CAM 20210

Biventricular Pacemakers (Cardiac Resynchronization Therapy) for the Treatment of Heart Failure

Category:Medicine   Last Reviewed:February 2019
Department(s):Medical Affairs   Next Review:February 2020
Original Date:July 1999    

Description:
Cardiac resynchronization therapy (CRT), which consists of synchronized pacing of the left and right ventricles, is intended to treat patients with heart failure and dyssynchronous ventricular contractions. Treatment involves placement of a device that paces both ventricles and coordinates ventricular pacing to maximize cardiac pumping function and left ventricular ejection fraction (LVEF).

For individuals who have New York Heart Association (NYHA) class III or IV heart failure with a LVEF of 35% or less who are in sinus rhythm, treated with guideline-directed medical therapy, and have either left bundle branch block (LBBB) or a QRS interval of 150 ms or more who receive CRT with or without defibrillator, the evidence includes randomized controlled trials (RCTs) and systematic reviews of RCTs. Relevant outcomes are overall survival, symptoms, functional outcomes, quality of life, hospitalizations, and treatment-related morbidity. There is a large body of clinical trial evidence supporting use of CRT in patients with NYHA class III or IV heart failure. The RCTs have consistently reported that CRT treatment reduces mortality, improves functional status, and improves quality of life for patients with NYHA class III or IV heart failure. Multiple subgroup analyses of RCTs have demonstrated that the benefit of CRT is mainly restricted to patients with LBBB or QRS interval greater than 150 ms. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have NYHA class II heart failure with a LVEF of 30% or less who are in sinus rhythm, treated with guideline-directed medical therapy, and have either LBBB or a QRS interval of 150 ms or more who receive CRT with or without defibrillator, the evidence includes RCTs and systematic reviews of RCTs. Relevant outcomes are overall survival, symptoms, functional outcomes, quality of life, hospitalizations, and treatment-related morbidity. For patients with NYHA class II heart failure, at least 4 RCTs assessing CRT have been published. A mortality benefit was reported in 1 of the 4 trials, the RAFT trial. None of the other 3 RCTs reported a mortality difference, but a subgroup analysis of the MADIT-CRT trial reported a mortality benefit for patients with LBBB. Among other outcome measures, hospitalizations for heart failure showed consistent improvements, but quality of life and functional status did not. Multiple subgroup analyses of RCTs have demonstrated that the benefit of CRT is mainly restricted to patients with LBBB or a QRS interval greater than 150 ms. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have NYHA class I heart failure who receive CRT with or without defibrillator, the evidence includes RCTs and systematic reviews of RCTs. Relevant outcomes are overall survival, symptoms, functional outcomes, quality of life, hospitalizations, and treatment-related morbidity. Few patients with NYHA class I heart failure have been included in RCTs. The MADIT-CRT trial included 265 patients with class I. While the treatment effect on death and hospitalization favored combined implantable cardiac defibrillator (ICD) plus CRT devices versus ICD alone for class I patients, the confidence interval was large and included a 25% to 30% increase in events. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have heart failure and atrial fibrillation who receive CRT with or without defibrillator, the evidence includes 4 RCTs and observational studies. Relevant outcomes are overall survival, symptoms, functional outcomes, quality of life, hospitalizations, and treatment-related morbidity. Data from RCTs have reported conflicting results, with 1 reporting improvements for patients with atrial fibrillation and others reporting no significant improvements. Results from observational studies are also conflicting. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have heart failure and atrioventricular (AV) nodal block who receive CRT, the evidence includes RCTs and systematic reviews of RCTs. Relevant outcomes are overall survival, symptoms, functional outcomes, quality of life, hospitalizations, and treatment-related morbidity. One large RCT demonstrated that CRT led to improvements in heart failure-related hospitalizations and urgent care visits among patients with heart failure and AV block but who would not necessarily meet conventional criteria for CRT. For patients who require ventricular pacing but have no left ventricular dysfunction, results of 1 small RCT have suggested that biventricular pacing is associated with improved measures of cardiac function, but the trial was small and underpowered to detect differences in clinical outcomes. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome. 

For individuals who have heart failure who receive triple-site CRT, the evidence includes small RCTs. Relevant outcomes are overall survival, symptoms, functional outcomes, quality of life, hospitalizations, and treatment-related morbidity. The available RCTs have reported improved outcomes on at least 1 measure of functional status or quality of life with triple-site CRT compared to conventional CRT. However, the trials are small and have methodologic limitations. In addition, outcomes reported differed across studies. Triple-site CRT was also associated with higher radiation exposure and a greater number of additional procedures postimplantation. Larger, high-quality RCTs are needed to better define the benefit-risk ratio for triple-site CRT compared to conventional CRT. The evidence is insufficient to determine the effects of the technology on health outcomes. 

For individuals who have heart failure who receive CRT combined with remote fluid monitoring, the evidence includes 3 RCTs. Relevant outcomes are overall survival, symptoms, functional outcomes, quality of life, hospitalizations, and treatment-related morbidity. Three RCTs have reported no improvement in outcomes associated with remote fluid monitoring for patients with heart failure. The evidence is insufficient to determine the effects of the technology on health outcomes.

Background
Heart Failure 
It is estimated that 20% to 30% of patients with heart failure have intraventricular conduction disorders resulting in a contraction pattern that is not coordinated and a wide QRS interval on the electrocardiogram. This abnormality appears to be associated with increased morbidity and  mortality.

Treatment 
Biventricular pacemakers using 3 leads (1 in the right atrium, 1 endocardial in the right ventricle, 1 epicardial for the left ventricle), also known as cardiac resynchronization therapy (CRT), have been investigated as a technique to coordinate the contraction of the ventricles, thus improving patients’ hemodynamic status. Several types of CRT devices are available, including those that incorporate biventricular pacing into automatic implantable cardiac defibrillators (ICDs), stand-alone biventricular pacemakers, and biventricular pacemakers that incorporate fluid monitoring via bioimpedance. 

Originally developed CRT devices typically used 2 ventricular leads for biventricular pacing. Devices and implantation techniques have been developed to allow for multisite pacing, with the goal of improving CRT response. This may be accomplished in 1 of 2 ways: through the use of multiple leads within the coronary sinus (triventricular pacing) or through the use of multipolar left ventricular pacing leads, which can deliver pacing stimuli at multiple sites. Wireless left ventricular endocardial pacing is also being evaluated for patients who are not candidates for or do not respond to standard epicardial  pacing leads.  

Regulatory Status 
There are numerous CRT devices, combined ICD plus CRT devices (CRT-D), and combined CRT plus fluid monitoring devices. Some devices are discussed here. For example, in 2001, the InSync® Biventricular Pacing System (Medtronic), a stand-alone biventricular pacemaker, was approved by the U.S. Food and Drug Administration (FDA) through the premarket approval process for the treatment of patients with New York Heart Association (NYHA) class III or IV heart failure, on a stable pharmacologic regimen, who also have a QRS duration of 130 ms or longer and a left ventricular ejection fraction (LVEF) of 35% or less. Devices by Guidant (CONTAK-CD®CRT-D System) and Medtronic (InSync® ICD Model 7272) have been approved by FDA through the premarket approval process for combined CRT defibrillators for patients at high risk of sudden cardiac death due to ventricular arrhythmias and who have NYHA class III or IV heart failure with a LVEF of 35% or less, QRS interval 130 ms or longer (≥120 ms for the Guidant device), and remain symptomatic despite a stable, optimal heart failure drug therapy. In 2006, Biotronik Inc. received premarket approval from FDA for its combined ICD-D device with ventricular pacing leads (Tupos LV/ATx CRT-D/Kronos LV-T CRT-D systems1,); in 2013, the company received FDA approval for updated ICD-D devices (Ilesto/Iforia  series).2,

In September 2010, FDA expanded indications for some CRT devices to include patients with class I and II heart failure. Based  on data from the MADIT-CRT study, indications for 3 Guidant CRT-D (Cognis®, Livian®, and Contak Renewal; Boston Scientific) devices were expanded to include patients with heart failure who receive stable optimal pharmacologic therapy for heart failure and who meet any of the following   classifications3,:

  • Moderate-to-severe heart failure (NYHA class III-IV) with an ejection fraction less than 35% and QRS interval greater than 120 ms.
  • Left bundle branch block with a QRS interval greater than or equal to 130 ms, ejection fraction less than 30%, and mild (NYHA class II) ischemic or nonischemic heart failure or asymptomatic (NYHA class I) ischemic heart failure.

In April 2014, FDA further expanded indications for multiple Medtronic CRT devices to include patients with NYHA class I, II, or III heart failure, who have a LVEF of 50% or less on stable, optimal heart failure medical therapy, if indicated, and have atrioventricular block that is expected to require a high percentage of ventricular pacing that cannot be managed with algorithms to minimize right ventricular pacing. The expanded indication was based on data from the BLOCK HF study, a Medtronic- sponsored randomized controlled trial that evaluated the use of CRT in patients with NYHA class I, II, or III heart failure, LVEF of 50% or less, and atrioventricular  block. 

Several CRT devices have incorporated a fourth lead, providing quadripolar pacing. The Medtronic Viva™ Quad XT and the Viva Quad S have a fourth lead, and the Medtronic Attain Performa® has a left ventricular lead, which received clearance for marketing from FDA in August 2014. The Dynagen™ X4 and Inogen™ X4 devices (Boston Scientific) also incorporate a fourth lead. Other CRT devices with quadripolar leads have been approved for use outside of the United States (e.g., St. Jude Quartet™ left ventricular  lead). 

Multiple devices manufactured by Medtronic combine a CRT with the OptiVol™ monitoring system. For example, in 2005, the InSync Sentry® system was approved by FDA through the supplemental premarket approval process. This combined biventricular pacemaker plus ICD is also equipped to monitor intrathoracic fluid levels using bioimpedance technology, referred to as OptiVol™ Fluid Status Monitoring. Bioimpedance measures, defined as the electrical resistance of tissue to flow of  current, are performed many times a day using a vector from the right ventricular coil on the lead in the right side of the heart to  the implanted pacemaker devices; changes in bioimpedance reflect intrathoracic fluid status and are evaluated using a computer algorithm. For example, changes in a patient's daily average of intrathoracic bioimpedance can be monitored; differences in  the daily average are compared with a baseline and reported as the OptiVol™ Fluid Index. It has been proposed that these data may be used as an early warning system of cardiac decompensation or may provide feedback that enables a physician to tailor medical therapy. Evidence review 20224 addresses the use of external bioimpedance devices as stand-alone devices to assess cardiac output noninvasively. 

The WiSE-CRT (EBR Systems) provides CRT with a small wireless electrode that is implanted within the left ventricle and controlled by ultrasound. It has European CE approval and is being studied in a multicenter pivotal trial. 

FDA product code: NIK.  

Related Policies
20224 Cardiac Hemodynamic Monitoring for the Management of Heart Failure in the Outpatient Setting
70144 Implantable Cardioverter Defibrillator (ICD)

Policy:
Biventricular pacemakers with or without an accompanying implantable cardiac defibrillator (ie, a combined biventricular pacemaker plus implantable cardiac defibrillator) may be considered MEDICALLY NECESSARY as a treatment of heart failure in patients who meet all of the following criteria: 

For New York Heart Association class III or IV,

  • Left ventricular ejection fraction ≤35%
  • Sinus rhythm
  • Patients treated with guideline-directed medical therapy (see Policy Guidelines section)

AND 

  • Either left bundle branch block OR QRS interval  ≥150 ms.

For New York Heart Association class  II,

  • Left ventricular ejection  fraction ≤30%
  • Sinus rhythm
  • Patients treated with a guideline-directed medical therapy (see Policy Guidelines section)

AND 

  • Either left bundle branch block OR QRS interval ≥150 ms. 

For patients who do not meet the criteria outlined above, but have an indication for a ventricular pacemaker or biventricular pacemakers with or without an accompanying implantable cardiac defibrillator (i.e., a combined biventricular pacemaker/implantable cardiac defibrillator) may be considered MEDICALLY NECESSARY as an alternative to a right ventricular pacemaker in patients who meet all of the following criteria: 

  • New York Heart Association class I, II, III, or IV   heart failure;
  • Left ventricular ejection fraction ≤50%;
  • The presence of atrioventricular block with requirement for a high percentage of ventricular pacing (see Policy Guidelines section); and
  • Patients treated with guideline-directed medical therapy (see Policy Guidelines section). 

Biventricular pacemakers, with or without an accompanying implantable cardiac defibrillator (i.e., a combined biventricular pacemaker plus implantable cardiac defibrillator), are considered INVESTIGATIONALas a treatment for patients with New York Heart Association class I heart failure who do not meet the above criteria.  

Biventricular pacemakers, with or without an accompanying implantable cardiac defibrillator (i.e., a combined biventricular pacemaker plus implantable cardiac defibrillator), are considered INVESTIGATIONAL as a treatment for heart failure in patients with atrial fibrillation who do not meet the above  criteria. 

Triple-site (triventricular) cardiac resynchronization therapy, using an additional pacing lead, is considered INVESTIGATIONAL. An intrathoracic fluid monitoring sensor is considered INVESTIGATIONAL as a component of a biventricular pacemaker.

Cardiac resynchronization therapy with wireless left ventricular endocardial pacing is considered INVESTIGATIONAL. 

Policy Guidelines
Definitions
Atrioventricular block with a requirement for a high percentage of ventricular pacing is considered to be present when there is either:

  • Third-degree atrioventricular block;  or
  • Second-degree atrioventricular block or a PR interval of ≥300 ms when paced at 100 beats per minute. 

Guideline-directed medical therapy for heart failure is outlined in 2013 American College of Cardiology Foundation and American Heart Association guidelines for the management of heart failure (Yancy et al (2013)). 

Coding 
Note that CPT "dual-chamber" codes describe combined right atrial and right ventricular electrode placement. CPT "biventricular" codes describe the additional placement of a left ventricular electrode via the cardiac vein. A left ventricular pacing lead is placed in the marginal branch of the coronary sinus and into a cardiac vein to allow for biventricular pacing for cardiac resynchronization. CPT notes the  following: 

"A single chamber pacemaker system includes a pulse generator and 1 electrode inserted in either the atrium or the ventricle. A dual chamber pacemaker system includes a pulse generator and 1 electrode inserted in the right atrium and 1 electrode inserted in the right ventricle. In certain circumstances, an additional electrode may be required to achieve pacing of the left ventricle (bi-ventricular pacing). In this event, transvenous (cardiac vein) placement of the electrode should be separately reported using code 33224 or 33225. Epicardial placement of the electrode should be separately reported using 33202-33203." 

  • 33224 Insertion of pacing electrode, cardiac venous system, for left ventricular pacing, with attachment to previously placed pacemaker or implantable defibrillator pulse generator (including revision of pocket, removal, insertion, and/or replacement of existing generator).
  • 33225 Insertion of pacing electrode, cardiac venous system, for left ventricular pacing, at time of insertion of implantable defibrillator or pacemaker pulse generator (e.g., for upgrade to dual chamber system) (List separately in addition to code for primary procedures). 

Use 33225 in conjunction with 33206, 33207, 33208, 33212, 33213, 33214, 33216, 33217, 33221, 33223, 33228, 33229, 33230, 33231, 33233, 33234, 33235, 33240, 33249, 33263, and   33264. 

Thus, CPT describes 33225 as  an "add-on" code to other pacing or implantable defibrillator procedures.    

Benefit Application
BlueCard®/National Account Issues
It may be difficult to distinguish the use of biventricular pacemakers for the treatment of heart failure from those used for various cardiac arrhythmias. However, CPT codes 33224 and 33225 used in conjunction with ICD-9 codes describing heart failure (428 code range) may identify the subset of patients receiving biventricular pacemakers as a treatment of heart failure.

Rationale
This evidence review was created in July 1999 and has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through March 5, 2018. 

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function—including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms. 

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical uses of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice. 

Cardiac Resynchronization Therapy for Heart Failure Systematic Reviews
Use of biventricular pacemakers with or without an accompanying implantable cardiac defibrillator (ICD) for select patients    with advanced heart failure is supported by a large body of clinical trial evidence. At least 13 systematic reviews have   consistently found benefit for cardiac resynchronization therapy (CRT) vs comparators for all-cause mortality and heart failure- related hospitalizations.4-16, The 5 systematic reviews published after 2010 that include meta-analyses   with comparisons of CRT plus ICD (CRT-D) vs ICD alone and/or CRT vs drug therapy are shown in Table 1 and AMSTAR (A MeaSurement Tool to Assess systematic Reviews) quality ratings are shown in Table 2. 

Trial characteristics can be found in the following section in Table 3. The majority of patients included in RCTs had New York Heart Association (NYHA) functional class II or III with a left ventricular ejection fraction (LVEF) of less than 35%, prolonged QRS interval (≥120 ms), and in sinus rhythm. On average, about 75% of participants were men, although the percentages of en ranged from 46% to 100%. Just over half of participants included had ischemic heart disease. The systematic reviews consistently reported a 15% to 20% reduction in mortality with CRT-D vs ICD alone and a 25% reduction in mortality of CRT vs drug therapy. Reviews providing results stratified by NYHA class I or II vs NYHA class III or IV have shown significant effects on mortality in both groups, although few patients in class I were enrolled in RCTs. The individual patient data network meta-analysis by Woods et al (2015) included 12,638 patients and reported a larger reduction in mortality (»40%) for CRT vs drug therapy compared with the other systematic reviews.14, The meta-analysis by Sun et al (2016) demonstrated that effects on mortality persist when only pooling trials with more than 1 year of   follow-up.15,

Randomized Controlled Trials 
At least 30 RCTs have evaluated CRT have been published and are included in at least one of the meta-analyses listed above.17-46, Table 3 shows the baseline characteristics of the RCTs. The 2 largest RCTs (MADIT-CRT, RAFT) are described below.

Table 1. Systematic Reviews on RCTs of the Efficacy of CRT for the Treatment of Heart Failure

Study Dates Population Interventions Studies (N)  Trials Included Results

Sun et al (2016)15

Through 2015

NYHA class I/II

  • CRT-D
  • ICD alone

3 RCTs (N=3,858) with 12+ mo of followup

REVERSE, MADIT-CRT, RAFT

CRT-D vs ICD
Heart failure hospitalizations

  • OR=0.67 (95% CI, 0.50 to 0.89)

Mortality

  • OR=0.78 (95% CI, 0.63 to 0.96) 

Woods et al (2015)14

1990-2015

LVEF ≤40%

  • CRT or CRT-D
  • Drug therapy alone or ICD alone

13 RCTs (N=12,638)

CARE-HF, MIRACLE, REVERSE, MUSTICSR, RESPONSE, VECTOR, COMPANION, CONTAK-CD, MADIT-CRT, RAFT, REThinQ, REVERSE CRT, Piccirillo (2006), Pinter (2009), RHYTHM-ICD, DEFINITE a, MADITa, MADIT IIa, SCD HeFTa, AMIOVIRTa, CATa

CRT-D vs drug therapy
Mortality

  • HR=0.58 (95% CrI, 0.50 to 0.68) CRT-D vs ICD

Mortality

  • HR=0.82 (95% CrI, 0.72 to 0.93)

Chen et al (2013)13

Through 2012

LVEF ≤35%; QRS interval ≥120 ms

  • CRT-D
  • ICD alone

8 RCTs (N=5,674)  

Lozano (2000), CONTAK-CD, MIRACLE-ICD, MIRACLE-ICD II, RHYTHM-ICD, REVERSE, MADIT-CRT, RAFT

CRT-D vs ICD
Hospitalization

  • OR=0.70 (95% CI, 0.60 to 0.81)

Mortality

  • OR=0.80 (95% CI, 0.67 to 0.95) 

Wells et al (2011)12

1980-2010

QRS interval ≥120 ms

  • CRT or CRT- D
  • ICD alone or drug therapy alone

12 RCTs (N=7,538)

Lozano (2000), MUSTIC, MIRACLE, MIRACLE-ICD, MIRACLE-ICD II, COMPANION, RHYTHM-ICD, CARE-HF, VECTOR, REVERSE, MADIT-CRT, RAFT

CRT vs no CRT
Mortality

  • RR=0.78 (95% CI, 0.70 to 0.87)

CRT vs drug therapy
Mortality

  • RR=0.73 (95% CI 0.62 to 0.85)

CRT-D vs ICD
Mortality

  • RR=0.83 (95% CI, 0.72 to 0.96)

Bertoldi et al (2011)8

 

LV systolic dysfunction

  • CRT or CRT-D
  • ICD alone

12 RCTs (N=8,284)

 

MUSTIC-SR, MUSTIC-AF, MIRACLE, CONTAK-CD, MIRACLE-ICD, MIRACLE-ICD II, COMPANION, CARE-HF, HOBIPACE, REVERSE, MADIT-CRT, RAFT

CRT vs drug therapy
Mortality

  • 0.76 (95% CI, 0.64 to 0.90)

CRT-D vs ICD alone
Mortality

  • 0.83 (95% CI, 0.72 to 0.96) 

CI: confidence interval; CrI: credible interval; CRT: cardiac resynchronization therapy; CRT-D: cardiac resynchronization therapy with implantable cardioverter defibrillator; HR: hazard ratio; ICD: implantable cardioverter defibrillator; LV: left ventricular; LVEF: left ventricular ejection fraction; NYHA: New York Heart Association; RR: relative risk; OR: odds ratio; RCT: randomized controlled trial; RR: relative risk.
a Trials of ICD vs medical therapy; used in the indirect comparisons in the network meta-analysis.

Table 2. AMSTAR Quality of Systematic Reviews of Cardiac Resynchronization Therapy

Study

A Priori Design

Duplicate Selection/Extraction

Comp Literature Search

Search for Gray Literature

Included/Excluded Studies Provided

Study Characteristics Provided

Study Scientific Quality Assessed and Documented

Scientific Quality Used in Formulated Conclusions

Appropriate Methods for Synthesis

Publication Bias Assessed

COI Included

Sun (2016)

Can't answer Yes Yes Yes No Yes Yes Yes Yes No No

Woods (2015)

Can't answer Yes Yes No No Yes Yes Yes Yes No Yes

Chen (2013)

Can't answer Can't answer Yes Yes No Yes Yes Yes Yes No No

Wells (2011)

Can't answer

Yes Yes Yes Yes Yes Yes Yes Yes No No

Bertoldi (2011)

Can't answer Yes Yes No No Yes No Yes Yes Yes No

For a description of AMSTAR items, see https://amstar.ca/docs/AMSTARguideline.pdf.
AMSTAR: A MeaSurement Tool to Assess systematic Reviews; COI: conflict of interest; Comp: comprehensive.

Table 3. RCTs of Cardiac Resynchronization Therapy for the Treatment of Heart Failure

Study Dur Funding Source Treatment Groups n Percent NYHA Class Mean LVEF (SD) Mean QRS (SD), ms Percent ECG Pattern % AF
   

 

    I II III IV     LBBB RBBB  

Lozano (2000)17

3 mo

Unclear

  • CRT-D
  • ICD
  • 109
  • 113
NA
  • 35
  • 57
  • 8
  • 0.22 (0.07) 
NR  NR NR NR

Lozano (2000)17

3 mo

Unclear

  • CRT-D
  • ICD
  • 109
  • 113
NA
  • 35
  • 57
  • 8
  • 0.22 (0.07)  
NR  NR NR NR

MUSTIC-SR (2001)18

3 mo

Industry

  • CRT-D
  • Inactive first
  • 29
  • 29
NA NA
  • 100
  • 100
NA
  • 0.23 (0.07) 
  • 172 (22)
  • 175 (19)
  • 87 
NR EX

Garrigue (2002)19 

2 mo

Unclear

  • CRT first
  • LV first
  • 6
  • 7
NA NA
  • 77
  • 23
  • 0.25 (0.08) 
  • 208 (15)
NR  NR
  • 100

MUSTIC-AF (2002)2

3 mo

Industry

  • CRT first
  • RV first
  • 25
  • 18
NA NA
  • 100
  • 100
NA
  • 0.23 (0.07)
  • 0.30 (0.12)
  • 209 (21)
  • 208 (12)
NR  NR
  • 100
  • 100

MIRACLE (2002)21

6 mo

Industry

  • CRT
  • Inactive
  • 228
  • 225
NA NA
  • 90
  • 91
  • 10
  • 9
  • 0.22 (0.06)
  • 0.22 (0.06)
  • 167 (21)
  • 165 (20)
NR  NR EX

PATH-CHF (2002)22 

1 mo

Industry

  • CRT first
  • Uni-V first
  • 24
  • 17
NA NA
  • 88
  • 82
  • 12
  • 18
  • 0.21 (0.06)
  • 0.20 (0.07)
  • 174 (30)
  • 178 (34)
  • 87
  • 100
  • 13
  • 0
EX

PATH-CHF II (2003)3 

3 mo

Industry

  • CRT first
  • Inactive first
  • 43
  • 43
NA
  • 37
  • 28
NA
  • 63
  • 72
  • 0.23 (0.07)
  • 0.23 (0.08)
  • 154 (18)
  • 157 (23)
  • 91
  • 86
 
NR EX

CONTAKCD (2003)24 

3 mo

Industry

  • CRT-D
  • ICD
  • 245
  • 245
NA
  • 32
  • 33
  • 60
  • 57
  • 8
  • 10
  • 0.21 (0.07)
  • 0.22 (0.07)
  • 160 (27)
  • 156 (26)
  • 54
  • 55 
  • 14
  • 12
EX

MIRACLEICD (2003)25

6 mo

Industry

  • CRT-D
  • ICD
  • 187
  • 182
NA NA
  • 88
  • 89
  • 12
  • 11
  • 0.24 (0.07)
  • 0.24 (0.06)
  • 165 (22) 
NR 
  • 13
  • 13
EX

COMPANIO N (2004)26 

15 mo

Industry

  • CRT
  • Usual care
  • 617
  • 308
NA NA
  • 87
  • 82
  • 13
  • 18
  • 0.20ª
  • 0.22ª
  • 160ª
  • 156ª
  •  69
  • 70
 NR EX

MIRACLEICD II (2004)27 

6 mo

Industry

  • CRT-D
  • ICD
  • 85
  • 101
NA
  • 100
  • 100
  NA
  • 0.24 (0.07)
  • 0.25 (0.07)
  • 166 (25)
  • 165 (23)
NR  
  • 12
  • 21
EX

CARE-HF (2005)28 

29 mo

Industry 

  • CRT
  • Usual care 
  • 409
  • 404
NA   
  • 94
  • 93
  • 6
  • 0.25a
  • 0.25a
  • 160a
  • 160a 
 NR NR EX 

RHYTHMICD (2005)29 

12 mo 

Industry 

  • CRT
  • ICD 
  • 119
  • 59 
  • 1
  • 2
  • 5
  • 87
  • 87 
  • 7
  • 6  
  • 0.26 (0.08)
  • 0.23 (0.06)
  • 169 (16)
  • 167 (15)
 
NR  NR  EX 

VecTOR (2005)30 

6 mo 

Industry 

  • CRT
  • Inactive
  • 59
  • 47 
 
  •  29
  • 65
  • <0.35 
  • >140 
NR  NR  EX 

BELIEVE (2006)31 

12 mo 

Unclear 

  • CRT-D
  • LV-ICD
  • 33
  • 36
NA 
  • 42
  • 33  
  • 58
  • 67 
NA
  • 0.26 (0.06)
  • 0.25 (0.06)
  • 176 (25)
  • 169 (31)
NR  NR  EX 

HOBIPACE (2006)32 

3 mo 

Govt 

  • CRT
  • RV
  • 15
  • 15

Mean (SD), 3.0 (0.6)

  • 0.26 (0.08) 
  • 174 (42) 
  • 63
NR 
  • 37

Piccirillo (2006)33 

1 y 

Unclear 

  • CRT-D
  • ICD

 

  • 16
  • 15 
NA  NA  
  • 33
  • 31  
  • 67
  • 69  
  • 0.22 (0.08)
  • 0.23 (0.04)
  • 159 (8)
  • 160 (4)
NR  NR  NR 

DECREASE -HF (2007)34 

6 mo 

Industry 

  • BiV-ICDb
  • LV-ICD
  • 205
  • 101
NA  NA  
  • 98
  • 97  
  • 2
  • 3  
  • 0.23 (0.07)
  • 0.23 (0.07)
  • 167 (16)
  • 165 (15)
  • 94
  • 93 
  • 0
EX 

RD-CHF (2007)35 

3 mo 

Unclear 

  • CRT first
  • RV first  
  • 25
  • 19 

Mean (SD), 3.2 (0.4)   

  • 0.24 (0.10)
  • 0.27 (0.09)
  • 212 (28)
  • 199 (21)
NR  NR 
  • 56
  • 63  

RethinQ (2007)36 

6 mo 

Industry 

  • CRT-D
  • ICD
 
  • 87
  • 85 
NA   NA  
  • 100
  • 99 
NA 
  • 0.25 (0.05)
  • 0.26 (0.06) 
  • 107 (12)
  • 106 (13)
EX  EX  EX 

Piepoli (2008)47 

12 mo 

Unclear 

  • CRT
  • Usual care
  • 44
  • 45 
NA   NA  
  • 90
  • 89  
  • 10
  • 11  
  • 0.24 (0.01)
  • 0.23 (0.07)
  • 164 (18)
  • 160 (20)
NR  NR  EX 

REVERSE (2008)38 

12 mo 

Industry 

  • CRT on
  • CRT off 
  • 419
  • 191
  • 18
  • 17 
  • 82
  • 83  
NA  NA 
  • 0.27 (0.07)
  • 0.26 (0.07)
  • 153 (21)
  • 154 (24)
NR  NR  EX 

MADIT-CRT (2009)39 

2.4 y 

Industry 

  • CRT-D
  • ICD 
 
  • 1,089
  • 731 
  • 14
  • 16  
  • 86
  • 85 
NA  NA 
  • 0.24 (0.05)
  • 0.24 (0.05) 
  • >150,  64%
  • >150, 65%
 
  • 70
  • 71  
  • 13
  • 13  
EX 

Pinter (2009)40 

6 mo 

Unclear 

  • CRT-D
  • ICD 
  • 36
  • 36 
 NR NR  NR  NR 
  • 0.21 (0.08)
  • 0.24 (0.08)
NR  NR  NR  NR 

B-LEFT HF (2010)41 

6 mo 

Industry 

  • CRT-D
  • LV-ICD
  • 90
  • 86
NA   NA 
  • 93
  • 94 
  • 7
  • 6  
  • 0.26(0.06)
  • 0.25 (0.06)
  • 160 (19)
  • 162 (20)
  • 90
  • 87  
NR  EX 

COMBAT (2010)42 

3 mo 

Industry 

  • RV-BiV-RV
  • BiV-RV-BiV  
  • 27
  • 27
NA  
  • 16
  • 17 
  • 52
  • 52 
  • 32
  • 31
  • 0.29 ((0.07)
  • 0.30 (0.09) 
  • 154 (13)
  • 148 (16)
NR  NR  EX 

RAFT (2010)43 

40 mo 

Govt, Industry 

  • CRT-D
  • ICD 
  • 894
  • 904 
NA  
  • 79
  • 81
  • 21
  • 19 
NA 
  • 0.262(0.05)
  • 0.22 (0.05) 
  • 157 (24)
  • 158 (24)
  • 73
  • 71  
  • 8
  • 10 
  • 13
  • 13 

Greater-EARTH (2011)44 

6 mo 

Govt 

  • BiV-ICD first
  • LV-ICD first
  • 61
  • 60
  • 8
  • 59
  • 63 
  • 33
  • 28  
NA 
  • 0.24 (0.07)
  • 0.24 (0.06) 
  • 157 (24)
  • 153 (22)
NR  NR  NR 

van Geldorp (2010)45 

6 mo 

Industry 

  • CRT first
  • RV first 
  • 19
  • 18 
  • 26
  • 24 
  • 47
  • 59  
  • 26
  • 18  
NA 
  • 0.36 (0.09)
  • 0.36 (0.11)
  • 196 (29)
  • 193 (23) 
NR  NR 
  • 63
  • 41 

RESPOND (2011)46

6 mo

Unclear 

  • CRT
  • Usual care
  • 29
  • 31 
NA   NA  
  • 65
  • 84  
  • 35
  • 16  
  • 0.22 (0.08)
  • 0.22 (0.10)
  • 98 (11)
  • 98 (13)   
NR  NR  NR 

Adapted from Al-Majed (2011).4
AF: atrial fibrillation; BiV: biventricular; CRT: cardiac resynchronization therapy; CRT-D: cardiac resynchronization therapy with implantable cardioverter defibrillator; Dur: duration; ECG: electrocardiogram; ex: Excluded; Govt: Government; ICD: implantable cardioverter defibrillator; LBBB: left bundle branch block; LV: left ventricular; LVEF: left ventricular ejection fraction; NA: not applicable; NR: not reported; NYHA: New York Heart Association; RBBB: right bundle branch block; RV: right ventricular; Uni-V: univentricular.
a  Median. 
b  Simultaneous and sequential BiV+ICD.

MADIT-CRT Trial 
The largest trial published to date is the single-blind Multicenter Automatic Implantation Trial-Cardiac Resynchronization (MADIT-CRT) trial, which randomized 1820 patients with NYHA class I (n=265) or II (n=1555) heart failure and an LVEF 30% or less to an ICD alone or a CRT-D device.39, The MADIT-CRT trial reported a reduction for the CRT-D group on the primary outcome (ie, death or acute heart failure exacerbation). The primary end point was reached by 17.2% of patients in the CRT-D group compared with 25.3% of patients in the ICD alone group. The first component of the composite outcome (acute heart failure events) occurred in 22.8% of patients in the ICD alone group compared with 13.9% of patients in the CRT-D group (relative risk reduction, 39%; absolute risk reduction, 8.9%; number needed to treat, 11.2). This difference in acute heart failure events accounted entirely for the difference on the primary composite outcome. The death rate was similar between groups. Subgroup analyses found significantly reduced mortality of CRT-D vs ICD for NYHA ischemic and nonischemic class II; however, the effect in NYHA class I patients was not statistically significant. The interaction for class by treatment group was not given but was reported to be not statistically significant. 

A follow-up from the MADIT-CRT trial, published by Goldenberg et al (2011), analyzed the reduction in recurrent heart failure events.48, This analysis supplemented the original MADIT-CRT outcome of time to first heart failure event, by comparing total heart failure events during an average follow-up of 2.6 years. Over this time period, there was a 38% relative reduction in heart failure events in the CRT group (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.45 to 0.85; p=0.003). On subgroup analysis, the benefit was evident in patients with left bundle branch block (LBBB; HR=0.50; 95% CI, 0.33 to 0.76; p=0.001) but not in patients without LBBB (HR=0.99; 95% CI, 0.58 to 1.69;   p=0.96). 

Goldenberg et al (2014) analyzed mortality in MADIT-CRT trial subjects with follow-up through 7 years, stratified by the presence or absence of LBBB.49, Follow-up was available for a median 5.6 years among all 1691 surviving patients enrolled in  the trial, and beyond that for 854 subjects enrolled in posttrial registries. Seventy-three percent and 75% of the ICD-only and CRT-D groups, respectively, had LBBB; 69% of each group had a QRS interval of a least 150 ms. At 7-year follow-up, the cumulative rate of death from any cause among patients with LBBB was 29% in the ICD-only group compared with 18% in the CRT-D group (p=0.002; adjusted HR in the CRT-D group, 0.59; 95% CI, 0.43 to 0.80; p<0.001). The benefit associated with ICD-CRT was consistent in subgroup analysis among patients with a prolonged QRS interval (≥150 ms) and a shorter QRS interval (<150 ms). In multivariable analysis, there was no significant interaction between QRS interval and overall survival. Among patients without LBBB, there was no significant difference in the cumulative rate of death from any cause between the ICD-only and CRT-D  groups. 

RAFT Trial 
A second, large RCT was the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT), which randomized 1798 patients with class II or III heart failure and an LVEF of 30% or less to CRT-D or ICD alone, with a mean follow-up 40 months.43, Unlike most previous trials, this trial did not confine enrollment to patients with sinus rhythm but also allowed   patients with atrial arrhythmias to participate. However, the number of patients who were not in sinus rhythm was only 12.8% (229/1798). On formal quality assessment, this trial met all quality indicators and was given a "good" quality rating.

The primary outcome (death from any cause or hospitalization for heart failure) was reduced in the CRT-D group (33.2%) compared with the ICD alone group (40.3%; p<0.001). There were significant reductions in both individual components of the primary outcome, overall mortality (20.8% vs 26.1%; p=0.003) and hospitalizations (19.5% vs 26.1%; p<0.001), all respectively. When restricted to patients with NYHA class II heart failure, improvements in the outcomes of mortality and hospitalizations remained significant. The mortality rate for class II patients in the CRT-D group was 15.5% vs 21.1% in the ICD alone group (HR=0.71; 95% CI, 0.56 to 0.91; p<0.006). Hospitalizations for class II patients occurred in 16.2% of patients   in the CRT-D group and 21.1% in the ICD alone group (HR=0.70; 95% CI, 0.55 to 0.89; p<0.003). 

In a preplanned subgroup analysis of RAFT data focusing on hospitalization rates over the 18-month follow-up period, Gillis et   al (2014) reported that the fewer patients in the CRT-D group (11.3%) were hospitalized for heart failure than those in the ICD alone group (15.6%; p=0.003).50, Although the total number of hospitalizations for any cause was lower in the CRT-D group (1448 vs 1553; p=0.042), patients randomized to CRT-D had more hospitalizations for device-related indications (246 vs 159; p<0.001). 

Subgroup analyses from RAFT reported that female sex, a QRS interval of 150 ms or more, an LVEF less than 20%, and QRS morphologic features were predictive of benefit. Of these factors, the QRS interval was the strongest. Patients with a QRS interval of 150 ms or more had an RR for the primary outcome of approximately 0.50, compared with an RR of approximately 1.0 for patients with a QRS interval less than 150 ms (p=0.003 for the difference between the RRs). There was a trend for greater improvement in patients with sinus rhythm compared with patients with atrial arrhythmias, but this difference was not statistically significant. 

Safety of CRT Placement
Several systematic reviews have reported on complication rates. Three reviews published after 2010 are shown in Table 4. Van Rees et al (2011) focused on complications from CRT treatment.51, This analysis included 7 trials of CRT that reported on in- hospital mortality and complications related to device placement. In all 7 CRT trials, the device was placed percutaneously without a thoracotomy. In-hospital mortality occurred at a rate of 0.3%, and 30-day mortality was 0.7%. The most common complications related to placement of the left ventricular (LV) lead. Lead dislodgement occurred in 5.9% of patients. Other LV lead placement complications included coronary vein dissection (1.3%) and coronary vein perforation (1.3%). Pneumothorax occurred in 0.9% of patients, and hematoma at the insertion site occurred in 2.4% of patients. Other systematic reviews have reported similar implant success rates, 30-day mortality, and lead   problems..   

Table 4. Systematic Reviews of Safety of CRT for Treatment of Heart Failure

Study Dates Population Studies (N) Designs Included Outcome Measures Results (95% CI)
CRT

van Rees et al (2011)51

Through 2010

Undergoing elective CRT 7 RCTs (N=4,512) RCTs
  • Implant success rate
  • In-hospital mortality
  • Mortality within 30 days
  • Pneumothorax
  • Coronary dissection
  • Coronary perforation
  • Pocket hematoma
  • Lead dislodgement
  • 92.5%
  • 0.3%
  • 0.7%
  • 0.9%
  • 1.3%
  • 1.3%
  • 2.4%
  • 5.9%

Al-Majed et al (2011)4

1950-2010 EF ≤40% 23 RCTs (N=8,374) RCTs
  • Implant success rate
  • Mechanical complications
  • Device malfunction
  • Lead problems
  • Infections
  • Peri-implantation death)
  • 94.4% (93.8% to 94.8%)
  • 3.2% (2.8% to 3.6%)
  • 1.9% (1.5% to 2.4%)
  • 6.2% (5.6% to 6.8%)
  • 1.4% (1.1% to 1.7%)
  • 0.3% (0.2% to 0.5%)
CRT vs ICD

Adabag et al (2011)7

1960-2010
  • NYHA class I/II
  • EF ≤40%
  • QRS interval ≥120 ms
4 studies (N=4,414) RCTs
  • In hospital death
  • Pneumothorax
  • Lead dislodgment
  • Coronary sinus dissection
  • Implant failure
  • Any adverse event
  • 0.05% vs 0.06%
  • 1.5% vs 0.8%
  • 5.1% vs 0%
  • 0.8% vs 0%
  • 6.6% vs <0.1%
  • 18% vs 4%

CI: confidence interval; CRT: cardiac resynchronization therapy; EF: ejection fraction; NYHA: New York Heart Association: RCT: randomized controlled trial.

Hosseini et al (2017) reported on in-hospital complication rates of CRT from 2003 to 2013 using data from the National Inpatient Sample and the Nationwide Inpatient Sample (NIS), the largest all-payer inpatient database of hospital discharge  records in the United States.52, The NIS includes approximately 20% of discharges from U.S. hospitals and sampling weights provided by the NIS can be used to produce national estimates from NIS data. A total of 92,480 unweighted records (corresponding to 376,045 weighted records) were analyzed. In patients receiving CRT-D and CRT with a pacemaker (CRT-P), 6.04% and 6.54% had at least 1 complication, respectively. The overall rate of at least 1 complication increased from 5.86% in 2003 to 6.95% in 2013 (p=0.01) for CRT-D and from 5.46% to 7.11% (p=0.01) in CRT-P. In the CRT-D group, the overall increase in complications was driven by increases in pericardial complications, vascular complications, and postoperative infections. In the CRT-P group, the overall increase in complications was driven by an increase in vascular complications. The most common adverse outcomes were pulmonary complications (1.48%), hemorrhage/hematoma (1.41%), and infection (1.17%). The in-hospital mortality rate was 0.70% for CRT-D and 1.08% for CRT-P. 

Predictors of Response to CRT 
For patients who meet indications for CRT treatment, there is a large variability in the magnitude of response. Some patients do not respond at all, while others have very substantial benefit. As a result, there is interest in defining the clinical features that predict response to better target therapy to those who will benefit most. There is a large body of literature examining predictors of outcomes after CRT placement, and numerous clinical and demographic factors have been identified that predict response. A smaller number of predictors have been proposed as potential selection criteria for CRT placement. 

An example of a study examining general predictors of outcome is The Predictors of Response to Cardiac Resynchronization Therapy (PROSPECT) trial.53, This prospective, multicenter trial evaluated the utility of echocardiographic parameters to predict response to CRT. Trial results indicated that the 12 individual echocardiographic parameters varied widely in ability to predict response.54, The sensitivity of these individual measures ranged from 6% to 74%, and the specificity ranged from 35%   to 91%. The authors concluded it was unlikely that these measures could improve patient selection for CRT. Three additional selection factors are reviewed here: QRS interval /morphology, prolonged PR interval, and ventricular dyssynchrony on echocardiography. 

QRS Interval/Morphology 
It is well accepted that patients with a QRS complex of less than 120 ms who are not selected for dyssynchrony do not benefit from CRT. LESSER-EARTH was an RCT designed to compare CRT with no CRT in patients with a QRS complex of less than 120 ms, whether or not ventricular dyssynchrony was present.55, This trial was terminated early after 85 patients had been enrolled. Interim analysis revealed futility in achieving benefit on the primary outcomes and a trend toward greater adverse  events. 

A more controversial issue is whether patients with a moderately prolonged QRS interval (120-150 ms) benefit from CRT, or whether the benefit is confined to subsets of patients such as those with a markedly prolonged QRS interval (>150-160 ms) or LBBB. Several meta-analyses of the association between QRS interval and outcomes have been published. Two patient-level meta-analyses have evaluated QRS duration. In a patient-level meta-analysis of data from 3 RCTs (total N=4076 patients), Zusterzeel et al (2014) evaluated whether women with LBBB benefit from combined CRT-D implantation at a shorter QRS interval than men with LBBB.56 For patients with LBBB and a QRS interval from 130 to 149 ms, women experienced a  significant reduction in risk of heart failure or death (absolute risk difference between CRT-D and ICD alone, 23%; HR=0.24;  95% CI, 0.11 to 0.53; p<0.001), while men had no significant reduction in risk of heart failure or death (absolute risk difference, 4%; HR=0.85; 95% CI, 0.60 to 1.21; p=0.38). Men and women with LBBB and QRS durations longer than 150 ms benefited   from CRT-D therapy, while neither men nor women with LBBB and QRS intervals shorter than 130 ms benefited. This trial's conclusion is strengthened because of the patient-level data examined, but somewhat limited because not all RCTs had patient-level data available. 

In a second review including individual patient data, Woods et al (2015) performed a network meta-analysis of ICDs to inform a National Institute for Health and Care Excellence guidance.14, Thirteen RCTs with 12,638 patients were included. Estimates of CRT effect on mortality were given for 16 subgroups (men vs women; <60 years vs ≥60 years; QRT interval ≥120 ms to <150 ms vs ≥ 150 ms; LBBB vs no LBBB; see Table 5). In women in both age groups, CRT-D statistically significantly reduced mortality compared with medical therapy alone for both QRS intervals (≥120 ms to <150 ms and ≥150 ms) with and without LBBB. Also, in women of both age groups, CRT-P significantly reduced mortality compared with medical therapy alone with  QRS intervals of 150 ms or more and LBBB. CRT-D significantly reduced mortality compared with ICD alone for women younger than 60 with a QRS of 150 ms or more and LBBB, women older than 60 with QRS intervals ranging from 120 ms to 150 ms and LBBB, and women older than 60 with QRS intervals of 150 ms or more with or without LBBB. For men in both age groups, CRT-D reduced mortality compared with medical therapy alone in both QRS groups with and without LBBB. However, CRT-P significantly improved survival compared with medical therapy alone only in men older than 60 years with QRS intervals of 150 ms or more and LBBB. Likewise, CRT-D improved survival compared with ICD alone in men older than 60 years with QRS intervals of 150 ms or more and LBBB.   

Table 5. Subgroup-Specific Treatment Effects in Network Meta-Analysis Reported in Woods et al (2015)14

Sex Age QRS LBBB CRT-D vs MT CRT-P vs MT CRT-D vs ICD
        HR (95% CI) HR (95% CI) HR (95% CI)
Women <60 ≥120 to <150 N

0.62

(0.40 to 0.96)

0.86

(0.50 to 1.48) 

0.90 

(0.58 to 1.39) 

Women <60 ≥120 to <150 Y

0.55

(0.36 to 0.84)

0.76

(0.46 to 1.25) 0.74

(0.48 to 1.13) 

Women <60 ≥150 N

0.55

(0.35 to 0.(86)

0.74

(0.42 to 1.28)

0.71

(0.46 to 1.12) 

Women <60 ≥150 Y

0.48

(0.33 to 0.72)

0.65 (0.42 TO 1.00)  0.59  (0.40 to 0.87)
Women ≥60 ≥120 to <150 N

0.60

(0.41 to 0.90)

0.75

(0.46 to 1.21)

0.71 

(0.48 to 1.04) 

Women ≥60 ≥120 to <150 Y

0.53

(0.37 to 0.78)

0.65

(0.42 to 1.02)

0.59 

(0.41 to 0.84) 

Women ≥60 ≥150 N

0.53

(0.35 to 0.80)

0.64

(0.39 to 1.03)

0.57 

0.38 to 0.84) 

Women ≥60 ≥150 Y

0.47

(0.34 to 0.66)

0.56

(0.40 to 0.79)

0.47 

(0.34 to 0.64) 

Men <60 ≥120 to <150 N

0.72

(0.51 to 1.01)

1.07

(0.70 to 1.64)

1.37 

(0.98 to 1.92)

Men <60 ≥120 to <150 Y

0.63

(0.44 to 0.91)

0.94

(0.61 to 1.43)

1.13 

(0.80 to 1.61) 

Men <60 ≥150 N

0.63

(0.44 to 0.91)

0.91

(0.58 to 1.42)

1.10 

(0.78 to 1.54) 

Men <60 ≥150 Y

0.56

(0.40 to 0.77)

0.80 

(0.56 to 1.14)

0.90  (0.67 to 1.23)
Men ≥60 ≥120 to <150 N

0.70

(0.53 to 0.92)

0.92 

(0.64 to 1.32)

1.09 

(0.85 to 1.39) 

Men ≥60 ≥120 to <150 Y

0.62

(0.46 to 0.83)

0.81 

(0.57 to 1.16)

0.90

(0.69 to 1.16) 

Men ≥60 ≥150 N

0.62

(0.46 to 0.83)

 0.79

(0.55 to 1.12)

0.87 

(0.67 to 1.12) 

Men ≥60 ≥150 Y

0.54

(0.43 to 0.69)

 0.69

(0.55 to 0.87)

0.72 

(0.59 to 0.87)

Adapted from Woods et al (2015).
CI: confidence interval; CRT-D: cardiac resynchronization therapy with implantable cardioverter defibrillator; CRTP: cardiac resynchronization therapy with pacemaker; HR: hazard ratio; ICD: implantable cardioverter defibrillatorl; LBBB: left bundle branch block; MT: medical therapy; N: no; Y: yes 

Other meta-analyses have come to similar conclusions, reporting benefits for patients with a QRS interval of more than 150 ms, and little to no benefit for patients with shorter QRS intervals.57-62, In one of these studies, the benefit of CRT was confined to patients with LBBB.60, There was no benefit demonstrated for patients with right bundle branch block or intraventricular conduction delay. These reviewers suggested that QRS morphology may be as important, or more important,   than QRS duration in predicting response to  CRT. 

Peterson et al (2013) published results of a retrospective cohort study of Medicare beneficiaries who underwent combined CRT-D placement to assess associations between QRS interval and morphology and outcomes.63 Among 24,169 patients admitted for CRT-D placement and followed for up to 3 years, rates of 3-year mortality and 1-year all-cause rehospitalization were lowest in patients with LBBB and QRS intervals of 150 ms or more. Patients with no LBBB and QRS intervals from 120 to 149 ms had an adjusted HR of 1.52 (95% CI, 1.38 to 1.67) after controlling for a number of clinical and demographic confounders (vs those with LBBB and markedly prolonged QRS  interval).

Prolonged PR Interval 
The data are inconsistent on the association between PR interval and outcomes in CRT. 

Kutyifa et al (2014) evaluated whether prolonged PR predicts heart failure or death among 537 (30%) of MADIT-CRT trial subjects who did not have an LBBB.64 Among the 96 patients with a prolonged PR interval, compared with ICD alone, CRT-D treatment was associated with reduced risk of heart failure or death (HR=0.27; 95% CI, 0.13 to 0.57; p<0.001). In contrast,  among the 438 subjects with a normal PR interval, CRT-D treatment was associated with a nonsignificant trend toward   increased risk of heart failure or death (HR=1.45; 95% CI, 0.96 to 2.19; p=0.078). In long-term follow-up of MADIT-CRT, the reduction in mortality for CRT-D vs ICD in those with prolonged PR was similar to the short-term results (HR=0.24; 95% CI, 0.07 to 0.80), but the increase in mortality for CRT-D vs ICD in normal PR was larger than in the short-term results (HR=2.27; 95% CI, 1.16 to 4.44).65,

In an analysis of 26,451 CRT-eligible (ejection fraction ≤35, QRS interval ≥120 ms) patients from the National Cardiovascular Data Registry, Friedman et al (2016) examined the association between prolonged PR interval (≥230 ms), receipt of CRT-D vs ICD-only, and outcomes.66 All Medicare beneficiaries who receive a primary prevention ICD are enrolled in this ICD registry. Patients with a prolonged PR interval were more often male, older, with comorbid ischemic heart disease, atrial arrhythmias, cerebrovascular disease, diabetes, and chronic kidney disease. After adjusting for other risk factors, a prolonged PR was   associated with increased risk of heart failure hospitalization or death among CRT-D (HR=1.2; 95% CI, 1.1 to 1.3; p<0.001) compared with normal PR interval. There was no association between PR interval and hospitalization or death among ICD-only recipients (HR=1.1; 95% CI, 1.0 to 1.2; p=0.17). CRT-D was associated with lower rates of heart failure hospitalization or death compared with ICD-only among patients who had a PR interval less than 230 (HR=0.79; 95% CI, 0.73 to 0.85; p<0.001) but not with PR interval of 230 or more (HR=1.01; 95% CI, 0.87 to 1.17; p=0.90). Limitations of this analysis included lack of randomization (ie, residual confounding) and potential inaccuracies in registry data. 

Lin et al (2017) reported on a secondary analysis of mortality and hospitalization including 903 patients stratified by normal (255 patients ≤230 ms) or prolonged PR interval (53 patients >230 ms) from the medical therapy and CRT-D arms of the COMPANION trial.67, Mortality was significantly reduced in patients with a prolonged PR interval who received CRT-D vs medical therapy (HR=0.37; 95% CI, 0.21 to 0.67). However, the association was smaller and not significantly significant in those with a normal PR interval (HR=0.73; 95% CI, 0.52 to 1.03). 

Ventricular Dyssynchrony 
Observational studies of patients who meet criteria for CRT have shown that measures of dyssynchrony on echocardiography correlate with treatment response, as defined by improvements in LV end-systolic volume (LVESV), ejection fraction, or clinical criteria.68 This finding prompted investigation of whether ventricular dyssynchrony could discriminate between   responders and nonresponders to CRT, for patients who would otherwise qualify for CRT and for those who would not (ie, those with a narrow QRS  interval). 

A small RCT that compared CRT outcomes in patients who had ventricular dyssynchrony with those without was published by Diab et al (2011).69, A total of 73 patients with NYHA class II, III, IV heart failure were evaluated, 44 of whom had dyssynchrony on echocardiography. These 44 patients were randomized to CRT-D or ICD alone. Outcomes measures were maximal oxygen consumption (VO2max), NYHA class, and echocardiographic parameters. At 6-month follow-up, more patients   in the CRT group had an increase of at least 1 mL/kg/min in VO2max (62% vs 50% p=0.04). There were significant within- group improvements in NYHA class and echocardiographic measures, but between-group comparisons with the no CRT group were not statistically  significant. 

The NARROW-CRT RCT compared CRT using dual-chamber ICD among patients who had heart failure (NYHA class II-III) of ischemic origin, ejection fraction of 35% or less, QRS interval less than 120 ms, and marked mechanical dyssynchrony on echocardiogram.70 One hundred twenty patients were randomized to CRT (n=60) or ICD (n=60). For the trial's primary outcome (heart failure clinical composite score), compared with those in the ICD group, patients in the CRT were more likely to have improved clinical composite scores at 1 year postimplantation (41% vs 16%, p=0.004). Patients in the CRT group had  higher rates of avoiding the combined end point of heart failure hospitalization, heart failure death, and spontaneous ventricular fibrillation (p=0.028). 

The EchoCRT study was intended to evaluate the role of CRT for subjects with heart failure (NYHA class III or IV) with narrow QRS interval (<130 ms) and echocardiographic evidence of ventricular dyssynchrony. All enrolled patients were implanted with a CRT-D, and then randomized to CRT with the device on or off. The study was stopped for futility after enrollment of 809 patients; results from the enrolled patients who had been followed for a mean of 19.4 months were reported by Ruschitzka et al (2013).71, Four hundred four patients were randomized to the CRT group and 405 to the control group. The primary efficacy outcome (death from any cause or hospitalization for worsening heart failure) occurred in 116 (28.7%) of 404 patients in the CRT group and 102 (25.2%) of 405 in the control group (HR with CRT, 1.20; 95% CI, 0.92 to 1.57; p=0.15).

There was a significantly higher death rate in the CRT group: 45 (11.1%) of 404 patients died in the CRT group while 26 (6.4%)  of 50 died in the control group (HR=1.81; 95% CI, 1.11 to 2.93;   p=0.02). 

The Resynchronization Therapy in Normal QRS Trial (RethinQ study) randomized 172 patients with a narrow QRS interval and evidence of dyssynchrony to a CRT device, turned on or not, who were followed for 6 months.36 CRT-treated patients (46%)   were no more likely than non-CRT patients (41%) to show improvement (meet the end point of improvement in exercise capacity [VO2peak]). A subset of patients with QRS intervals of 120 to 130 ms or more showed improvement (p=0.02), whereas those with a QRS interval less than 120 ms did not (p=0.45). 

Section Summary: Cardiac Resynchronization Therapy for Heart Failure
NYHA Class III or IV Heart Failure
There is a large body of clinical trial evidence that supports the use of CRT in patients with NYHA class III or IV heart failure. Results of RCTs have consistently reported that CRT treatment leads to reduced mortality, improved functional status, and improved quality of life (QOL) for patients with NYHA class III or IV heart failure. 

NYHA Class I or II Heart Failure 
For patients with mild heart failure (NYHA class I or II), at least 4 RCTs of CRT have been published. A mortality benefit was reported in 1 trial (RAFT). This trial was free of major bias and reported a fairly large absolute difference in overall mortality (5.3%). None of the other 3 RCTs reported a mortality difference. While 2 of the other 3 trials were underpowered to detect differences in mortality, MADIT-CRT was approximately the same size as RAFT and did not show any improvement in mortality. In a subgroup analysis of the MADIT-CRT trial, a mortality benefit was shown in patients with LBBB. It is possible that the sicker patient population and longer follow-up in RAFT accounted for the mortality difference. Among other outcome measures, hospitalizations for heart failure showed consistent improvements, but QOL and functional status did not. Most patients in these trials had class II congestive heart failure. Hence it is not possible to determine separately whether patients with class I heart failure achieved benefit. However, when mild heart failure is considered as a group (class I or II), these data are sufficient to determine that outcomes are improved for patients with mild heart failure. 

Predictors of Response 
The presence of dyssynchrony on echocardiography may risk-stratify patients, but it is not a good discriminator of responders from nonresponders. A QRS interval of more than 150 ms or the presence of LBBB appears to discriminate well between responders and nonresponders and represents a potential factor in selecting patients for CRT treatment. Subgroup analyses across multiple RCTs, corroborated by pooling of these subgroups in meta-analyses, have reported that QRS intervals of 150 to  160 ms or more or the presence of LBBB are accurate in discriminating responders from nonresponders. Subgroup analyses of 2 RCTs and 1 registry study have provided inconsistent results on the role of prolonged PR interval. Two patient-level meta-analyses reported that women might benefit at a shorter QRS interval than men. 

CRT for Heart Failure and Atrial Fibrillation 
There is controversy whether CRT leads to health outcome benefits for patients with atrial fibrillation (AF). Many experts believe that, if CRT is used, it should be combined with ablation of the atrioventricular (AV) node to avoid transmission of atrial impulses through the node that might result in rapid ventricular rates, thus undermining the efficacy of CRT. Most trials of CRT have excluded patients with permanent AF; however, 2 trials (APAF, MUSTIC-AF) have examined CRT specifically in this population, and other RCTs have reported subgroup analyses in patients with permanent or intermittent AF. Systematic reviews of observational studies have also been performed, and analysis from the National Cardiovascular Data Registry is available. 

Randomized Controlled Trials
Kalscheur et al (2017) reported on a comparison of outcomes between CRT-P and medical therapy in patients with intermittent AF or atrial flutter (n=293) and those without (n=887) in COMPANION.72, Intermittent AF and atrial flutter were determined from medical history and chart review at enrollment. Cox proportional hazard models were used to estimate effects. The interaction between history of intermittent AF and atrial flutter and CRT treatment group was statistically significant for both death and hospitalization outcomes (p<0.05). In CRT-P group, there was a significant reduction in the composite outcome of death or any hospitalization (HR=0.73; 95% CI, 0.60 to 0.89; p=0.002) and in the composite of death or heart failure hospitalization (HR=0.53; 95% CI, 0.41 to 0.68; p<0.001). In contrast, in the intermittent AF and atrial flutter group (n=293), CRT-P did not result in improved outcomes vs medical therapy (death or any hospitalization HR=1.16; 95% CI, 0.83 to 1.63; p=0.38; death or heart failure hospitalization HR=0.97; 95% CI, 0.64 to 1.46;    p=0.88). 

The 2011 Ablate And Pace Therapy for Permanent Atrial Fibrillation (APAF) RCT compared CRT with right ventricular (RV) pacing alone in patients with AF.73 A total of 186 patients had AV nodal ablation, implantation of a CRT device, and were then randomized to echo-optimized CRT or RV pacing alone and followed for a median of 20 months. The primary outcome measure was a composite of death from heart failure, hospitalization for heart failure, or worsening heart failure. This combined end point occurred in 11% of the CRT group and 26% of the RV pacing group (HR=0.37; 95% CI, 0.18 to 0.73; p=0.005). For the individual outcome measures, there was no significant reduction in mortality (HR=1.57; 95% CI, 0.58 to 4.27; p=0.37), but  there were significant reductions in hospitalizations (HR=0.20; 95% CI, 0.06 to 0.72; p=0.013) and worsening heart failure (HR=0.27; 95% CI, 0.12 to 0.58; p=0.37). There were no differences in outcomes on subgroup analysis, including analysis by ejection fraction, NYHA class, and/or QRS  interval. 

In the MUltisite STimulation In Cardiomyopathies and Atrial Fibrillation (MUSTIC-AF) trial, 59 NYHA class III patients with  LV systolic dysfunction, slow and permanent AF of greater than 3 months duration, and a paced QRS interval greater than 200   ms were randomized in a single-blinded, crossover design to RV vs biventricular pacing with 3 months for each period.20, The primary outcome was the 6-minute walk distance; secondary outcomes were VO2max, QOL, hospitalizations, patients' preferred study period and mortality. Only 37 patients completed both crossover periods. In intention-to-treat analyses, no significant differences were observed between assigned  groups. 

A post hoc analysis of patients with AF enrolled in RAFT was published by Healey et al (2012).74, Randomization in this trial  was stratified for the presence of AF, allocating 114 patients with AF to the CRT plus defibrillator group and 115 patients with AF to the defibrillator group alone. There was no difference between groups in the primary outcome of death or hospitalization due to heart failure (HR=0.96; 95% CI, 0.65 to 1.41; p=0.82). There were also no differences in cardiovascular death or functional status. There was a trend for patients in the CRT group to have fewer hospitalizations for heart failure than those in the defibrillator-alone group, but the difference was not statistically significant. 

Systematic Reviews
A systematic review by Wilton et al (2011) compared outcomes of CRT in patients with and without AF.75, This analysis  included 23 observational studies enrolling 7495 patients, 1912 of whom had AF. Outcomes in patients with AF were less favorable on all measures. They included overall mortality (RR=1.5; 95% CI, 1.08 to 2.09; p=0.015), nonresponse to CRT (RR=1.32; 95% CI, 1.12 to 1.55; p=0.001), change in Minnesota Living with Heart Failure Questionnaire QOL score (mean difference, -4.1; 95% CI, -1.7 to -6.6; p=0.001), and change in 6-minute walk distance (mean difference, -14.1 meters; 95% CI, -28.2 to 0.0 meters; p=0.05). Five studies compared outcomes of patients with AF who had or did not have AV nodal ablation. A pooled analysis from these studies indicated that AV nodal ablation was associated with a lower rate of nonresponse (RR=0.40; 95% CI, 0.28 to 0.58;  p<0.001). 

A systematic review by Ganesan et al (2012) evaluated the role of AV node ablation in patients with AF treated with CRT.76, Reviewers included nonrandomized studies that reported on outcomes for CRT and medical therapy. Six studies were included, enrolling 768 patients, 339 of whom underwent AV node ablation and 429 of whom did not. AV nodal ablation was associated with improvements in the outcomes of all-cause mortality (RR=0.42; 95% CI, 0.26 to 0.68), cardiovascular mortality (RR=0.44; 95% CI, 0.24 to 0.81), and change in NYHA class (mean difference, -0.34; 95% CI, -0.56 to -0.13; p=0.002). 

Yin et al (2014), in another systematic review and meta-analysis, evaluated the effects of AV nodal ablation; it included 13 observational studies (total N=1256 patients) of CRT patients with AF who received AV nodal ablation or medical therapy.77, In pooled analysis of patients with inadequate biventricular pacing (<90% biventricular pacing), AV nodal ablation was associated with lower risk of all-cause mortality than no ablation (RR=0.63; 95% CI, 0.42 to 0.96), along with a reduced risk of CRT nonresponse (RR=0.41; 95% CI, 0.31 to 0.54). In contrast, among patients with adequate biventricular pacing (>90% biventricular pacing), AV nodal ablation was not significantly associated with risk of CRT nonresponse (RR=0.97; 95% CI, 0.72 to 1.32). 

Registry Data
Khazanie et al (2016) analyzed data from the National Cardiovascular Data Registry, which linked with Medicare claims and compared beneficiaries who receive CRT-D with those who received ICD alone.78, The dataset included 8951 patients with heart failure and AF with a QRS interval of 120 ms or more and a LEVF of 35% or less who had a registry record for CRT-D or ICD placement between 2006 and 2009 who were discharged alive to home. The authors used Cox proportional hazard models and inverse probability-weighted estimates to compare outcomes. CRT-D was associated with lower mortality (HR=0.83; 95% CI, 0.75 to 0.92), all-cause readmission (HR=0.86; 95% CI, 0.80 to 0.92), and heart failure readmission (HR=0.68; 95% CI, 0.62 to 0.76) compared with ICD  alone. 

Section Summary: CRT for Heart Failure and Atrial  Fibrillation 
There is insufficient evidence to determine whether CRT improves outcomes for patients with AF and heart failure. Data from 2 RCTs enrolling only patients with AF showed different results, with one reporting improvements for patients with AF and another reporting no significant improvements. Subgroup analyses of the RAFT and COMPANION trials did not show the benefit of CRT in patients with permanent or intermittent AF. Similarly, systematic reviews of observational studies have   reported conflicting results. A registry study including almost 9000 Medicare beneficiaries reported significant improvements in mortality and hospitalizations for patients with heart failure and AF treated with CRT-D compared with ICD alone. 

CRT for Heart Failure and AV Nodal Block 
Patients with heart failure may require pacemakers for symptomatic bradycardia; those patients have a high risk of mortality or require heart transplant due to progressive heart failure, which is thought to be due, in part, to dyssynchronous contraction caused by RV pacing. 

In 2014, the U.S. Food and Drug Administration expanded the indications for several CRT devices to include patients with  NYHA functional class I, II, or III heart failure and an LVEF of 50% or less, and AV block. A high percentage of these patients are expected to require ventricular pacing that cannot be managed with algorithms to minimize RV pacing. The Food and Drug Administration approval was based on results of the BLOCK HF trial, in which patients with an indication for a pacemaker and NYHA class I, II, or III heart failure were implanted with a combined CRT-P or CRT-D (if indicated) and randomized to standard RV pacing or biventricular pacing.79, Patients with permanent atrial arrhythmias and intrinsic AV block or AV block   due to AV node ablation could be enrolled if they met other enrollment criteria. At baseline, patients met the requirement for ventricular pacing, either because of documented third-degree AV block or a second-degree AV block or a PR interval of 300 ms or more when paced at 100 beats per  minute. 

Nine-hundred eighteen patients were enrolled, 691 of whom underwent randomization after 30 to 60 days of RV pacing, during which time appropriate pharmacologic therapy was established. Approximately half of all enrolled patients (51.6% of the CRT group, 54.1% of the RV pacing group) had AF. After accounting for censored data due to missing measures of LVESV index, the primary outcome (first event of death from any cause, an urgent care visit for heart failure requiring intravenous therapy, or an increase in the LVESV index of ≥15%) occurred in 160 (45.8%) of 349 patients in the biventricular pacing group and in 190 (55.6%) of 342 in the RV pacing group. In a hierarchical Bayesian proportional hazards model, the hazard ratio for the primary outcome was 0.74 for the comparison between biventricular pacing and RV pacing (95% CI, 0.60 to 0.90; posterior probability of HR being ≤1, 0.9978, which is greater than the prespecified threshold for superiority of biventricular to RV pacing of 0.9775). The prespecified secondary outcomes of an urgent care visit for heart failure, death or hospitalization for heart failure, and hospitalization for heart failure were less likely in the biventricular pacing group; however, the secondary outcome of death alone did not differ significantly between groups. LV lead-related complications occurred in 6.4% of patients. In another publication from the BLOCK HF study, reported by Curtis et al (2016), patients in the CRT group showed greater improvements in NYHA class at 12 months (19% improved, 61% unchanged, 17% worsened) compared with the RV group (12% improved, 61% unchanged, 23% worsened; posterior probability, 0.99).80, At 6 months, Packer clinical composite score was improved, unchanged, or worsened in 53%, 24%, and 24% in the CRT group compared with 39%, 33%, and 28% in the RV arm (posterior probability, ≥0.99), respectively. The Packer clinical composite score classifies patients into 3 categories   (improved, worsened, unchanged) using clinical outcomes, heart failure status, and patient symptoms.

Results of the BLOCK HF RCT were compared with results from the an earlier trial (PACE), in which 177 patients with bradycardia and a normal ejection fraction in whom a biventricular pacemaker had been implanted were randomized to biventricular pacing (n=89) or RV apical pacing (n=88).81,82, In the trial's main results, at 12 months postenrollment,  subjects who underwent standard pacing had lower mean LVEF than those randomized to biventricular pacing (54.8% vs 62.2%; p<0.001) and higher mean LVESV (35.7 mL vs 27.6 mL; p<0.001). No significant differences were reported for QOL or functional measures or rates of heart failure hospitalization. In long-term follow-up over a mean duration of 4.8 years among 149 subjects, biventricular pacing continued to be associated with improved LV functioning and less LV remodeling.83, Also, during long-term follow-up, heart failure hospitalization occurred more frequently in the RV pacing group (23.9% vs 14.6%; p<0.001). 

Several other RCTs have also corroborated the results of the BLOCK and PACE trials.32,42,84, These trials reported  improvements in physiologic parameters of LV function and improvements in functional status measured by the 6-minute walk test. Some, but not all, of these trials also reported improvements in QOL for patients treated with CRT. 

Section Summary: CRT for Heart Failure and AV Nodal Block 
For patients who have AV nodal block, some degree of LV dysfunction, and who would not necessarily meet conventional criteria for CRT but would require ventricular pacing, a large RCT has demonstrated improvements in heart failure-related hospitalizations and urgent care visits among patients treated with CRT instead of RV pacing alone. For patients who require ventricular pacing but have no LV dysfunction, results of a small RCT have suggested that biventricular pacing is associated with improved measures of cardiac function, but the trial was small and underpowered to detect differences in clinical outcomes. 

Triple-Site CRT 
Triple-site CRT, or triventricular pacing, is a variation of conventional CRT that uses an additional pacing lead. The rationale behind triventricular pacing is that a third pacing lead may improve electromechanical synchrony, and thereby lead to better outcomes. To demonstrate improved outcomes, RCTs are needed that compare outcomes of triple-site CRT with conventional CRT. 

Five RCTs were identified for this review85-89, and are summarized in Table 6. The largest published trial, by Lenarczyk   et al (2012), reported on the first 100 patients randomized to triple-site or conventional CRT in the Triple-Site versus Standard Cardiac Resynchronization Therapy Randomized Trial (TRUST CRT).87 After a follow-up of 1 year, more patients in the conventional arm (30%) were in NYHA class III or IV heart failure than those in the triple-site CRT group (12.5%; p<0.05). Implantation success was similar in the triple-site (94%) and conventional groups (98%; p=NS), but triple-site implantation was associated with longer surgical time and a higher fluoroscopic exposure. Also, more patients in the triple-site group required additional procedures (33% vs 16%,  p<0.05). 

The other 4 trials were smaller, enrolling between 43 and 76 patients. Follow-up in these studies was generally short, with the longest being 1 year. Outcomes reported varied across studies and were a mix of physiologic measures, functional status, and QOL. No outcome measures reported were common across all studies.Three of the 4 studies reported significant improvements  on at least 1 outcome measure, and the fourth study reported no significant differences for the 3 outcomes measured. Adverse events were not  well-reported..

Table 6. Randomized Controlled Trials Comparing Triple-Site CRT With Standard CRT

Study N Group Outcomes
      6MWT MLHFQ NYHA Class Response Rate Ejection Fraction QOL
Rogers et al (2012)89 43a Triple-site CRT

+91 m

-24 points NR NR NR NR
    Standard CRT +65 m -18 points        
P     0.008 <0.001        
Lenarczyk et al (2012)87 100 Triple-site CRT NR NR 12.5%b NR NR NR
    Standard CRT     30%      
P         <0.05      
Bencardino et al (2016)86 43 Triple-site CRT NR NR 96% NR +10% NR
    Standard CRT     60%   +4%  
P         <0.05   <0.001  
Anselme et al (2016)85 76 Triple-site CRT +50 m NR NR 78.8% NR -8.4 points
    Standard CRT +73 m     81.6%   -15.0 points
P     0.40     0.90   0.20
Pappone et al (2015)88 44 Triple-site CRT NR NR NR 76% +15% NR
    Standard CRT       57% +5%  
P           0.33 <0.001  

CRT: cardiac resynchronization therapy; MLHFQ: Minnesota Living with Heart Failure Questionnaire; NR; not reported; NYHA: New York Heart Association; QOL: quality of life; 6MWT: 6-minute walk test.
a All patients had triple-site device implanted. Device programmed to triple-site or standard CRT in random order.
b Percentage of patients in NYHA class III/IV heart failure.
c Percentage of patients who improved at least 1 NYHA class. 

Zhang et al (2018) conducted a meta-analysis of RCTs and comparative observational studies (total N=251 patients) that   evaluated similar outcomes.90, The meta-analysis included 1 RCT (Anselme et al [2016]85,; described above), 2 randomized crossover studies, and 2 nonrandomized comparative studies. Two different pacing modalities were used. One type used 1 lead in the right ventricle and leads in 2 different tributaries in the left ventricle. The other used 2 leads in the right ventricle. Patients in the triple-site pacing group had greater improvement in LVEF (weighted mean difference, 4.04; 95% CI, 2.15 to 5.92;   p<0.001) and NYHA classes (weighted mean difference, -0.27; 95% CI, -0.42 to -0.11; p=0.001). However, there were no significant differences in LV end-diastolic volume or LVESV, 6-minute walk distance, or Minnesota Living with Heart Failure Questionnaire. 

Section Summary: Triple-Site CRT 
For the use of CRT with triple-site pacing requiring implantation of an additional lead, 5 small RCTs with limited follow-up and a  meta-analysis that included nonrandomized studies were identified. All trials except one reported improved outcomes on at least 1 measure of functional status and QOL with triple-site CRT compared with conventional CRT. However, the outcomes reported differed across studies, with no common outcomes reported by all studies. Triple-site CRT was also associated with  higher radiation exposure and a greater number of additional procedures postimplantation. Modest improvements in some   outcome measures were found in the meta-analysis. Larger, high-quality RCTs are needed to better define the benefit-risk ratio for triple-site CRT compared with conventional  CRT. 

CRT Combined With Remote Fluid  Monitoring 
Intrathoracic fluid status monitoring has been proposed as a more sensitive way to monitor fluid status leading to prompt identification of impending heart failure, permitting early intervention, and potentially decreased rates of hospitalization. 

Randomized Controlled Trials 
Three RCTs were identified that compared management of patients with heart failure using remote fluid monitoring to usual monitoring; these trials are summarized in Table 7.91,92,93, Luthje et al (2015) was an unblinded, single-site RCT sponsored by   the manufacturer of the OptiVol device.92, Patients in the remote monitoring group had alarms set for a rising fluid index, with most patients having their diuretic increased by 50% in response to an alert. Median follow-up was not reported. Outcomes were reported as 1-year estimates using Cox proportional hazards. Four patients were lost to follow-up. Domenichini et al (2016) was   an unblinded, single-site RCT sponsored by the U.K. National Health Service.91, Patients in the remote monitoring group had alarms set for a rising fluid index, with most patients having their diuretic increased by 50% in response to an alert. Median follow-up was 375 days (range, 350-430 days). One patient was lost to follow-up, and 71 (89%) of 80 patients had complete data on patient-reported outcomes. Bohm et al (2016) was an unblinded, multicenter RCT conducted in Germany and also sponsored by the device manufacturer.93, One thousand two patients with NYHA class II or III heart failure and an LVEF of 35% or less were randomized to have their ICD or CRT-D devices automatically transmit fluid index telemedicine alerts or not. Alerts were triggered by intrathoracic fluid index threshold crossing, which was programmed at the investigator's discretion. Patients were followed for a mean of 1.9 years. All patients were included in the intention-to-treat Cox proportional hazard analyses. 

None of the 3 RCTs reported improvements for the remote monitoring group on any outcome measures (see Table 7). In the Domenichini study, there were no significant differences reported between groups for hospitalizations rates, functional status, or QOL. Luthje reported no differences in mortality or hospitalizations. Also, Luthje reported a HR for time to the first   hospitalization that was not significant at 1.23 (95% CI, 0.62 to 2.44, p=0.55). Mean number of emergency department visits did not differ between the remote monitoring group (0.10) and the usual care group (0.10; p=0.73), but the mean number of urgent   care visits was higher for remote monitoring (0.30) than for usual care (0.10; p=0.03). Bohm reported no differences in the composite outcome of all-cause death and cardiovascular hospitalization (HR=0.87; 95% CI, 0.72 to 1.04) or mortality (HR=0.89; 95% CI, 0.62 to  1.28).   

Table 7. Randomized Controlled Trials of Remote Monitoring With Combined Cardiac Resynchronization Therapy and Fluid Monitoring Device

Study/Year  Group   Outcomes   
      Mortality  Hospitalizations  6MWT MLHFQ

Bohm et al (2016)93

1,002  Remote fluid monitoring  44.7%  21%     
    Usual care  12.7%  25%     
Domenichini (2016)91 80  Remote fluid monitoring   0.3 (SD= 0.9) per patientb  +1.5 m  -3 points 
    Usual Care    0.2 (SD=0.4) per patient  -53.5 m  +10 points 
P value        0.95  0.83  0.07 
 Luthje (2015)92 176  Remote fluid monitoring  8.6%a  27% (20/73)     
    Usual Care   4.6%  27% (20/82)     
P value      0.51 NR     

MLHFQ: Minnesota Living with Heart Failure Questionnaire; NR: not reported; 6MWT: 6-minute walk test.
a Kaplan-Meier estimate of 1-year mortality rate.
b Total hospitalizations per patient over study period 

Section Summary: CRT Combined With Remote Fluid  Monitoring 
Three RCTs have reported no improvements in outcomes associated with remote fluid monitoring for patients with heart failure. These RCTs do not a support a benefit from remote monitoring of fluid status vs usual care. 

Summary of Evidence 
For individuals who have NYHA class III or IV heart failure with a left ventricular ejection fraction of 35% or less who are in sinus rhythm, treated with guideline-directed medical therapy, and have either LBBB or a QRS interval of 150 ms or more who receive CRT with or without defibrillator, the evidence includes RCTs and systematic reviews of RCTs. Relevant outcomes are overall survival, symptoms, functional outcomes, quality of life, hospitalizations, and treatment-related morbidity. There is a large body of clinical trial evidence supporting the use of CRT in patients with NYHA class III or IV heart failure. The RCTs have consistently reported that CRT reduces mortality, improves functional status, and improves quality of life for patients with NYHA class III or IV heart failure. Multiple subgroup analyses of RCTs have demonstrated that the benefit of CRT is mainly restricted to patients with LBBB or QRS interval greater than 150 ms. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome. 

For individuals who have NYHA class II heart failure with a left ventricular ejection fraction of 30% or less who are in sinus rhythm, treated with guideline-directed medical therapy, and have either LBBB or a QRS interval of 150 ms or more who receive CRT with or without defibrillator, the evidence includes RCTs and systematic reviews of RCTs. Relevant outcomes are overall survival, symptoms, functional outcomes, quality of life, hospitalizations, and treatment-related morbidity. For patients with NYHA class II heart failure, at least 4 RCTs assessing CRT have been published. A mortality benefit was reported in 1 of  the 4 trials, the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial. None of the other 3 RCTs reported a mortality difference, but a subgroup analysis of the MADIT-CRT trial reported a mortality benefit for patients with LBBB. Among other outcome measures, hospitalizations for heart failure showed consistent reductions, but quality of life and functional status did not improve. Multiple subgroup analyses of RCTs have demonstrated that the benefit of CRT is mainly restricted to patients with LBBB or a QRS interval greater than 150 ms. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome. 

For individuals who have NYHA class I heart failure who receive CRT with or without defibrillator, the evidence includes RCTs and systematic reviews of RCTs. Relevant outcomes are overall survival, symptoms, functional outcomes, quality of life, hospitalizations, and treatment-related morbidity. Few patients with NYHA class I heart failure have been included in RCTs. The MADIT-CRT trial included 265 patients with class I. While the treatment effect on death and hospitalization favored combined implantable cardiac defibrillator plus CRT devices vs implantable cardiac defibrillator alone for class I patients, the confidence interval was large and included a 25% to 30% increase in events. The evidence is insufficient to determine the  effects of the technology on health outcomes. 

For individuals who have heart failure and atrial fibrillation who receive CRT with or without defibrillator, the evidence   includes 4 RCTs and observational studies. Relevant outcomes are overall survival, symptoms, functional outcomes, quality of life, hospitalizations, and treatment-related morbidity. Results from RCTs have been conflicting, with one reporting improvements for patients with atrial fibrillation and others reporting no significant improvements. Results from observational studies are also conflicting. The evidence is insufficient to determine the effects of the technology on health outcomes. 

For individuals who have heart failure and atrioventricular nodal block who receive CRT, the evidence includes RCTs and systematic reviews of RCTs. Relevant outcomes are overall survival, symptoms, functional outcomes, quality of life, hospitalizations, and treatment-related morbidity. One large RCT demonstrated that CRT led to reductions in heart failure-related hospitalizations and urgent care visits among patients with heart failure and atrioventricular block but who would not necessarily meet conventional criteria for CRT. For patients who require ventricular pacing but have no left ventricular dysfunction, results of a small RCT have suggested that biventricular pacing is associated with improvement in cardiac function, but the trial was small and underpowered to detect differences in clinical outcomes. The evidence is sufficient to determine that   the technology results in a meaningful improvement in the net health outcome. 

For individuals who have heart failure who receive triple-site CRT, the evidence includes small RCTs and a meta-analysis that included nonrandomized studies. Relevant outcomes are overall survival, symptoms, functional outcomes, quality of life, hospitalizations, and treatment-related morbidity. The available RCTs have reported improved outcomes on at least 1 measure of functional status or quality of life with triple-site CRT compared with conventional CRT. However, the trials were small and had methodologic limitations. Also, outcomes reported differed across studies. Triple-site CRT was also associated with higher radiation exposure and a greater number of additional procedures postimplantation. Larger, high-quality RCTs are needed to define better the benefit-risk ratio for triple-site CRT compared with conventional CRT. The evidence is insufficient to   determine the effects of the technology on health   outcomes. 

For individuals who have heart failure who receive CRT combined with remote fluid monitoring, the evidence includes 3 RCTs. Relevant outcomes are overall survival, symptoms, functional outcomes, quality of life, hospitalizations, and treatment-related morbidity. Three RCTs have reported no improvement in outcomes associated with remote fluid monitoring for patients with  heart failure. The evidence is insufficient to determine the effects of the technology on health outcomes.   

Clinical Input From Physician Specialty Societies and Academic Medical  Centers 
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted. 

In response to requests, input was received from 1 physician specialty society and 8 academic medical centers while this policy  was under review in 2012. There was consensus with the medically necessary statements. For patients with class I heart failure, there was mixed input as to whether cardiac resynchronization therapy should be medically necessary. Regarding the duration of the QRS complex, commentators acknowledged that the literature supported use mainly in patients with a QRS interval greater  than 150 ms, but most reviewers disagreed with restricting cardiac resynchronization therapy use to patients in that group because that duration was not currently the accepted standard of care. For patients with atrial fibrillation, the input was mixed on whether biventricular pacing improves  outcomes. 

Practice Guidelines and Position Statements
American College of Cardiology et al
In 2013, the American College of Cardiology Foundation and American Heart Association published joint guidelines for the management of heart failure.94, These guidelines made recommendations on cardiac resynchronization therapy (CRT) for heart failure that are in line with those made by the American College of Cardiology Foundation, American Heart Association, and Heart Rhythm Society related to CRT for heart failure outlined   next. 

A focused update to 2008 guidelines95, for device-based treatment of cardiac rhythm abnormalities was published jointly by American College of Cardiology Foundation, American Heart Association, and Heart Rhythm Society in 2012.96, These guidelines included the following recommendations on CRT for heart failure (see Table 8). 

Table 8. Joint Guidelines on Treatment of Cardiac Rhythm Abnormalities

Recommendation Class LOE

RT is indicated for patients who have LVEF less than or equal to 35%, sinus rhythm, LBBB with a QRS duration greater than or equal to 150 ms, and NYHA class II, III, or ambulatory IV symptoms on GDMT

I

Aa
Bb

CRT can be useful for patients who have LVEF less than or equal to 35%, sinus rhythm, LBBB with a QRS duration 120 to 149 ms, and NYHA class II, III, or ambulatory IV symptoms on GDMT

IIa

 B
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 GDMT

IIa

CRT can be useful in patients with atrial fibrillation and LVEF less than or equal to 35% on GDMT if a) the patient requires ventricular pacing or otherwise meets CRT criteria and b) AV nodal ablation or pharmacologic rate control will allow near 100% ventricular pacing with CRT 

IIa 

CRT can be useful for patients on GDMT who have LVEF less than or equal to 35% and are undergoing new or replacement device placement with anticipated requirement for significant (>40%) ventricular pacing  

IIa 

CRT may be considered for patients who have LVEF less than or equal to 30%, ischemic etiology of heart failure, sinus rhythm, LBBB with a QRS duration of greater than or equal to 150 ms, and NYHA class I symptoms on GDMT  

IIb 

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 GDMT 

IIb 

CRT may be considered 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 II symptoms on GDMT 

IIb 

CRT is not recommended for patients with NYHA class I or II symptoms and non-LBBB pattern with QRS duration less than 150 ms 

IIIc 

CRT is not indicated for patients whose comorbidities and/or frailty limit survival with good functional capacity to less than 1 year

IIIc 

AV: atrioventricular; CRT: cardiac resynchronization therapy; GDMT: guideline-directed medical therapy; LBBB: left bundle branch block; LOE: level of evidence; LVEF: left ventricular ejection fraction; NYHA: New York Heart Association.
a For NYHA class III or IV heart failure.
b For NYHA class II heart failure.
c No benefit. 

European Society of Cardiology and European Heart Rhythm  Association 
The European Society of Cardiology and the European Heart Rhythm Association released guidelines on cardiac pacing and CRT in 2013.97 These guidelines included the following recommendations on CRT for heart failure with sinus rhythm (see Table 9).  

Table 9. Joint Guidelines on Cardiac Pacing and CRT

Recommendation Class LOE

LBBB with QRS duration greater than 150 ms. CRT is recommended in chronic heart failure patients and LVEF less than or equal to 35% who remain in NYHA functional class II, III, and ambulatory IV despite adequate medical treatment

I

  A

LBBB with QRS duration from 120 to 150 ms. CRT is recommended in chronic heart failure patients and LVEF less than or equal to 35% who remain in NYHA functional class II, III, and ambulatory IV despite adequate medical treatment 

I

B

Non-LBBB with QRS duration greater than 150 ms. CRT should be considered in chronic heart failure patients and LVEF less than or equal to 35% who remain in NYHA functional class II, III, and ambulatory IV despite adequate medical treatment

IIa

Non-LBBB with QRS duration 120-150 ms. CRT may be considered in chronic heart failure patients and LVEF less than or equal to 35% who remain in NYHA functional class II, III, and ambulatory IV despite adequate medical treatment 

IIb 

CRT in patients with chronic heart failure with QRS duration less than 120 ms is not recommended 

IIia 

CRT: cardiac resynchronization therapy; CRT: cardiac resynchronization therapy; LBBB: left bundle branch block; LOE: level of evidence; LVEF: left ventricular ejection fraction; NYHA: New York Heart Association.
a No benefit.

Heart Failure Society of America
The Heart Failure Society of America (2010) released comprehensive guidelines on the management of heart failure.98  The guidelines included the following recommendations on the use of CRT (see Table 10).

Table 10. Guidelines on Management of Heart Failure

Recommendation LOE

Biventricular pacing therapy is recommended for patients in sinus rhythm with a widened QRS interval (≥120 ms) and severe LV systolic dysfunction (LVEF ≤ 35%) who have persistent, moderate to severe HF (NYHA III) despite optimal medical therapy.

  A

Biventricular pacing therapy may be considered for patients with atrial fibrillation with a widened QRS interval (≥120 ms) and severe LV systolic dysfunction LVEF ≤35% who have persistent, moderate to severe HF (NYHA III) despite optimal medical therapy

B

Selected ambulatory NYHA IV patients in sinus rhythm with QRS ≥120 ms and LV systolic dysfunction may be considered for biventricular pacing therapy.

Biventricular pacing therapy may be considered in patients with reduced LVEF and QRS ≥ 150 ms who have NYHA I or II HF symptoms.

In patients with reduced LVEF who require chronic pacing and in whom frequent ventricular pacing is expected, biventricular pacing may be considered. 

C

HF: heart failure; LOE: level of evidence; LV: left ventricular; LVEF: left ventricular ejection fraction; NYHA: New York Heart Association.

National Institute for Health and Care Excellence
The National Institute for Health and Care Excellence’s 2014 guidance provided recommendations on CRT for heart failure.99 The recommendations for patients with left ventricular ejection fraction of 35% or less are list in Table 11. 

Table 11. Guidelines on Management of Cardiac Resynchronization Therapy for Heart Failure

Indication LOE

NYHA class I-IV with QRS interval < 120 ms

 CRT not recommended

NYHA class IV with QRS interval 120 to 149 ms and without LBBB

CRT-P recommended 

NYHA class II-III with QRS interval 120 to 149 ms and with LBBB

CRT-D recommended 

NYHA class III-IV with QRS interval 120 to 149 ms and with LBBB

CRT-P recommended

NYHA class I-III with QRS interval ≥ 150 ms (with or without LBBB)       

CRT-D recommended

NYHA class III-IV with QRS interval ≥ 150 ms (with or without LBBB)

CRT-P recommended

CRT-D: cardiac resynchronization therapy with implantable cardiac defibrillator; CRT-P: cardiac resynchronization therapy with pacemaker; LBBB: left bundle branch block; NYHA: New York Heart Association.

U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATIONS
Not applicable.

ONGOING AND UNPUBLISHED CLINICAL TRIALS
Some currently unpublished trials that might influence this review are listed in Table 12.

Table 12. Summary of Key Active Trials

NCT No. Trial Name Planned Enrollment Completion Date

Ongoing

NCT02454439 

Assessment of Cardiac Resynchronization Therapy in Patients With Wide QRS and Non-specific Intraventricular Conduction Delay: a Randomized Trial 

200 

Nov 2018 

NCT01994252

Resynchronization/Defibrillation for Ambulatory Heart Failure Trial in Patients With Permanent Atrial Fibrillation (RAFT-PermAF)

950

Dec 2018

NCT02137187

A Randomized Controlled Trial of Atrioventricular (AV) Junction Ablation and Biventricular Pacing Versus Optimal Pharmacological Therapy in Patients With Permanent Atrial Fibrillation

1,830

May 2019

NCT02962791 

Prospective Randomized Trial Comparing TRIPLE Site ventriculAr Stimulation Versus Conventional Pacing in CRT canDidates: TRIPLEAD Trial 

166 

May 2020 

NCT02922036

Stimulation Of the Left Ventricular Endocardium for Cardiac Resynchronization Therapy in Non-Responders and Previously Untreatable Patients (SOLVE CRT)

350

Sep 2020

NCT01522898a

Cardiac Resynchronisation Therapy and AV Nodal Ablation Trial in Atrial Fibrillation (CAAN-AF)

590

Jan 2022

Unpublished

NCT00187278

Biventricular Pacing for Atrioventricular Block in Left Ventricular Dysfunction to Prevent Cardiac Desynchronization

1,833

Oct 2014 (completed)

 NCT: national clinical trial.
ª Denotes industry-sponsored or cosponsored trial.  

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  81. Yu CM, Chan JY, Zhang Q, et al. Biventricular pacing in patients with bradycardia and normal ejection fraction. N Engl J Med. Nov 26 2009;361(22):2123-2134. PMID 19915220 
  82. Chan JY, Fang F, Zhang Q, et al. Biventricular pacing is superior to right ventricular pacing in bradycardia patients with preserved systolic function: 2-year results of the PACE trial. Eur Heart J. Oct 2011;32(20):2533-2540. PMID 21875860 
  83. Yu CM, Fang F, Luo XX, et al. Long-term follow-up results of the pacing to avoid cardiac enlargement (PACE) trial. Eur J Heart Fail. Sep 2014;16(9):1016-1025. PMID  25179592 
  84. Doshi RN, Daoud EG, Fellows C, et al. Left ventricular-based cardiac stimulation post AV nodal ablation evaluation (the PAVE study). J Cardiovasc Electrophysiol. Nov 2005;16(11):1160-1165. PMID  16302897 
  85. Anselme F, Bordachar P, Pasquie JL, et al. Safety, feasibility, and outcome results of cardiac resynchronization with triple-  site ventricular stimulation compared to conventional cardiac resynchronization. Heart Rhythm. Jan 2016;13(1):183-189. PMID 26325531 
  86. Bencardino G, Di Monaco A, Russo E, et al. Outcome of patients treated by cardiac resynchronization therapy using a quadripolar left ventricular lead. Circ J. Feb 25 2016;80(3):613-618. PMID  26821688 
  87. Lenarczyk R, Kowalski O, Sredniawa B, et al. Implantation feasibility, procedure-related adverse events and lead   performance during 1-year follow-up in patients undergoing triple-site cardiac resynchronization therapy: a substudy of TRUST CRT randomized trial. J Cardiovasc Electrophysiol. Nov 2012;23(11):1228-1236. PMID  22651239 
  88. Pappone C, Calovic Z, Vicedomini G, et al. Improving cardiac resynchronization therapy response with multipoint left ventricular pacing: Twelve-month follow-up study. Heart Rhythm. Jun 2015;12(6):1250-1258. PMID 25678057 
  89. Rogers DP, Lambiase PD, Lowe MD, et al. A randomized double-blind crossover trial of triventricular versus biventricular pacing in heart failure. Eur J Heart Fail. May 2012;14(5):495-505. PMID  22312038 
  90. Zhang B, Guo J, Zhang G. Comparison of triple-site ventricular pacing versus conventional cardiac resynchronization therapy in patients with systolic heart failure: A meta-analysis of randomized and observational studies. J Arrythmia. 2018;34:55-64. PMID 
  91. Domenichini G, Rahneva T, Diab IG, et al. The lung impedance monitoring in treatment of chronic heart failure (the LIMIT- CHF study). Europace. Mar 2016;18(3):428-435. PMID  26683599 
  92. Luthje L, Vollmann D, Seegers J, et al. A randomized study of remote monitoring and fluid monitoring for the management  of patients with implanted cardiac arrhythmia devices. Europace. Aug 2015;17(8):1276-1281. PMID 25983310 
  93. Bohm M, Drexler H, Oswald H, et al. Fluid status telemedicine alerts for heart failure: a randomized controlled trial. Eur Heart J. Nov 01 2016;37(41):3154-3163. PMID   26984864 
  94. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. Oct 15 2013;128(16):1810-1852. PMID   23741057 
  95. Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac  Pacemakers and Antiarrhythmia Devices): developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. Circulation. May 27 2008;117(21):e350-408. PMID  18483207 
  96. Tracy CM, Epstein AE, Darbar D, et al. 2012 ACCF/AHA/HRS focused update of the 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. [corrected]. Circulation. Oct 2 2012;126(14):1784-1800.  PMID 22965336 
  97. European Society of Cardiology, European Heart Rhythm Association, Brignole M, et al. 2013 ESC guidelines on cardiac pacing and cardiac resynchronization therapy: the task force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Europace.  Aug  2013;15(8):1070-1118.  PMID 23801827 
  98. Heart Failure Society of America, Lindenfeld J, Albert NM, et al. HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail. Jun 2010;16(6):e1-194. PMID   20610207
  99. National Institute for Health and Care Excellence (NICE). Implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure [TA314]. 2014; https://www.nice.org.uk/guidance/ta314. Accessed April 20, 2018.

Coding Section

Codes Number Description
CPT 33208

Insertion or replacement of permanent pacemaker with transvenous electrode(s); atrial and ventricular

  33211

Insertion or replacement of temporary transvenous dual chamber pacing electrodes (separate procedure)

  33213 Insertion of pacemaker pulse generator only; with existing dual leads (code descriptor revised effective 01/01/12)
  33214  Upgrade of implanted pacemaker system, conversion of single chamber system to dual chamber system (includes removal of previously placed pulse generator, testing of existing lead, insertion of new lead, insertion of new pulse   generator) 
  33221  Insertion of pacemaker pulse generator only; with existing multiple leads 
  33224 Insertion of pacing electrode, cardiac venous system, for left ventricular pacing, with attachment to previously placed pacemaker or pacing cardioverter-defibrillator pulse generator (including revision of pocket, removal, insertion and/or replacement of existing generator) (code descriptor revised effective 01/01/12)
  33225

Insertion of pacing electrode, cardiac venous system, for left ventricular pacing, at time of insertion of pacing cardioverter-defibrillator or pacemaker pulse generator, (including upgrade to dual chamber system and pocket revision) (List separately in addition to code for primary procedures) (code descriptor revised effective 01/01/12)

  33233 Removal of permanent pacemaker pulse generator only
  33228

Removal of permanent pacemaker pulse generator with replacement of pacemaker pulse generator; dual lead system (new code 01/01/12)

HCPCS    
ICD-10-CM (effective 10/01/15)  15.20-150.9  Congestive heart failure, code range 
ICD-10-PCS (effective 10/01/15)  02H63MA, 02H73MA, 02HK3MA, 02HL3MA  Surgical, heart and great vessels, insertion, percutaneous, pacemaker lead, code by body part (right atrium, left atrium, right ventricle, or left ventricle) 
  02H63ME, 02H73ME, 02HK3ME, 02HL3ME

Surgical, heart and great vessels, insertion, percutaneous, defibrillator lead, code by body part (right atrium, left atrium, right ventricle, or left ventricle)

  0JH63P0, 0JH60P0 

Surgical, subcutaneous tissue and fascia, insertion, chest, pacemaker single chamber, code by approach (percutaneous or open)

  0JH63P1, 0JH60P1  Surgical, subcutaneous tissue and fascia, insertion, chest, pacemaker single chamber rate responsive, code by approach (percutaneous or open) 
  0JH63P2, 0JH60P2 

Surgical, subcutaneous tissue and fascia, insertion, chest, pacemaker dual chamber, code by approach (percutaneous or open)

  0JH63P3, 0JH60P3  Surgical, subcutaneous tissue and fascia, insertion, chest, cardiac resynchronization pacemaker pulse generator, code by approach (percutaneous or open) 
  0JH63P4, 0JH60P4  Surgical, subcutaneous tissue and fascia, insertion, chest, defibrillator generator, code by approach (percutaneous or open) 
  0JH63P5, 0JH60P5  Surgical, subcutaneous tissue and fascia, insertion, chest, cardiac resynchronization defibrillator pulse generator, code by approach (percutaneous or open) 
  0JH63PA, 0JH60PA  Surgical, subcutaneous tissue and fascia, insertion, chest, contractility modulation device, code by approach (percutaneous or open) 
  0JH63PY, 0JH60PY  Surgical, subcutaneous tissue and fascia, insertion, chest, other cardiac rhythm related device, code by approach (percutaneous or open) 
  0JH83P0, 0JH80P0 

Surgical, subcutaneous tissue and fascia, insertion, abdomen, pacemaker single chamber, code by approach (percutaneous or open)

  0JH83P1, 0JH80P1  Surgical, subcutaneous tissue and fascia, insertion, abdomen, pacemaker single chamber rate responsive, code by approach (percutaneous or open) 
  0JH83P2, 0JH80P2  Surgical, subcutaneous tissue and fascia, insertion, abdomen, pacemaker dual chamber, code by approach (percutaneous or open) 
  0JH83P3, 0JH80P3  Surgical, subcutaneous tissue and fascia, insertion, abdomen, cardiac resynchronization pacemaker pulse generator, code by approach (percutaneous or open) 
  0JH83P4, 0JH80P4  Surgical, subcutaneous tissue and fascia, insertion, abdomen, defibrillator generator, code by approach (percutaneous or open) 
  0JH83P5, 0JH80P5 

Surgical, subcutaneous tissue and fascia, insertion, abdomen, cardiac resynchronization defibrillator pulse generator, code by approach (percutaneous or open)

 

0JH83PA, 0JH80PA 

 Surgical, subcutaneous tissue and fascia, insertion, abdomen, contractility modulation device, code by approach (percutaneous or open)
  0JH83PY, 0JH80PY

Surgical, subcutaneous tissue and fascia, insertion, abdomen, other cardiac rhythm related device, code by approach (percutaneous or open)

Type of Service  Cardiology   
Place of Service   Inpatient  

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

History From 2014 Forward     

02/05/2019 

Annual review, updating policy for clarity and consistency of available products, adding investigational statement regarding wireless left ventricular pacing. Also updating background, regulatory status, guidelines, rationale, references and coding. 

03/07/2018 

Annual review, no change to policy intent. Updating background, description, rationale and references. 

02/01/2017 

Annual review, no change to policy intent. Updating background, description, regulatory status, rationale and references. 

02/23/2016 

Annual review, policy updated to include: Policy statements for CRT in class II and II/IV heart failure changed to include presence of LBBB (and QRS >120-130 ms) OR QRS >150 ms as medically necessary criteria. Policy statement added that CRT in patients with heart failure and AV block may be considered medically necessary with criteria. Also updated description, background rationale and references.

02/12/2015 

Annual review, no change to policy intent. Updated background, rationale and references. Added regulatory status, related policies, guidelines and coding. 

02/4/2014

Annual review, updated title, description, rationale, references. Added related policies and benefit application. Added the following policy verbiage "Triple-site (triventricular) CRT, using an additional pacing lead is considered investigational."  


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