 22±9 21±9

Creatinine (mg/dl) 1.14±0.32 1.23±0.46† 1.28±0.53 1.18±0.40†

Baseline Clinical Characteristics of MADIT-CRT Patients Baseline Clinical Characteristics of MADIT-CRT Patients by QRS Morphologyby QRS Morphology

* P<0.05; † P<0.01 when comparing with LBBB patients* P<0.05; † P<0.01 when comparing with LBBB patients

Clinical Characteristics LBBBn=1,281

Non-LBBBn=536

RBBBn=228

IVCDn=308

Echo ParametersEcho 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

Medication:

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%) 147 (64%) 206 (67%)

Baseline Clinical Characteristics of MADIT-CRT Patients Baseline Clinical Characteristics of MADIT-CRT Patients by QRS Morphologyby QRS Morphology

* P<0.05; † P<0.01 when comparing with LBBB patients* P<0.05; † P<0.01 when comparing with LBBB patients

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

LBBB QRS Pattern in MADIT-CRT PatientsLBBB QRS Pattern in MADIT-CRT Patients

LBBBLBBB Non-LBBBNon-LBBB

RBBBRBBB IVCDIVCD

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

QRS Pattern in MADIT-CRT PatientsQRS Pattern in MADIT-CRT Patients

LBBBLBBB Non-LBBBNon-LBBB

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

in MADIT-CRT Patientsin MADIT-CRT Patients

LBBBLBBB Non-LBBBNon-LBBB

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

in MADIT-CRT Patientsin MADIT-CRT Patients

Endpoint LBBBn=1,281

Non-LBBBn=536

P value for Inter-action

Heart Failure Event HR 0.47 1.24

or Death 95% CI 0.37,0.61 0.85,1.81

P value <0.001 0.257 <0.001

Heart Failure Event HR 0.41 1.23

95% CI 0.31,0.54 0.76,1.68

P value <0.001 0.559 <0.001

Death HR 0.75 1.79

95% CI 0.49,1.16 0.90,3.57

P value 0.196 0.097 0.037

Hazard Ratios for Clinical Endpoints by QRS MorphologyHazard Ratios for Clinical Endpoints by QRS Morphology

* The model adjusted for sex, ischemic or nonischemic cardiomyopathy, prior * The model adjusted for sex, ischemic or nonischemic cardiomyopathy, prior hospitalizations for heart failure, ejection fraction, QRS>150, left ventricular ejection hospitalizations for heart failure, ejection fraction, QRS>150, left ventricular ejection fraction, left ventricular end-systolic volume. fraction, left ventricular end-systolic volume.

Endpoint LBBBn=1,281

Non-LBBBn=536

P value for Inter-action

VT/VF HR 0.67 1.11

95% CI 0.52,0.87 0.77,1.60

P value 0.002 0.574 0.028

VF HR 0.54 1.24

95% CI 0.33,0.87 0.58,2.66

P value 0.011 0.585 0.070

VT/VF/Death HR 0.69 1.21

95% CI 0.55,0.87 0.87,1.69

P value 0.002 0.254 0.006

Hazard Ratios for Clinical Endpoints by QRS MorphologyHazard Ratios for Clinical Endpoints by QRS Morphology

* The model adjusted for sex, ischemic or nonischemic cardiomyopathy, prior * The model adjusted for sex, ischemic or nonischemic cardiomyopathy, prior hospitalizations for heart failure, ejection fraction, QRS>150, left ventricular ejection hospitalizations for heart failure, ejection fraction, QRS>150, left ventricular ejection fraction, left ventricular end-systolic volume. fraction, left ventricular end-systolic volume.

0.0

0.5

1.0

1.5

2.0

2.5

HF or Death HF Death VT/VF/Death VF/Death

LBBB

Non-LBBB

RBBB

IVCD

Hazard Ratios for Primary and Secondary Hazard Ratios for Primary and Secondary Endpoints by QRS Morphology in MADIT-CRTEndpoints by QRS Morphology in MADIT-CRT

**p<0.05p<0.05

********

Hazard Ratios for Primary Endpoint by QRS Morphology Hazard Ratios for Primary Endpoint by QRS Morphology and Duration by Genderand Duration by Gender

MalesMales FemalesFemalesnn HR HR P valueP value nn HR HR P valueP value

QRS DurationQRS Duration <140 ms<140 ms 240240 1.691.69 0.0630.063 61 61 0.200.20 0.0080.008 140-159 ms140-159 ms 465465 0.770.77 0.1640.164 178178 0.310.31 0.0010.001 160-179 ms160-179 ms 417417 0.510.51 0.0030.003 153153 0.420.42 0.0360.036 ≥ ≥180 ms180 ms 242242 0.500.50 0.0190.019 61 61 0.330.33 0.1000.100

QRS MorphologyQRS Morphology LBBB*LBBB* 887887 0.56 0.56 <0.001<0.001 394394 0.25 0.25 <0.001<0.001 Non-LBBBNon-LBBB 477477 1.25 1.25 0.273 0.273 59 59 1.551.55 0.5160.516 RBBBRBBB 210210 0.94 0.94 0.841 0.841 18 18 NANA

IVCD IVCD 267267 1.49 1.49 0.133 0.133 41 41 1.311.31 0.7010.701

* p=0.006 for interaction comparing HR = 0.56 in males vs. HR = 0.25 in females* p=0.006 for interaction comparing HR = 0.56 in males vs. HR = 0.25 in females

-23

-35

12

-16

-26

9

-40

-30

-20

-10

0

10

20

LVEDV LVESV EF

LBBBNon-LBBB

Mean Change in Echocardiographic Parameters Mean Change in Echocardiographic Parameters from Enrollment to 12 months in CRT-D Patientsfrom Enrollment to 12 months in CRT-D Patients

**

**

**

* p<0.001 when comparing * p<0.001 when comparing LBBB and Non-LBBB patientsLBBB and Non-LBBB patients(all changes within subgroups (all changes within subgroups were significant)were significant)

ConclusionsConclusions

1.1. Heart failure patients with NYHA class I or II and Heart failure patients with NYHA class I or II and ejection fraction ejection fraction ≤30% who present with LBBB derive ≤30% who present with LBBB derive substantial benefit from CRT-D: reduction in heart substantial benefit from CRT-D: reduction in heart failure progression and reduction in the risk of failure progression and reduction in the risk of ventricular tachyarrhythmias. ventricular tachyarrhythmias.

2.2. No evidence of CRT-D benefit was observed in patients No evidence of CRT-D benefit was observed in patients with Non-LBBB QRS pattern: RBBB or IVCD with Non-LBBB QRS pattern: RBBB or IVCD regardless of their QRS duration. regardless of their QRS duration.

3.3. Beneficial effect of CRT-D in LBBB patients was Beneficial effect of CRT-D in LBBB patients was observed in all studied subjects: males and females, observed in all studied subjects: males and females, ischemic and non-ischemic, QRS>150 and QRS<150 ms. ischemic and non-ischemic, QRS>150 and QRS<150 ms.