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
An estimated 6 million adults in the United States 20 years of age and older had heart failure between 2015 and 2018.¹ The prevalence continues to increase over time with the aging of the population. Prevalence of disease is higher in women than men 80 years of age and older. Overall prevalence is especially high in Black individuals. A 2008 study demonstrated that Black individuals had the highest risk of developing heart failure, followed by Hispanic, White, and Chinese individuals in the United States.² Higher risk reflected differential prevalence of hypertension, diabetes, and lower socioeconomic status. Black individuals also had the highest proportion of incident heart failure not preceded by myocardial infarction (75%). Additionally, Black individuals have a greater 5-year case fatality rate associated with heart failure compared to White individuals.3,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. 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 implantable cardioverter-defibrillator (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 the 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 the FDA for its combined CRT-D device with ventricular pacing leads (Tupos LV/ATx CRT-D/Kronos LV-T CRT-D systems⁴); in 2013, the company received the FDA approval for updated CRT-D devices (Ilesto/Iforia series).⁵ On the basis of the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (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 classifications⁴:

• Moderate-to-severe heart failure (NYHA class III or 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, the 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 Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block (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 the 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 U.S. (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 the 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 2.02.24 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 (i.e., 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)
• 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 investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY as 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 investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY 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 investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY.

An intrathoracic fluid monitoring sensor is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY as a component of a biventricular pacemaker.

Cardiac resynchronization therapy with wireless left ventricular endocardial pacing is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY.

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.
• 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 
Please see the Codes table for details

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 PubMed database. The most recent literature update was performed through April 5, 2022.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are the 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, two domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent 1 or more intended clinical use 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. Randomized controlled trials 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
Clinical Context and Therapy Purpose
The purpose of cardiac resynchronization therapy (CRT) in patients who have heart failure is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of CRT improve the net health outcome in patients with heart failure?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients with heart failure in the following situations:

• New York Heart Association (NYHA) class III or IV heart failure with a left ventricular ejection fraction (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
• NYHA class II heart failure with an 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
• NYHA class I heart failure

Interventions
The therapy being considered is CRT with or without defibrillator.

Several types of CRT devices are available, including those that incorporate biventricular pacing into automatic implantable cardioverter-defibrillators (ICDs), stand-alone biventricular pacemakers, and biventricular pacemakers that incorporate fluid monitoring via bioimpedance.

Comparators
The following therapies are currently being used to treat heart failure: medical care and medical care plus defibrillator.

Outcomes
The general outcomes of interest are overall survival (OS), symptoms, functional outcomes, quality of life, hospitalizations, and treatment-related morbidity. Function may be measured by the 6-minute walk test (6MWT). Outcomes for patients with heart failure are assessed between 3 months and 2 years.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
The use of 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 CRT versus comparators for all-cause mortality and heart failure-related hospitalizations.^{6,7,8,9,10,11,12,13,14,15,16,17,18,} The systematic reviews published after 2010 that include meta-analyses with comparisons of CRT plus ICD (CRT-D) versus ICD alone and/or CRT versus 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 NYHA functional class II, III, or IV with an LVEF of less than 35%, prolonged QRS interval ( ≥ 120 ms), and were in sinus rhythm. On average, about 75% of participants were men, although the percentages of men 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 versus ICD alone and a 25% reduction in mortality of CRT versus drug therapy. Reviews providing results stratified by NYHA class I or II versus 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 versus drug therapy compared with the other systematic reviews.16, 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.¹⁷

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

AMIOVIRT: Amiodarone Versus Implantable Cardioverter-Defibrillator Randomized Trial; CARE-HF: Cardiac Resynchronization — Heart Failure; CAT: Cardiomyopathy Trial; CI: confidence interval; COMPANION: Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure; CONTAK-CD: VENTAK CHF/CONTAK CD/EASYTRAK Biventricular Pacing Study; CrI: credible interval; CRT: cardiac resynchronization therapy; CRT-D: cardiac resynchronization therapy with implantable cardioverter-defibrillator; DEFINITE: Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation; HR: hazard ratio; ICD: implantable cardioverter-defibrillator; LVEF: left ventricular ejection fraction; MADIT: Multicenter Automatic Defibrillator Implantation Trial; MADIT-CRT: Multicenter Automatic Implantation Trial-Cardiac Resynchronization; MIRACLE: Multicenter InSync Randomized Clinical Evaluation; MUSTIC-SR: Multisite Stimulation in Cardiomyopathies; NYHA: New York Heart Association; OR: odds ratio; RAFT: Resynchronization-Defibrillation for Ambulatory Heart Failure Trial; RCT: randomized controlled trial; RESPOND: Resynchronization in Patients with Heart Failure and a Normal QRS Duration; REThinQ: Resynchronization Therapy In Narrow QRS; REVERSE: REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction; RHYTHM-ICD: Resynchronisation for HemodYnamic Treatment for Health failure Management ICD; SCD HeFT: Sudden Cardiac Death in Heart Failure Trial; VECTOR: Ventricular Resynchronization Therapy Randomized Trial.
^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

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.

Randomized Controlled Trials
At least 30 RCTs evaluating CRT have been published and are included in at least 1 of the meta-analyses listed above.^{19-30,4,4,31-46} Table 3 shows the baseline characteristics of the RCTs that have over 100 patients per group. These RCTs evaluated mostly patients with NYHA class II, III, or IV heart failure. Few patients were enrolled who had NYHA class I heart failure. The 2 largest RCTs (Resynchronization-Defibrillation for Ambulatory Heart Failure Trial [RAFT], Multicenter Automatic Implantation Trial-Cardiac Resynchronization [MADIT-CRT]) are described in greater detail below.

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

New York Heart Association Class II or III Heart Failure
Resynchronization-Defibrillation for Ambulatory Heart Failure Trial
The RAFT trial 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 Race and ethnicity of participants were not described. 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 < .001).⁴³ There were significant reductions in both individual components of the primary outcome, overall mortality (20.8% vs 26.1%; p = .003) and hospitalizations (19.5% vs 26.1%; p < .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% versus 21.1% in the ICD alone group (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.56 to 0.91; p < .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 < .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 fewer patients in the CRT-D group (11.3%) were hospitalized for heart failure than those in the ICD alone group (15.6%; p = .003).⁴⁷ Although the total number of hospitalizations for any cause was lower in the CRT-D group (1448 vs 1553; p = .042), patients randomized to CRT-D had more hospitalizations for device-related indications (246 vs 159; p < .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.⁴³ Of these factors, the QRS interval was the strongest. Patients with a QRS interval of 150 ms or more had a HR for the primary outcome of approximately 0.50, compared with a HR of approximately 1.0 for patients with a QRS interval less than 150 ms (p = .003 for the difference between the HRs). 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.

New York Heart Association Class I or II Heart Failure
Multicenter Automatic Implantation Trial-Cardiac Resynchronization Trial
The largest trial published to date is the single-blind 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,Of the patients included in the study, 90.5% of patients were White, 7.9% of patients were Black, and 1.6% of patients did not have their race or ethnicity described. The MADIT-CRT trial reported a reduction for the CRT-D group in the primary outcome (i.e., death or acute heart failure exacerbation). The primary endpoint 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 in the primary composite outcome. The death rate was similar between groups. Subgroup analyses found significantly reduced mortality of CRT-D versus 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 (HR, 0.62; 95% CI, 0.45 to 0.85; p = .003). On subgroup analysis, the benefit was evident in patients with LBBB (HR, 0.50; 95% CI, 0.33 to 0.76; p = .001) but not in patients without LBBB (HR, 0.99; 95% CI, 0.58 to 1.69; p = .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 = .002; adjusted HR in the CRT-D group, 0.59; 95% CI, 0.43 to 0.80; p < .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 OS. 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.

Safety of Cardiac Resynchronization Therapy Placement
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 U.S.⁵⁰ 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 = .01) for CRT-D and from 5.46% to 7.11% (p = .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.

Factors Influencing Outcomes
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 trial.⁵¹ 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.⁵² 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. Four additional selection factors are reviewed here: QRS interval/morphology, LBBB, 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. A more controversial issue is whether patients with a moderately prolonged QRS interval (120 to 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 to 160 ms) or LBBB.

The Evaluation of Resynchronization Therapy for Heart Failure trial 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.⁵³ 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.

Several meta-analyses of the association between QRS interval and outcomes have been published. Woods et al. (2015) performed a network meta-analysis of ICDs to inform a National Institute for Health and Care Excellence guidance.¹⁶ 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; QRS interval ≥ 120 ms to < 150 ms vs ≥ 150 ms; LBBB vs no LBBB; see Table 4). 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. Mortality was significantly reduced with CRT-D compared with ICD alone for women younger than 60 years with a QRS of 150 ms or more and LBBB, women older than 60 years with QRS intervals ranging from 120 ms to 150 ms and LBBB, and women older than 60 years 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 4. Subgroup-Specific Treatment Effects in a Network Meta-Analysis

Adapted from Woods et al. (2015).¹⁶
CI: confidence interval; CRT-D: cardiac resynchronization therapy with implantable cardioverter-defibrillator; CRT-P: cardiac resynchronization therapy with pacemaker; HR: hazard ratio; ICD: implantable cardioverter-defibrillator; 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.^{54,55,56,57,58,59} In 1 of these studies, the benefit of CRT was confined to patients with LBBB.⁵⁷ 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.

Left Bundle Branch Block
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.⁶⁰ 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.⁶¹ 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 < .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 = .078). In long-term follow-up of MADIT-CRT, the reduction in mortality for CRT-D versus 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 versus ICD in normal PR was larger than in the short-term results (HR, 2.27; 95% CI, 1.16 to 4.44).⁶²

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 versus ICD-only, and outcomes.⁶³ 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 < .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 = .17). Receipt of 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 < .001) but not with PR interval of 230 or more (HR, 1.01; 95% CI, 0.87 to 1.17; p = .90). Limitations of this analysis included lack of randomization (i.e., residual confounding) and potential inaccuracies in registry data.

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 left ventricular (LV) end-systolic volume (LVESV), ejection fraction, or clinical criteria.⁶⁴ 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 (i.e., those with a narrow QRS interval).

The Narrow QRS Ischemic Patients Treated With Cardiac Resynchronization Therapy (NARROW-CRT) RCT compared CRT using dual-chamber ICD among patients who had heart failure (NYHA class II or III) of ischemic origin, ejection fraction of 35% or less, QRS interval less than 120 ms, and marked mechanical dyssynchrony on echocardiogram.⁶⁵ 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 group were more likely to have improved clinical composite scores at 1 year postimplantation (41% vs 16%, p = .004). Patients in the CRT group had higher rates of avoiding the combined endpoint of heart failure hospitalization, heart failure death, and spontaneous ventricular fibrillation (p = .028).

The Echocardiography Guided Cardiac Resynchronization Therapy (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).⁶⁶ 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 = .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 = .02).

The Resynchronization Therapy in Normal QRS Trial 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 The CRT-treated patients (46%) were no more likely than non-CRT patients (41%) to show improvement (meet the endpoint of improvement in exercise capacity [Vo2peak]). A subset of patients with QRS intervals of 120 to 130 ms or more showed improvement (p = .02), whereas those with a QRS interval less than 120 ms did not (p = .45).

Section Summary: Cardiac Resynchronization Therapy for Heart Failure
New York Heart Association 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 for patients with NYHA class III or IV heart failure.

New York Heart Association 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 quality of life 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.

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. A subgroup analys of an RCT and a registry study have provided inconsistent results on the role of prolonged PR interval. Patient-level meta-analyses reported that women might benefit at a shorter QRS interval than men.

Cardiac Resynchronization Therapy for Heart Failure and Atrial Fibrillation
Clinical Context and Therapy Purpose
The purpose of CRT in patients who have heart failure and atrial fibrillation (AF) is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of CRT improve the net health outcome in patients with heart failure and AF?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients with heart failure and AF.

Interventions
The therapy being considered is CRT with or without defibrillator.

Several types of CRT devices are available, including those that incorporate biventricular pacing into automatic ICDs, stand-alone biventricular pacemakers, and biventricular pacemakers that incorporate fluid monitoring via bioimpedance.

Comparators
The following therapies are currently being used to treat patients with heart failure and AF: medical care and medical care plus defibrillator.

Outcomes
The general outcomes of interest are OS, symptoms, functional outcomes, quality of life, hospitalizations, and treatment-related morbidity. Function may be measured by the 6MWT. Outcomes for patients with heart failure are assessed between 3 months and 2 years.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs. 
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
There is controversy whether CRT leads to health outcome benefits for patients with 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, 3 trials (Ablate And Pace Therapy for Permanent Atrial Fibrillation [APAF], MUltisite STimulation In Cardiomyopathies and Atrial Fibrillation [MUSTIC], Ablate and Pace in Atrial Fibrillation plus Cardiac Resynchronization Therapy [APAF-CRT] morbidity trial) have examined CRT specifically in this population. Other RCTs have reported subgroup analyses in patients with permanent or intermittent AF. Analysis from the National Cardiovascular Data Registry is also available.

Randomized Controlled Trials
The design, results, and limitations of the 4 RCTs examining CRT in patients with AF are summarized in Tables 5 through 8.

Brignole et al. (2018) reported results from the morbidity phase of the APAF-CRT trial, which compared AV junction ablation plus CRT (with or without defibrillator) to pharmacological rate control therapy (with or without defibrillator) in 102 patients with permanent AF, narrow QRS (110 ms or less), and at least 1 hospitalization for heart failure within the preceding year.⁶⁷ Race or ethnicity of the participants were not described. The APAF-CRT morbidity trial was stopped early after an interim analysis and enrolled only half of the planned number of patients; therefore, the authors caution that the results of the morbidity trial should be considered exploratory, pending confirmation from the APAF-CRT mortality trial. At a median follow-up of 16 months, the primary composite outcome of death due to heart failure, hospitalization due to heart failure, or worsening heart failure had occurred in 10 patients (20%) in the CRT arm and in 20 patients (38%) in the rate control arm (HR, 0.38; 95% CI, 0.18 to 0.81; p = .013). For the individual outcome measures, no significant difference in all-cause mortality was observed. Worsening heart failure was not significantly different between groups, but hospitalizations for heart failure were reduced with CRT.

Brignole et al. (2021) published the results of the APAF-CRT mortality trial.⁶⁸ A total of 133 patients were randomized and included for analysis (AV ablation plus CRT, n = 63; pharmacologic therapy, n = 70). Race or ethnicity of the participants were not described. The median duration of follow-up was 29 months (range, 1 to 56 months). The primary endpoint of all-cause mortality occurred in 7 patients (11%) in the CRT group and in 20 patients (29%) in the rate control group (HR, 0.26; 95% CI, 0.10 to 0.65; p = .004). The estimated death rates at 2 years were 5% and 21%, respectively, and at 4 years, 14% and 41%. The secondary composite endpoint consisting of all-cause mortality or heart failure hospitalization, whichever came first, was significantly lower in the CRT arm (29%) compared to rate control arm (51%; HR, 0.40; 95% CI, 0.22 to 0.73; p = .002). In the prespecified subgroup analysis of ejection fraction, a benefit in all-cause mortality was seen in patients with ejection fraction greater than 35% (HR, 0.27; 95% CI, 0.08 to 0.84; p = .024), but not in patients with ejection fraction less than or equal to 35% (HR, 0.34; 95% CI, 0.06 to 1.92; p = .22).

The APAF (2011) RCT compared CRT with right ventricular (RV) pacing alone in patients with AF.⁶⁹ 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.Race or ethnicity of the participants were not described. The primary outcome measure was a composite of death from heart failure, hospitalization for heart failure, or worsening heart failure. This combined endpoint 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 = .005). For the individual outcome measures, there was no significant reduction in mortality (HR, 1.57; 95% CI, 0.58 to 4.27; p = .37), but there were significant reductions in hospitalizations (HR, 0.20; 95% CI, 0.06 to 0.72; p = .013) and worsening heart failure (HR, 0.27; 95% CI, 0.12 to 0.58; p = .37). There were no differences in outcomes on subgroup analysis, including analysis by ejection fraction, NYHA class, and/or QRS interval.

In the MUSTIC 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 versus biventricular pacing with 3 months for each period.²² Race or ethnicity of the participants were not described. The primary outcome was the 6MWT; secondary outcomes were maximal oxygen uptake (Vo2max), quality of life, hospitalizations, patients' preferred study period, and mortality. Only 37 patients completed both crossover periods. In intention-to-treat analyses (which included 43 patients), no significant differences were observed between assigned groups.

Table 5. Summary of Key RCT Characteristics

AF: atrial fibrillation; APAF: Ablate And Pace Therapy for Permanent Atrial Fibrillation; APAF-CRT: Ablate and Pace in Atrial Fibrillation plus Cardiac Resynchronization Therapy; AV: atrioventricular; CRT: cardiac resynchronization therapy; LV: left ventricular; MUSTIC: MUltisite STimulation In Cardiomyopathies and Atrial Fibrillation; NYHA: New York Heart Association; RCT: randomized controlled trial; RV: right ventricular.

Table 6. Summary of Key RCT Results

APAF: Ablate And Pace Therapy for Permanent Atrial Fibrillation; APAF-CRT: Ablate and Pace in Atrial Fibrillation plus Cardiac Resynchronization Therapy; AV: atrioventricular; CI: confidence interval; CRT: cardiac resynchronization therapy; HR: hazard ratio; MUSTIC: MUltisite STimulation In Cardiomyopathies and Atrial Fibrillation; NR: not reported; NS: not significant; RCT: randomized controlled trial; RV: right ventricular; SD: standard deviation; 6MWD: 6-minute walk distance.
aComposite outcome of death from any cause or hospitalization for heart failure (whichever came first). 
bFrom supplemental information file.

Table 7. Study Relevance Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. 
APAF: Ablate And Pace Therapy for Permanent Atrial Fibrillation; APAF-CRT: Ablate and Pace in Atrial Fibrillation plus Cardiac Resynchronization Therapy; MUSTIC: MUltisite STimulation In Cardiomyopathies and Atrial Fibrillation.

a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other.
b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.
c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 8. Study Design and Conduct Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
APAF: Ablate And Pace Therapy for Permanent Atrial Fibrillation; APAF-CRT: Ablate and Pace in Atrial Fibrillation plus Cardiac Resynchronization Therapy; MUSTIC: MUltisite STimulation In Cardiomyopathies and Atrial Fibrillation.
a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

In addition to the RCTs described above, 2 subgroup analyses of RCTs have reported on outcomes in patients with AF. 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 the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial.⁷⁰ 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 < .05). In the 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 = .002) and in the composite of death or heart failure hospitalization (HR, 0.53; 95% CI, 0.41 to 0.68; p < .001). In contrast, in the intermittent AF and atrial flutter group (n = 293), CRT-P did not result in improved outcomes versus medical therapy (death or any hospitalization HR, 1.16; 95% CI, 0.83 to 1.63; p = .38; death or heart failure hospitalization HR, 0.97; 95% CI, 0.64 to 1.46; p = .88).

A post hoc analysis of patients with AF enrolled in RAFT was published by Healey et al. (2012).⁷¹ 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 alone group. 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 = .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.

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.⁷² The dataset included 8951 patients with heart failure and AF with a QRS interval of 120 ms or more and an LVEF 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. Receipt of 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: Cardiac Resynchronization Therapy for Heart Failure and Atrial Fibrillation
Data from 4 RCTs enrolling only patients with AF showed different results, with three reporting improvements for patients with AF. One reported an all-cause mortality benefit in an advanced heart failure population, 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. 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.

Cardiac Resynchronization Therapy for Heart Failure and Atrioventricular Nodal Block
Clinical Context and Therapy Purpose
The purpose of CRT in patients who have heart failure and AV nodal block is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of CRT improve the net health outcome in patients with heart failure and AV block?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients with heart failure in the following situations:

• NYHA class I, II, III or IV heart failure with LVEF of 50% or less and the presence of AV block with requirement for a high percentage of ventricular pacing
• Heart failure and AV nodal block

Interventions
The therapy being considered is CRT with or without defibrillator.

Several types of CRT devices are available, including those that incorporate biventricular pacing into automatic ICDs, stand-alone biventricular pacemakers, and biventricular pacemakers that incorporate fluid monitoring via bioimpedance.

Comparators
The following therapies are currently being used to treat patients with heart failure and AV block: medical care and medical care plus defibrillator.

Outcomes
The general outcomes of interest are OS, symptoms, functional outcomes, quality of life, hospitalizations, and treatment-related morbidity. Function may be measured by the 6MWT. Outcomes for patients with heart failure are assessed between 3 months and 2 years.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs. 
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
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.

Randomized Controlled Trials
In 2014, the U.S. Food and Drug Administration (FDA) 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 FDA approval was based on results of the Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block (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.⁷³ Race or ethnicity of participants were not described. 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 HR 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. Left ventricular 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).⁷⁴ 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, a and patient symptoms.

Results of the BLOCK HF RCT were compared with results from an earlier trial (the Pacing to Avoid Cardiac Enlargement trial), 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).^75,76 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 < .001) and higher mean LVESV (35.7 mL vs 27.6 mL; p < .001). No significant differences were reported for quality of life 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.⁷⁷ Also, during long-term follow-up, heart failure hospitalization occurred more frequently in the RV pacing group (23.9% vs 14.6%; p < .001).

Several other RCTs have also corroborated the results of the BLOCK HF and the Pacing to Avoid Cardiac Enlargement trials.^32,42,78 These trials reported improvements in physiologic parameters of LV function and improvements in functional status measured by the 6MWT. Some, but not all, of these trials also reported improvements in quality of life for patients treated with CRT.

Section Summary: Cardiac Resynchronization Therapy for Heart Failure and Atrioventricular 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 Cardiac Resynchronization Therapy for Heart Failure
Clinical Context and Therapy Purpose
The purpose of triple-site CRT in patients who have heart failure is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of triple-site CRT improve the net health outcome in patients with heart failure?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients with heart failure.

Interventions
The therapy being considered is 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.

Comparators
The following therapies are currently being used to treat heart failure: standard CRT.

Outcomes
The general outcomes of interest are OS, symptoms, functional outcomes, quality of life, hospitalizations, and treatment-related morbidity. Function may be measured by the 6MWT. Outcomes for patients with heart failure are assessed between 3 months and 2 years.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
To demonstrate improved outcomes, RCTs are needed that compare outcomes of triple-site CRT with conventional CRT. Six RCTs were identified for this review^{79,80,81,82,83,84,84} and are summarized in Table 9. 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.⁸¹ 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 < .05). Implantation success was similar in the triple-site (94%) and conventional groups (98%; p = not significant), 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 < .05).

The other 5 trials were smaller, enrolling between 43 and 95 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 quality of life. No outcome measures reported were common across all studies. Three of the 5 studies reported significant improvements on at least 1 outcome measure, and the fourth and fifth studies reported no significant differences for the outcomes measured. Adverse events were not well-reported.

Table 9. Randomized Controlled Trials Comparing Triple-Site CRT With Standard CRT

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 randomly.
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 (N = 251 patients) that evaluated similar outcomes.⁸⁵ The meta-analysis included 1 RCT (Anselme et al. [2016]⁷⁹; 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 < .001) and NYHA classes (weighted mean difference, -0.27; 95% CI, -0.42 to -0.11; p = .001). However, there were no significant differences in LV end-diastolic volume or LVESV, 6MWT, or Minnesota Living with Heart Failure Questionnaire (MLHFQ).

Section Summary: Triple-Site Cardiac Resynchronization Therapy for Heart Failure
For the use of CRT with triple-site pacing requiring implantation of an additional lead, six small RCTs with limited follow-up and a meta-analysis that included nonrandomized studies were identified. All trials except 1 reported improved outcomes on at least 1 measure of functional status and quality of life 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.

Cardiac Resynchronization Therapy Combined With Remote Fluid Monitoring for Heart Failure
Clinical Context and Therapy Purpose
The purpose of CRT combined with remote fluid monitoring in patients who have heart failure is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of CRT combined with remote fluid monitoring improve the net health outcome in patients with heart failure?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients with heart failure.

Interventions
The therapy being considered is CRT combined with remote fluid monitoring.

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

Comparators
The following therapies are currently being used to treat heart failure: standard CRT only.

Outcomes
The general outcomes of interest are OS, symptoms, functional outcomes, quality of life, hospitalizations, and treatment-related morbidity. Function may be measured by the 6MWT. Outcomes for patients with heart failure are assessed between three months and two years.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Randomized Controlled Trials
Three RCTs were identified that compared management of patients with heart failure using remote fluid monitoring to usual monitoring.^86,87,88 Luthje et al. (2015) was an unblinded, single-site RCT sponsored by the manufacturer of the OptiVol device.⁸⁷ 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.⁸⁶ 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 to 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.⁸⁸ 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. In the Domenichini et al. (2016) study, there were no significant differences reported between groups for hospitalizations rates, functional status, or quality of life.⁸⁶ Luthje et al. (2015) reported no differences in mortality or hospitalizations.⁸⁷ Also, Luthje et al. (2015) reported a HR for time to the first hospitalization that was not significant at 1.23 (95% CI, 0.62 to 2.44, p = .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 = .73), but the mean number of urgent care visits was higher for remote monitoring (0.30) than for usual care (0.10; p = .03). Bohm et al. (2016) 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).⁸⁸

Section Summary: Cardiac Resynchronization Therapy Combined With Remote Fluid Monitoring for Heart Failure
Three RCTs have reported no improvement in outcomes associated with remote fluid monitoring for patients with heart failure.

Summary of Evidence
For individuals who have NYHA class III or IV heart failure with an LVEF 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 OS, 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 an improvement in the net health outcome.

For individuals who have NYHA class II heart failure with an 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 OS, 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 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 an 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 OS, 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 heart failure. While the treatment effect on death and hospitalization favored combined 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 that the technology results in an improvement in the net health outcome.

For individuals who have NYHA class I, II, III or IV heart failure with LVEF of 50% or less and AV nodal block with requirement for a high percentage of ventricular pacing, treated with guideline-directed medical therapy, who receive CRT with or without defibrillator, the evidence includes RCTs. Relevant outcomes are OS, symptoms, functional outcomes, quality of life, hospitalizations, and treatment-related morbidity. 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. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have heart failure and atrial fibrillation who receive CRT with or without defibrillator, the evidence includes 6 RCTs and a registry study. Relevant outcomes are OS, symptoms, functional outcomes, quality of life, hospitalizations, and treatment-related morbidity. Results from RCTs have been conflicting, with 3 reporting improvements for patients with atrial fibrillation, including an all-cause mortality benefit, and others reporting no significant improvements. A registry study reported significant improvements in mortality and hospitalizations for patients with heart failure and atrial fibrillation treated with CRT plus defibrillator compared with implantable cardioverter-defibrillator alone. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have heart failure and AV nodal block who receive CRT, the evidence includes RCTs. Relevant outcomes are OS, 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 AV block who would not necessarily meet conventional criteria for CRT. For patients who require ventricular pacing but have no LV 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 an 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 OS, 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 that the technology results in an improvement in the net health outcome.

For individuals who have heart failure who receive CRT combined with remote fluid monitoring, the evidence includes 3 RCTs. Relevant outcomes are OS, 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 that the technology results in an improvement in the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

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.

2012 Input
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 (CRT) 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 CRT 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.

Further details from clinical input are included in the Appendix.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American College of Cardiology et al.
The American College of Cardiology (ACC), American Heart Association, and Heart Rhythm Society (2019) published joint guidelines on the evaluation and management of patients with bradycardia and cardiac conduction delay.⁸⁹ These guidelines included the following recommendations on CRT (see Table 10).

Table 10. Joint Guidelines on Treatment of Patients with Bradycardia and Cardiac Conduction Delay

Table 11. Joint Guidelines on Device-Based Treatment of Cardiac Rhythm Abnormalities

AV: atrioventricular; COR: class of recommendation; CRT: cardiac resynchronization therapy; CRT-D: cardiac resynchronization therapy with defibrillation; GDMT: guideline-directed medical therapy; LBBB: left bundle branch block; LOE: level of evidence; LVEF: left ventricular ejection fraction; NYHA: New York Heart Association.
aModerate quality evidence from 1 or more RCTs..
bModerate-quality evidence from 1 or more well-designed, well-executed nonrandomized studies, observational studies, or registry studies. 
cNo benefit.
dLimited data. 

Heart Failure Society of America
The Heart Failure Society of America (2010) released comprehensive guidelines on the management of heart failure.⁹⁴ The guidelines included the following recommendations on the use of CRT (see Table 12). The guidelines were updated in conjunction with the ACC and American Heart Association in 202293; updated recommendations can be found above, in Table 11.

Table 12. Guidelines on Management of Heart Failure

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 NICE (2014) guidance provided recommendations on CRT for heart failure.⁹⁵ The recommendations for patients with left ventricular ejection fraction of 35% or less are listed in Table 13.

Table 13. Guidelines on Management of Cardiac Resynchronization Therapy for Heart Failure

CRT: cardiac resynchronization therapy; CRT-D: cardiac resynchronization therapy with implantable cardioverter-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 ongoing and unpublished trials that might influence this review are listed in Table 14.

Table 14. Summary of Key Trials

NCT: national clinical trial.

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Coding Section 

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. 

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