Cardiol Res

Cardiology Research, ISSN 1923-2829 print, 1923-2837 online, Open Access

Article copyright, the authors; Journal compilation copyright, Cardiol Res and Elmer Press Inc

Journal website http://www.cardiologyres.org

Review

Volume 11, Number 1, February 2020, pages 1-8

Indications of Cardiac Resynchronization in Non-Left Bundle Branch Block: Clinical Review of Available Evidence

Figure 1. Different ECG morphological pattern of non-LBBB wide QRS complex. (a) Atypical LBBB. (b) Typical RBBB. (c) Nonspecific interventricular conduction block. ECG: electrocardiogram; LBBB: left bundle branch block; RBBB: right bundle branch block.

Figure 2. Atypical RBBB: broad, slurred, and notched R wave on leads I and aVL, together with a leftward axis deviation. RBBB: right bundle branch block.

Figure 3. Line-graph representing the volume of patients studied over time, both LBBB/unspecified (blue) and specified non-LBBB (red). Only since 2016 can we see the gap beginning to narrow.

**Table 1.** Summary of the CRT Landmark Clinical Trials
Study	Aim	Patients and randomization	QRS complex pattern	Results
The table summarized all landmark trials influencing CRT guidelines since 2002. Most of these trials do not have any subgroup analysis of patients with non-LBBB. The trials consist of patients of varying classes of NYHA, using different endpoints such as rehospitalization or mortality, the cohort however is primarily LBBB or non-specified QRS prolongation. CHF: congestive heart failure; CRT: cardiac resynchronization therapy; NYHA: New York Heart Association; ICD: implantable cardioverter defibrillator; IVCD: intraventricular conduction delay; NSIVCD: nonspecific interventricular conduction delay; LVEF: left ventricular ejection fraction; LBBB: left bundle branch block; RBBB: right bundle branch block; QOL: quality of life; HFrEF: heart failure with reduced ejection fraction; LBFB: left posterior fascicular block; LAFB: left anterior fascicular block; LV: left ventricular; RV: right left ventricular; AV: atrioventricular.
Path CHF, Auricchio et al, 2002 [13]	Compare the short- and long-term clinical effects of atrial synchronous, pre-excitation of univentricular or biventricular therapy with cardiac CRT.	N = 42; randomized to biventricular CRT (24)/univentricular CRT (17); followed for 9 months	QRS ≥ 120 ms; LBBB, 39 (93%)/ RBBB, 3 (7%)	CRT produces a long-term improvement in the clinical symptoms of patients with HF who have significant IVCD.
MIRACLE, Abraham et al, 2002 [14]	Evaluate the clinical benefit of CRT in symptomatic heart failure with IVCD.	N = 453; randomized to CRT group (228)/control (225); followed for 6 months	QRS ≥ 130ms	Significant clinical improvement in moderate to severe heart failure with IVCD.
CONTAK CD, Higgins et al, 2003 [15]	Assess the safety and effectiveness of cardiac CRT when combined with an ICD.	N = 490; randomized to CRT (245)/control (245); followed for 6 months	QRS ≥ 120 ms; CRT group: LBBB 50%/NSIVCD 32%/RBBB 18%; non-CRT group: LBBB 54%/NSIVCD 34%/RBBB 12%	CRT implant has improved the functional status in all patients that were indicated for ICD and have HFrEF and IVCD.
MIRACLE ICD, Young et al, 2003 [16]	Examine the efficacy and safety of combined CRT and ICD therapy in patients with NYHA class III or IV CHF despite appropriate medical management.	N = 369; randomized to CRT on (187)/ CRT off (182); followed for 6 months	QRS ≥ 130 ms; CRT group: LBBB 87%/RBBB 13%; control group: LBBB 86%/RBBB 14%	CRT improved quality of life, functional status, and exercise capacity in patients with moderate to severe HF, a wide QRS interval, and life-threatening arrhythmias. CRT effect on QOL score and NYHA functional class was not influenced by morphology of the BBB (R vs. L)
MIRACLE ICD II, Abraham et al, 2004 [17]	Assess the efficacy and safety of combined CRT and ICD therapy in patients with NYHA class II CHF despite appropriate medical management.	N = 186; randomized to CRT on (86)/control (101); followed for 6 months	QRS ≥ 130 ms; CRT group: LBBB 88%/RBBB 12%; non-CRT group: LBBB 79%/RBBB 21%	Significant improvement in cardiac structure and function over 6 months. CRT did not alter exercise capacity.
CARE HF, Cleland et al, 2005 [18]	Evaluation of CRT on morbidity and mortality in patients with NYHA class III or IV.	N = 813; randomized to CRT group (409)/control (404); followed for 18 months	QRS ≥ 120 ms	CRT improves symptoms, the QOL and reduces complications and improves mortality. The broader the QRS in general the overall better results.
REVERSE, Linde et al, 2008 [19]	Assess the effects of CRT use in patients with NYHA functional class I and II.	N = 610; randomized to CRT group (419)/control (191); followed for 12 months	QRS ≥ 120 ms	CRT in combination with optimal medical therapy (+/-defibrillator), reduces the risk for HF hospitalization and improves ventricular structure and function in NYHA I and II.
MADIT CRT, Breithardt et al, 2009 [20]	Determine whether CRT with biventricular pacing would reduce the risk of death or HF events in patients with NYHA I or II, reduced EF of ≤ 30% and QRS duration ≥ 130 ms.	N = 1,820; randomized to CRT (CRT and ICD on) group (1,089)/control (CRT off and ICD on) (731); followed for up of 2.4 years	QRS ≥ 130 ms; CRT group: LBBB (761)/RBBB (136); control: LBBB (520)/RBBB (92)	CRT combined with ICD decreased the risk of HF events in relatively asymptomatic patients with a low ejection fraction and wide QRS complex.
REVERSE, Daubert et al, 2009 [21]	Evaluate the long-term effects of CRT in the European cohort of patients enrolled in the REVERSE trial.	N = 262, randomized to CRT group (ICD activated, CRT on) (180)/control (ICD activated, CRT off) (82); followed for 24 months	QRS ≥ 120 ms	Clinical functional outcomes improved and LV end systolic volume decreased by a greater mean in CRT on than CRT off. First HF hospitalization or death was significantly delayed by CRT (HR: 0.38; P = 0.003).
COMPANION, Anand et al, 2009 [22]	Assess the use of CRT as a treatment of CHF on mortality and hospitalization.	N = 1,520; randomized in 1:2:2 ratios for optimal medical management (308)/CRT-p (617)/CRT-d (595); followed for 15 months	QRS ≥ 120 ms	CRT pacing with or without ICD capability was associated with a significant 1-year relative risk reduction of about 20% for all-cause death or hospitalization.
RAFT, Tang et al, 2010 [23]	Evaluate whether CRT benefits patients with LV systolic dysfunction and a wide QRS.	N = 1,798; randomized to CRT group (ICD activated, CRT on) (894)/control (ICD activated, CRT off) (904); followed up for 40 months	QRS ≥ 120 ms; CRT group: LBBB72.9%/NIVCD 11.9%/RBBB 7.6%; control group: LBBB71.1%/NIVCD11.2%/RBBB 7.4%	The combined use of CRT with ICD has reduced the mortality and hospitalization for HF patients.
BLOCK HF, Curtis et al, 2016 [24]	Assess biventricular pacing against primary end points of reduce mortality, morbidity, and adverse left ventricular remodeling in patients with high grade AV block; and NYHA class I, II, or III; and a LVEF of 50% or less.	N = 691; randomized to Biventricular pacing (349)/ RV pacing (342); followed for 24 months	QRS ≥ 120 ms; biventricular pacing: 1st AV block (68)/2nd AV block (119)/3rd AV block 162/LBBB (123)/RBBB (73); RV pacing: 1st AV block (66)/2nd AV block (108)/3rd AV block (167)/LBBB (102)/RBBB (74)	Biventricular pacing was superior to conventional right ventricular pacing alone in patients with AV block and left ventricular systolic dysfunction with NYHA class I, II, or III HF.
ENHANCE CRT, Singh et al, 2018 [25]	Evaluate the effect of a non-traditional LV lead implant strategy on the clinical composite score in a non-LBBB patient population.	N = 248; randomized to QLV implant strategy (161)/standard of care (81); followed up for 12 months	QRS ≥ 120 ms; QLV study arm: IVCD (55)/RBBB (86)/RBBB and LAFB (15)/RBBB and LPFB (2)/others (3); standard of care study arm: IVCD (33)/RBBB (36)/RBBB and LAFB (9)/RBBB and LPFB (1)/others (2)	CRT is an effective therapy in patients with non-LBBB. No apparent variation was documented in responses by subgroups analysis (i.e. RBBB vs. IVCD, QRS interval, sex, HF cause, or LVEF).

Table 1. Summary of the CRT Landmark Clinical Trials

Study

Aim

Patients and randomization

QRS complex pattern

Results

The table summarized all landmark trials influencing CRT guidelines since 2002. Most of these trials do not have any subgroup analysis of patients with non-LBBB. The trials consist of patients of varying classes of NYHA, using different endpoints such as rehospitalization or mortality, the cohort however is primarily LBBB or non-specified QRS prolongation. CHF: congestive heart failure; CRT: cardiac resynchronization therapy; NYHA: New York Heart Association; ICD: implantable cardioverter defibrillator; IVCD: intraventricular conduction delay; NSIVCD: nonspecific interventricular conduction delay; LVEF: left ventricular ejection fraction; LBBB: left bundle branch block; RBBB: right bundle branch block; QOL: quality of life; HFrEF: heart failure with reduced ejection fraction; LBFB: left posterior fascicular block; LAFB: left anterior fascicular block; LV: left ventricular; RV: right left ventricular; AV: atrioventricular.

Path CHF, Auricchio et al, 2002 [13]

Compare the short- and long-term clinical effects of atrial synchronous, pre-excitation of univentricular or biventricular therapy with cardiac CRT.

N = 42; randomized to biventricular CRT (24)/univentricular CRT (17); followed for 9 months

QRS ≥ 120 ms; LBBB, 39 (93%)/ RBBB, 3 (7%)

CRT produces a long-term improvement in the clinical symptoms of patients with HF who have significant IVCD.

MIRACLE, Abraham et al, 2002 [14]

Evaluate the clinical benefit of CRT in symptomatic heart failure with IVCD.

N = 453; randomized to CRT group (228)/control (225); followed for 6 months

QRS ≥ 130ms

Significant clinical improvement in moderate to severe heart failure with IVCD.

CONTAK CD, Higgins et al, 2003 [15]

Assess the safety and effectiveness of cardiac CRT when combined with an ICD.

N = 490; randomized to CRT (245)/control (245); followed for 6 months

QRS ≥ 120 ms; CRT group: LBBB 50%/NSIVCD 32%/RBBB 18%; non-CRT group: LBBB 54%/NSIVCD 34%/RBBB 12%

CRT implant has improved the functional status in all patients that were indicated for ICD and have HFrEF and IVCD.

MIRACLE ICD, Young et al, 2003 [16]

Examine the efficacy and safety of combined CRT and ICD therapy in patients with NYHA class III or IV CHF despite appropriate medical management.

N = 369; randomized to CRT on (187)/ CRT off (182); followed for 6 months

QRS ≥ 130 ms; CRT group: LBBB 87%/RBBB 13%; control group: LBBB 86%/RBBB 14%

CRT improved quality of life, functional status, and exercise capacity in patients with moderate to severe HF, a wide QRS interval, and life-threatening arrhythmias. CRT effect on QOL score and NYHA functional class was not influenced by morphology of the BBB (R vs. L)

MIRACLE ICD II, Abraham et al, 2004 [17]

Assess the efficacy and safety of combined CRT and ICD therapy in patients with NYHA class II CHF despite appropriate medical management.

N = 186; randomized to CRT on (86)/control (101); followed for 6 months

QRS ≥ 130 ms; CRT group: LBBB 88%/RBBB 12%; non-CRT group: LBBB 79%/RBBB 21%

Significant improvement in cardiac structure and function over 6 months. CRT did not alter exercise capacity.

CARE HF, Cleland et al, 2005 [18]

Evaluation of CRT on morbidity and mortality in patients with NYHA class III or IV.

N = 813; randomized to CRT group (409)/control (404); followed for 18 months

QRS ≥ 120 ms

CRT improves symptoms, the QOL and reduces complications and improves mortality. The broader the QRS in general the overall better results.

REVERSE, Linde et al, 2008 [19]

Assess the effects of CRT use in patients with NYHA functional class I and II.

N = 610; randomized to CRT group (419)/control (191); followed for 12 months

QRS ≥ 120 ms

CRT in combination with optimal medical therapy (+/-defibrillator), reduces the risk for HF hospitalization and improves ventricular structure and function in NYHA I and II.

MADIT CRT, Breithardt et al, 2009 [20]

Determine whether CRT with biventricular pacing would reduce the risk of death or HF events in patients with NYHA I or II, reduced EF of ≤ 30% and QRS duration ≥ 130 ms.

N = 1,820; randomized to CRT (CRT and ICD on) group (1,089)/control (CRT off and ICD on) (731); followed for up of 2.4 years

QRS ≥ 130 ms; CRT group: LBBB (761)/RBBB (136); control: LBBB (520)/RBBB (92)

CRT combined with ICD decreased the risk of HF events in relatively asymptomatic patients with a low ejection fraction and wide QRS complex.

REVERSE, Daubert et al, 2009 [21]

Evaluate the long-term effects of CRT in the European cohort of patients enrolled in the REVERSE trial.

N = 262, randomized to CRT group (ICD activated, CRT on) (180)/control (ICD activated, CRT off) (82); followed for 24 months

QRS ≥ 120 ms

Clinical functional outcomes improved and LV end systolic volume decreased by a greater mean in CRT on than CRT off. First HF hospitalization or death was significantly delayed by CRT (HR: 0.38; P = 0.003).

COMPANION, Anand et al, 2009 [22]

Assess the use of CRT as a treatment of CHF on mortality and hospitalization.

N = 1,520; randomized in 1:2:2 ratios for optimal medical management (308)/CRT-p (617)/CRT-d (595); followed for 15 months

QRS ≥ 120 ms

CRT pacing with or without ICD capability was associated with a significant 1-year relative risk reduction of about 20% for all-cause death or hospitalization.

RAFT, Tang et al, 2010 [23]

Evaluate whether CRT benefits patients with LV systolic dysfunction and a wide QRS.

N = 1,798; randomized to CRT group (ICD activated, CRT on) (894)/control (ICD activated, CRT off) (904); followed up for 40 months

QRS ≥ 120 ms; CRT group: LBBB72.9%/NIVCD 11.9%/RBBB 7.6%; control group: LBBB71.1%/NIVCD11.2%/RBBB 7.4%

The combined use of CRT with ICD has reduced the mortality and hospitalization for HF patients.

BLOCK HF, Curtis et al, 2016 [24]

Assess biventricular pacing against primary end points of reduce mortality, morbidity, and adverse left ventricular remodeling in patients with high grade AV block; and NYHA class I, II, or III; and a LVEF of 50% or less.

N = 691; randomized to Biventricular pacing (349)/ RV pacing (342); followed for 24 months

QRS ≥ 120 ms; biventricular pacing: 1st AV block (68)/2nd AV block (119)/3rd AV block 162/LBBB (123)/RBBB (73); RV pacing: 1st AV block (66)/2nd AV block (108)/3rd AV block (167)/LBBB (102)/RBBB (74)

Biventricular pacing was superior to conventional right ventricular pacing alone in patients with AV block and left ventricular systolic dysfunction with NYHA class I, II, or III HF.

ENHANCE CRT, Singh et al, 2018 [25]

Evaluate the effect of a non-traditional LV lead implant strategy on the clinical composite score in a non-LBBB patient population.

N = 248; randomized to QLV implant strategy (161)/standard of care (81); followed up for 12 months

QRS ≥ 120 ms; QLV study arm: IVCD (55)/RBBB (86)/RBBB and LAFB (15)/RBBB and LPFB (2)/others (3); standard of care study arm: IVCD (33)/RBBB (36)/RBBB and LAFB (9)/RBBB and LPFB (1)/others (2)

CRT is an effective therapy in patients with non-LBBB. No apparent variation was documented in responses by subgroups analysis (i.e. RBBB vs. IVCD, QRS interval, sex, HF cause, or LVEF).

**Table 2.** Summary of the CRT Landmark Clinical Trials
Guideline	Recommendation
The table showed the summary of different international guidelines on indications of CRT in patients with non-LBBB wide QRS complex pattern. ESC: European Society of Cardiology; GDM: guideline-directed medical therapy; OMT: optical medical therapy; HF: heart failure; CRT: cardiac resynchronization therapy; NYHA: New York Heart Association; ICD: implantable cardioverter defibrillator; LBBB: left bundle branch block; RBBB: right bundle branch block.
American College of Cardiology Foundation/American Heart Association 2013, ESC European Heart Rhythm Association 2013	CRT can be useful for patients who have LVEF less than or equal to 35%, sinus rhythm, a non-LBBB pattern with a QRS duration greater than or equal to 150 ms, and NYHA class III/ambulatory class IV symptoms on GDM. Class IIa, level of evidence A.
	CRT may be considered for patients who have LVEF less than or equal to 35%, sinus rhythm, a non-LBBB pattern with QRS duration 120 to 149 ms, and NYHA class III/ambulatory class IV on GDM. Class IIb, level of evidence B.
National Institute of Health and Care Excellence (NICE) guidelines for ICD and CRT for arrhythmia and HF 2014	CRT device insertion is indicated in patients with non-LBBB QRS morphology, who have QRS duration ≥ 150 ms and in NYHA functional classes II, III, and IV.
	CRT pacemaker without ICD insertion is indicated in patients with non-LBBB QRS morphology who have a QRS between 120 and 149 ms and in NYHA functional class IV.
ESC Heart Failure Association guidelines for the diagnosis and treatment of acute and chronic HF 2016	CRT should be considered for symptomatic patients with HF in sinus rhythm with QRS duration ≥ 150 ms and non-LBBB QRS morphology and with LVEF ≤ 35% despite OMT in order to improve symptoms and reduce morbidity and mortality. Class IIa, level of evidence B.
	CRT may be considered for symptomatic patients with HF in sinus rhythm with QRS duration of 130 to 149 ms and non-LBBB QRS morphology and with LVEF ≤ 35% despite OMT in order to improve symptoms and reduce morbidity and mortality. Class IIb, level of evidence B.
Comprehensive update of the Canadian Cardiovascular Society guidelines for the management of heart failure 2017	CRT may be considered for patients in sinus rhythm with NYHA class II, III, or ambulatory class IV HF despite optimal medical therapy, LVEF ≤ 35% and QRS duration ≥ 150 ms with non-LBBB (weak recommendation; low-quality evidence).
	There is no clear evidence of benefit with CRT among patients with QRS durations < 150 ms because of non-LBBB conduction.

Table 2. Summary of the CRT Landmark Clinical Trials

Guideline

Recommendation

The table showed the summary of different international guidelines on indications of CRT in patients with non-LBBB wide QRS complex pattern. ESC: European Society of Cardiology; GDM: guideline-directed medical therapy; OMT: optical medical therapy; HF: heart failure; CRT: cardiac resynchronization therapy; NYHA: New York Heart Association; ICD: implantable cardioverter defibrillator; LBBB: left bundle branch block; RBBB: right bundle branch block.

American College of Cardiology Foundation/American Heart Association 2013, ESC European Heart Rhythm Association 2013

CRT can be useful for patients who have LVEF less than or equal to 35%, sinus rhythm, a non-LBBB pattern with a QRS duration greater than or equal to 150 ms, and NYHA class III/ambulatory class IV symptoms on GDM. Class IIa, level of evidence A.

CRT may be considered for patients who have LVEF less than or equal to 35%, sinus rhythm, a non-LBBB pattern with QRS duration 120 to 149 ms, and NYHA class III/ambulatory class IV on GDM. Class IIb, level of evidence B.

National Institute of Health and Care Excellence (NICE) guidelines for ICD and CRT for arrhythmia and HF 2014

CRT device insertion is indicated in patients with non-LBBB QRS morphology, who have QRS duration ≥ 150 ms and in NYHA functional classes II, III, and IV.

CRT pacemaker without ICD insertion is indicated in patients with non-LBBB QRS morphology who have a QRS between 120 and 149 ms and in NYHA functional class IV.

ESC Heart Failure Association guidelines for the diagnosis and treatment of acute and chronic HF 2016

CRT should be considered for symptomatic patients with HF in sinus rhythm with QRS duration ≥ 150 ms and non-LBBB QRS morphology and with LVEF ≤ 35% despite OMT in order to improve symptoms and reduce morbidity and mortality. Class IIa, level of evidence B.

CRT may be considered for symptomatic patients with HF in sinus rhythm with QRS duration of 130 to 149 ms and non-LBBB QRS morphology and with LVEF ≤ 35% despite OMT in order to improve symptoms and reduce morbidity and mortality. Class IIb, level of evidence B.

Comprehensive update of the Canadian Cardiovascular Society guidelines for the management of heart failure 2017

CRT may be considered for patients in sinus rhythm with NYHA class II, III, or ambulatory class IV HF despite optimal medical therapy, LVEF ≤ 35% and QRS duration ≥ 150 ms with non-LBBB (weak recommendation; low-quality evidence).

There is no clear evidence of benefit with CRT among patients with QRS durations < 150 ms because of non-LBBB conduction.