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

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

Background

• It has been shown from meta-analysis ofrandomized clinical trials that patients with apre-CRT QRS duration (QRSD) >150 ms benefitmore than QRSD of 120-149 ms

• However, the benefits in the group of patientswith a very wide QRSD ≥180 ms (VWQRSD) hasnot been well studied, as these patients wereunder-represented in CRT trials

Sipahi I et al, Am Heart J 2012;163(2):260-67Cleland JG et al, Eur Heart J 2013;32(46):3547-56

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Causes of wide QRS complex

Conduction block(LBBB, RBBB, IVCD)

Electrical uncoupling

Combination of both

• Isolated diffuse left ventricular electrical uncoupling of the workingmyocardium alone produces a QRSD of 120 +/- 10ms

• With true left bundle branch block (LBBB), the QRSD is in the range of140 +/- 16 ms, and with true right bundle branch block (RBBB), theQRSD is even less

• Any further widening of the QRSD beyond 140 ms +/- 16 ms is due to acombined effect of BBB and electrical uncoupling

In the presence of significant electrical uncoupling, the benefits of CRT may be negated by slow and dispersed

conduction during pacing

Potse M et al. Europace 2012;14: v33–v39Potse M et al. J Cardiovasc Transl Res 2012;5:146–58

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BBB like morphology

Electrical uncoupling True BBBCombination of bothBBB and electrical

uncoupling

QRS < 130 ms QRS 140 ms +/- 16 ms QRS > 180 ms?ECHO CRT trial. Frank Ruschitzka, et al, N Engl J Med 2013; 369:1395-1405

Role of Cardiac Resynchronization Therapy (CRT)

Methods

Final analysis N=14,902 patients(Received CRT-D between Jan 2005 and April 2006)

Classified into 3 groups

based on theirQRS interval

120-149 ms 150-179 ms > 180 ms

Outcomes

1. Death 2. Composite of death and heart failure

hospitalization (HFH)

• 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

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HYPOTHESISWhen stratified by BBB

morphology, patients witha VWQRSD (≥180 ms) had worse clinical outcomes

than those with a QRSD of 150-179 ms.

Follow up of 6 years

VariableGroup 1 Group 2 Group 3

P valueQRS 120-149ms QRS 150-179ms QRS >= 180 ms(n=6010) (n=5983) (n=2909)

Age, mean +/SD yrs 72.4±10.7 73.3±10.4 73.8±10.4 <0.0001BBB Morphology

LBBB n (%) 3,928 (65.3%) 4,383 (73.3%) 2,019 (69.4%) <0.0001RBBB n (%) 705 (11.7%) 708 (11.8%) 218 (7.5%) <0.0001IVCD n (%) 1,377 (22.9%) 892 (14.9%) 672 (23.1%) <0.0001

LVEF mean +/-SD % 23.4±6.3 23.1±6.3 22.5±6.3 <0.0001SBP, mean +/- SD, mm Hg 126.7±23.2 127.0±22.1 124.8±21.1 0.002DBP, mean +/- SD, mm Hg 70.4±15.2 70.0±12.7 70.0±12.5 0.08Gender n (%)

Male 4,316 (71.8%) 4,225 (70.6%) 2,287 (78.6%) <0.001Female 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%) 0.5Class II 667 (11.1%) 654 (10.9%) 317 (10.9%) 0.56Class III 4,482 (74.6%) 4,426 (74.0%) 2,141 (73.6%) 0.56Class IV 799 (13.3%) 827 (13.8%) 408 (14.0%) 0.56

RESULTS: Table 1 Demographics by QRS group

Variable

Group 1 Group 2 Group 3

P valueQRS 120-149ms QRS 150-179ms QRS >= 180 ms

(n=6010) (n=5983) (n=2909)Ischemic CM, n (%) 4288 (71.4%) 4056 (67.8%) 1965 (67.6%) <0.0001

Atrial fibrillation, n (%) 1995 (33.2%) 1978 (33.1%) 1198 (41.2%) <0.0001

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%) 0.009

Diabetes Mellitus, n (%) 2202 (36.6%) 2160 (36.1%) 960 (33.0%) 0.003

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%) 0.006

Amiodarone 694 (11.6%) 789 (13.2%) 540 (18.6%) <0.0001

Digoxin 2391 (39.8%) 2472 (41.3%) 1349 (46.4%) <0.0001

Coumadin 1811 (30.1%) 1811 (30.3%) 1119 (38.5%) <0.0001

RESULTS: Table 1 Demographics by QRS group

Adjusted HR forMortality at 1 yr

(95% CI)P value

Adjusted HR for Mortality at 3 yrs

(95%CI)P value

Age (per year) 1.018 (1.012-1.023) <0.0001 1.019 (1.015-1.022) <0.0001Female Gender 0.89 (0.80-0.99) 0.048 0.85 (0.80-0.92) <0.0001QRS 150-179 ms

LBBB (REF) 1.00 N/A 1.00 N/ARBBB 1.48 (1.20-1.82) 0.0002 1.37 (1.20-1.57) <0.0001IVCD 1.30 (1.07-1.58) 0.01 1.22 (1.08-1.38) 0.002

QRS 120-149 msLBBB 1.33 (1.17-1.51) <0.0001 1.19 (1.10-1.29) <0.0001RBBB 1.65 (1.34-2.03) <0.0001 1.54 (1.36-1.76) <0.0001IVCD 1.53 (1.29-1.80) <0.0001 1.28 (1.15-1.43) <0.0001

QRS >=180 msLBBB 0.88 (0.75-1.04) 0.14 1.02 (0.93-1.13) 0.63RBBB 1.74 (1.28-2.38) 0.0005 1.72 (1.40-2.10) <0.0001IVCD 1.01 (0.80-1.28) 0.92 0.97 (0.84-1.13) <0.0001

Table 2 : Multivariable HRs for Early/Intermediate Time Points -- Death Outcome

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 (1.12-1.36) <0.0001 1.39 (1.29-1.49) <0.0001Atrial Fibrillation 1.24 (1.19-1.43) <0.0001 1.21 (1.13-1.28) <0.0001Diabetes Mellitus 1.36 (1.24-1.49) <0.0001 1.31 (1.23-1.39) <0.0001Ventricular Tachycardia 1.13(1.01-1.25) 00-Jan-00 1.12 (1.04-1.20) 0.002NYHA Class (REF=II)

Class III 1.46 (1.22-1.76) <0.0001 1.26 (1.14-1.40) <0.0001Class IV 2.64 (2.16-3.22) <0.0001 1.95 (1.73-2.19) <0.0001

LVEF (per 0.01) 0.973 (0.966-0.980) <0.0001 0.981 (0.976-0.985) <0.0001Systolic BP (per mm Hg) 0.991 (0.988-0.993) <0.0001 0.994 (0.992-0.996) <0.0001Diastolic BP (per mm Hg) 0.995 (0.991-0.999) 00-Jan-00 0.995 (0.992-0.998) 0.0003Beta Blockers 0.89 (0.80-0.99) 00-Jan-00 0.87 (0.82-0.94) <0.0001ACEI/ARB 0.65 (0.59-0.71) <0.0001 0.72 (0.68-0.77) <0.0001Diuretic 1.13 (1.00-1.27) 00-Jan-00 1.22 (1.13-1.31) <0.0001Amiodarone 1.34 (1.19-1.51) <0.0001 1.13 (1.04-1.22) <0.0001

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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) 1.004 (1.001-1.007) 0.02 1.008 (1.005-1.010) <0.0001

Female Gender 1.04 (0.97-1.13) 0.26 0.97 (0.92-1.02) 0.26QRS 150-179 ms

LBBB (REF) 1.00 N/A 1.00 N/ARBBB 1.40 (1.21-1.62) <0.0001 1.30 (1.17-1.45) <0.0001IVCD 1.10 (0.95-1.27) 0.26 1.09 (0.98-1.21) 0.1

QRS 120-149 msLBBB 1.31 (1.20-1.42) <0.0001 1.22 (1.15-1.30) <0.0001RBBB 1.43 (1.23-1.66) <0.0001 1.44 (1.29-1.61) <0.0001IVCD 1.39 (1.24-1.56) <0.0001 1.29 (1.19-1.41) <0.0001

QRS >=180 msLBBB 0.88 (0.79-0.98) 0.025 0.98 (0.91-1.06) 0.67RBBB 1.68 (1.34-2.10) <0.0001 1.60 (1.35-1.90) <0.0001IVCD 1.02 (0.86-1.20) 0.67 1.02 (0.91-1.15) 0.76

Table 3: Multivariable HRs for Early/Intermediate Time Points – Death/HF hospitalization Outcome

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

A (LBBB); 3 groups, p<0.0001 for QRS 120-149 ms v QRS 150-179ms,p=0.0009 for QRS 120-149 ms v QRS> 180 ms,p<0.0003 for QRS 150-179ms v QRS> 180 ms, overall log-rank p < 0.0001

B (RBBB); 3 groups, p=0.04 for QRS> 180 ms vs QRS 150-179ms, overall log-rank p = 0.07

C (IVCD); 3 groups, overall log-rank p =0.49

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

Free

dom

from

dea

th

Time (yrs)

p<0.0001 for QRS 120-149 ms v QRS 150-179ms, p<0.0001 for QRS 120-149 ms v QRS> 180 ms, p=0.0003 for QRS 150-179ms v QRS> 180 ms, overall log-rank p < 0.0001

p=0.10 for QRS> 180 ms v QRS 150-179ms, overall log-rank p = 0.15

p=0.08 for QRS 120-149 ms v QRS 150-179ms, p=0.03 for QRS 120-149 ms v QRS> 180 ms, overall log-rank p =0.08

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

Free

dom

from

dea

th /

HFH

Time (yrs)

Major findings

• In patients with RBBB, clinical outcomes withVWQRSD (≥180 ms) were worse when compared to aQRSD of 120 -149 ms and a QRSD of 150 -179 ms.There appears to be an incremental risk within thisgroup that increases with patients in the higher end ofthis range (QRSD > 210-249 ms).

• In patients with LBBB, clinical outcomes withVWQRSD (≥180 ms) were similar when compared toLBBB patients with QRSD of 150-179 ms.

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Limitations

• The Medicare ICD registry had a wide range ofpatient information, but certain importantpatient characteristics, such as biomarkers andright ventricular function, were missing

• No follow up ECGs or echocardiograms whichare markers of the remodeling effects of CRTimplantation

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In Conclusion…

VWQRSD prior to CRT implantation has complexlong-term effects on prognosis afterresynchronization, with a dependency on BBBmorphology.

In patients with RBBB, a VWQRSD is possibly amarker of advanced electrical remodeling andsuggests that CRT may be ineffective in restoringsynchronous contraction.

Outcomes were worst for the narrower QRSDgroup in LBBB, and the VWQRSD group inRBBB.

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Thank you

Veteran Affairs Medical Center, Cleveland

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