| Coverage Policy Manual | |
| Policy #: | 2002005 |
| Category: | Medicine |
| Initiated: | March 2002 |
| Last Review: | June 2023 |
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| Biventricular Pacemakers (Cardiac Resynchronization Therapy) for the Treatment of Congestive Heart Failure | |
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| Description: |
An estimated 6.7 million adults in the United States 20 years of age and older had heart failure between 2017 to 2020 (Tsao, 2023). 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 (Bahrami, 2008). 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 (Loehr, 2008). 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.
Biventricular pacemakers using three leads (one in the right atrium, one endocardial in the right ventricle, and one 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 the individuals 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.
There is some evidence that constant right ventricular pacing in patients with heart failure and reduced ejection fraction may, over time, induce left ventricular remodeling and failure. It is thought that these devices improve left ventricular function by restoring a more normal electrical activation sequence and improving left ventricular dyssynchrony.
Several devices have been FDA approved at the time of this writing. Some are stand-alone biventricular pacers and some combine a biventricular pacer with an implantable cardioverter defibrillator (ICD). At the time of this writing, these devices include:
Regulatory Status
There are numerous CRT devices, combined implantable cardioverter-defibrillator (ICD) plus CRT devices (CRT-D), and combined CRT plus fluid monitoring devices. 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 systems) (FDA, 2010). In 2013, the company received the FDA approval for updated CRT-D devices (Ilesto/Iforia series) (FDA, 2013). 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 classifications (FDA, 2010):
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.
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.
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Policy/ Coverage: |
Effective October 15, 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Biventricular pacemakers meet primary coverage criteria for effectiveness and are covered as a treatment of congestive heart failure in the following situations:
2. Biventricular pacing in combination with an implantable cardioverter defibrillator (ICD):
3. Patients undergoing placement of a right ventricular pacemaker for a bradycardic indication, regardless of the QRS duration, when all the following conditions are met:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Any other use of biventricular pacing, including, but not limited to treatment of atrial fibrillation, does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness.
For contracts without primary coverage criteria, any other use of biventricular pacing is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Triple-site (triventricular) CRT, using an additional pacing lead, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members without primary coverage criteria, triple-site (triventricular) CRT, using an additional pacing lead, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective May 2020 through October 14, 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Biventricular pacemakers meet primary coverage criteria for effectiveness and are covered as a treatment of congestive heart failure in the following situations:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Any other use of biventricular pacing, including, but not limited to treatment of atrial fibrillation, does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness.
For contracts without primary coverage criteria, any other use of biventricular pacing is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Triple-site (triventricular) CRT, using an additional pacing lead, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members without primary coverage criteria, triple-site (triventricular) CRT, using an additional pacing lead, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective Prior to May 2020
Biventricular pacemakers meet primary coverage criteria for effectiveness and are covered as a treatment of congestive heart failure in the following situations:
Any other use of biventricular pacing, including, but not limited to treatment of atrial fibrillation, does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness. For contracts without primary coverage criteria, any other use of biventricular pacing is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Triple-site (triventricular) CRT, using an additional pacing lead, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members without primary coverage criteria, triple-site (triventricular) CRT, using an additional pacing lead, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective April 2011 to March 2013
Biventricular pacemakers meet primary coverage criteria for effectiveness and are covered as a treatment of congestive heart failure in the following situations:
2) Biventricular pacing in combination with an implantable cardioverter defibrillator (ICD):
3) Patients undergoing placement of a pacemaker for a bradycardic indication, regardless of the QRS duration, when all the following conditions are met:
Any other use of biventricular pacing, including, but not limited to treatment of atrial fibrillation, does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness. For contracts without primary coverage criteria, any other use of biventricular pacing is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective, October 2010 to March 2011
Biventricular pacemakers meet primary coverage criteria for effectiveness and are covered as a treatment of congestive heart failure in the following situations:
For contracts without primary coverage criteria, an intrathoracic fluid monitoring sensor is considered investigational as a component of a biventricular pacemaker. Investigational services are contract exclusions in most member benefit certificates of coverage.
Any other use of biventricular pacing does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness.
Effective, April 2009 - September 2010
Biventricular pacemakers meet primary coverage criteria for effectiveness and are covered as a treatment of congestive heart failure in the following situations:
Any other use of biventricular pacing does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness.
For contracts without Primary Coverage Criteria, any other use of biventricular pacing is considered investigational and is not covered. Investigational services are an exclusion in the member benefit certificate.
Effective, March 2002 - March 2009
Biventricular pacemakers are covered as a treatment of congestive heart failure in patients who meet all of the following criteria:
The cardioverter defibrillator with cardiac resynchronization therapy system is covered for patients who meet all of the following criteria:
Patient populations at high risk of sudden cardiac death due to ventricular arrhythmias include, but are not limited to, those with:
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| Rationale: |
This evidence review was originally created in March 2002 and has been updated regularly with searches of the MEDLINE database. The most recent literature review was performed through March 2018.
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)
versus comparators for all-cause mortality and heart failure related hospitalizations (Al-Maiied, 2011; McAllister, 2007: McAllister, 2004; Adabag, 2011; Bertoldi, 2011; Nery 2011; tu, 2011; Santangeli, 2011; Wells, 2011; Chen, 2013; Woods, 2015; Sun, 2016; AliHassan, 2017).
The majority of patients included in randomized controlled trials (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 percentage of men ranged from 46% to 100%. Just over half of participants included had ischemic heart disease. The systematic reviews have consistently reported a 15% to 20% reduction in mortality of CRTD 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 Woods
individual patient data network meta-analysis included 12,638 patients and reported a larger reduction in
mortality (»40%) for CRT versus drug therapy compared to the other systematic reviews (Woods, 2015). The Sun meta-analysis demonstrated that effects on mortality persist when only including trials with more than 1 year of follow-up (Sun, 2016).
Randomized Controlled Trials
At least 30 RCTs on CRT have been published. The 2 largest RCTs (MADIT-CRT, RAFT) are described below.
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 a LVEF 30% or less to an ICD alone or to an CRT-D device (Moss, 2009). The MADITCRT 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 versus ICD for NYHA ischemic and nonischemic class II; however, the effect in NYHA class I patients was not statistically significant. The interaction p value 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 in 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).
In 2014, Goldenberg et al analyzed mortality in MADIT-CRT trial subjects with follow-up through 7 years, stratified by the presence or absence of LBBB (Goldenbert, 2014). 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) (Tang, 2010), which randomized 1798 patients with class II or III heart failure and a LVEF of 30% or less to CRT-D or ICD alone, with a mean follow-up 40 months. 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 CRTD 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 for class II patients in the CRT-D group was 15.5% versus 21.1% in the ICDalone 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 substudy of RAFT focusing on hospitalization rates over the 18-month follow-up period, Gillis et al 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) (Gillis, 2014). 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, a LVEF less than 20%, and QRS morphologic features were predictive of benefit. Of these factors, QRS interval was the strongest. Patients with a QRS interval of 150 ms or more had a relative risk (RR) for the primary outcome of approximately 0.50, compared with a relative risk of approximately 1.0 for patients with a QRS interval less than 150 ms (p=0.003 for difference between the relative risks). 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 rates of complications. Van Rees et al focused on complications from CRT treatment (Van Rees, 2011). This analysis included 7 trials of CRT treatment 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.
Hosseini et al reported in-hospital complication rates of CRT in the United States 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 (Hosseini, 2017). 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 included in analysis. In patients receiving CRT-D and cardiac resynchronization therapy with 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, overall increase in complications was driven by 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 (Yu, 2005). This prospective, multicenter trial evaluated the utility of echocardiographic parameters to predict response to CRT. Trial results indicated that the 12 individual chocardiographic parameters varied widely in ability to predict response Chung, 2008). 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 to no CRT in patients with a QRS complex of less than 120 ms, whether or not ventricular dyssynchrony was Present (Thibault, 2013). 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 evaluated whether women with LBBB benefit from combined CRT-D implantation at a shorter QRS interval than men with LBBB (Zusterzeel, 2014). 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 CRTD 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, performed a network metaanalysis of ICDs to inform the U.K. National Institute for Health and Care Excellence (NICE) guidance (Woods, 2017). 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. In women in both age groups, CRT-D statistically significantly reduced mortality compared to 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 to medical therapy alone with QRS intervals of 150 ms or more and LBBB. CRT-D significantly reduced mortality compared to ICD alone for women younger than 60 with a QRS of 150 ms or more and LBBB, women older than 60 with QRS intervals ≥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 to medical therapy alone in both QRS groups with and without LBBB. However, CRT-P significantly improved survival compared to 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 to ICD alone in men older than 60 years with QRS intervals of 150 ms or more and LBBB.
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 (Sipahi, 2011; Bryant, 2013; Stavrakis, 2012; Sipahi, 2012; Kang, 2015; Shah, 2015). In 1 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.
In 2013, Peterson et al 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 (Peterson, 2013). 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 hazard ratio 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.
In 2014, Kutyifa et al evaluated whether prolonged PR predicts heart failure or death among 537 (30%) of MADIT-CRT trial subjects who did not have a LBBB (Kutyifa, 2014). Among the 96 patients with a prolonged PR interval, compared with ICD therapy 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 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) (Stockburger, 2016).
In an analysis of 26,451 CRT-eligible (ejection fraction ≤35, QRS interval ≥120 ms) patients from the National Cardiovascular Data Registry ICD Registry, Friedman et al examined the association between prolonged PR interval (≥230 ms), receipt of CRT-D versus ICD-only, and outcomes (Friedman, 2016). All Medicare beneficiaries who receive a primary prevention ICD are enrolled in the 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 to 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 to ICD-only among patients with 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 include lack of randomization (ie, residual confounding) and potential inaccuracies in registry data.
Lin et al reported on a secondary analysis of mortality and hospitalization including 903 patients stratified by normal (≤230 ms; n=255) or prolonged PR interval (>230 ms; n=53) from the medical therapy and CRT-D arms of the COMPANION trial (Lin 2017). Mortality was significantly reduced in patients with a prolonged PR interval who received CRT-D versus 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 treatment have shown that measures of dyssynchrony on echocardiography correlate with treatment response, as defined by improvements in LV end systolic volume, ejection fraction, or clinical criteria (Hawkins 2006). 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 outcomes of CRT in patients with ventricular dyssynchrony and those without was published in 2011 (Diab, 2011). 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-ICD or to 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 with dual-chamber ICD among patients with 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 (Muto, 2013). One hundred twenty patients were randomized to CRT (n=60) or ICD (n=60). For the study’s primary outcome of the heart failure clinical composite score, compared with those in the ICD group, patients in the CRT were more likely to have an improvement in their clinical composite score 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 published by Ruschitzka et al (Ruschitzka, 2013). 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 (Beshai, 2007). CRT-treated patients (46%) were no more likely than non-CRT patients (41%) to show improvement (met 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).
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 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 to select patients for CRT treatment. Subgroup analyses across multiple RCTs, corroborated by pooling of these subgroup analyses 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 has reported inconsistent results on the role of
prolonged PR interval. Two patient-level meta-analyses reported that women may 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
The 2011 Ablate And Pace Therapy for Permanent Atrial Fibrillation (APAF) RCT compared CRT with right ventricular (RV) pacing alone in patients with AF (Brignole, 2007). 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 left ventricular 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.20 The primary outcome was the 6-minute walk distance; secondary outcomes were peak oxygen uptake, 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 2012 post hoc analysis of patients with AF enrolled in RAFT was published by Healey et al (Healey, 2012). 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.
Kalscheur et al 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 (Kalscheur, 2017). 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 versus 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).
Systematic Reviews
A 2011 systematic review compared outcomes of CRT in patients with and without AF (Wilton, 2011). 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 [MD], -4.1; 95% CI, -1.7 to -6.6; p=0.001), and change in 6-minute walk distance (MD = -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. 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 2012 systematic review evaluated the role of AV node ablation in patients with AF treated with CRT (Ganesan, 2012). Reviewers included nonrandomized studies that reported 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 (MD = -0.34; 95% CI, -0.56 to -0.13; p=0.002).
In 2014, Yin et al published another systematic review and meta-analysis on 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 (Yin, 2014). 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 reported analyses of data from the National Cardiovascular Data Registry’s ICD Registry linked with Medicare claims comparing beneficiaries who receive CRT-D with those who received ICD alone (Khazanie, 2016). The dataset included 8951 patients with heart failure and atrial fibrillation 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 April 2006 and December 2009 who were discharged alive to home. The authors used Cox proportional hazards 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.
In summary, 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 1 reporting improvements for patients with AF and another reporting no significant improvements. Subgroup analyses of the RAFT and COMPANION trials did not show 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 to 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 (FDA) expanded the indications for several CRT devices to include patients with NYHA functional class I, II, or III heart failure with a LVEF of 50% or less, with AV block. A high percentage of these patients are expected to require ventricular pacing that cannot be managed with algorithms to minimize RV pacing. FDA 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-pacemaker or ICD (if indicated) and randomized to standard RV pacing or biventricular pacing (Curtin, 2013). 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 left ventricular end-systolic volume (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 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, 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) (Curtis, 2016). 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 to RV apical pacing (n=88) (Yu, 2009; Chan, 2011). 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 for 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 left ventricular functioning and less left ventricular remodeling(Yu, 2014). In addition, 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 (Kinderman, 2006; Martinell, 2010; Doshi, 2005). These additional trials have 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.
To summarize, 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, 1 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 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.
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 review (Anselme, 2016; Bencardino, 2016; Lenarczyk, 2012; Pappone, 2015; Rogers, 2012). The largest published trial, by Lenarczyk et al, 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) (Lenarczyk,2012). 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. In addition, 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.
For the use of CRT with triple-site pacing requiring implantation of an additional lead, 5 small RCTs with limited follow-up were identified. All trials except 1 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. 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 (Domenichini, 2016; Luthie, 2015; Yancy, 2013). Luthje et all was an unblinded, single-site RCT sponsored by the manufacturer of the OptiVol device (Luthie, 2015). 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 (Domenichini, 2016). 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 (Bohm, 2016). One thousand two patients with NYHA class II or III heart failure and a 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 study, there were no significant differences reported between groups for hospitalizations rates, functional status, or QOL. Luthje reported no differences in mortality or hospitalizations. In addition, Luthje reported a hazard ratio for time to 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).
In summary, three RCTs have reported no improvement 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 versus usual care.
SUMMARY OF EVIDENCE
For individuals who have 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 who receive cardiac resynchronization therapy (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.
SUPPLEMENTAL INFORMATION
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 (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.
PRACTICE GUIDELINES AND POSITION STATEMENTS
American College of Cardiology et al
In 2013, the American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) published guidelines for the management of heart failure (Yancy, 2013). These guidelines made recommendations on cardiac resynchronization therapy (CRT) for heart failure that are in line with those made by the ACCF, AHA, and Heart Rhythm Society (HRS) related to CRT for heart failure.
A focused update to 2008 guidelines (Epstein, 2008), for device-based treatment of cardiac rhythm abnormalities was published jointly by ACC, AHA, and HRS in 2012 (Tracy, 2012).
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 (European Society of Cardiology,2013).
Heart Failure Society of America
The Heart Failure Society of America released comprehensive guidelines on the management of heart failure in 2010 (Heart Failure Society of America, 2010).
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 (NICE, 2016).
CLINICAL TRIALS
Some currently unpublished trials that might influence this review are listed below
Ongoing
NCT01786993 MultiPoint Pacing IDE Study
NCT02150538 BiventRicular Pacing in prolonged Atrio-Ventricular interval: the REAL-CRT Study
NCT01522898 Cardiac Resynchronisation Therapy and AV Nodal Ablation Trial in Atrial Fibrillation (CAAN-AF)
NCT02454439 Assessment of Cardiac Resynchronization Therapy in Patients with Wide QRS and Non-specific
NCT01994252 Resynchronization/Defibrillation for Ambulatory Heart Failure Trial in Patients With Permanent Atrial
NCT02137187 A Randomized Controlled Trial of Atrioventricular (AV) Junction Ablation and Biventricular Pacing Versus
Unpublished
NCT01735916 MIRACLE EF Clinical Study
NCT00941850 Triple-site Ventricular Pacing in Non-responders To Conventional Dual Ventricular Site Cardiac
NCT01510652 More Options Available With a Quadripolar Left Ventricular (LV) Lead provide In-clinic Solutions to
NCT00187278 Biventricular Pacing for Atrioventricular Block in Left Ventricular Dysfunction to Prevent Cardiac
Expected Completion Date: Oct 2014 (completed)
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2019. No new literature was identified that would prompt a change in the coverage statement.
2020 Update
A literature search was conducted through March 2020. There was no new information identified that would prompt a change in the coverage statement.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Brignole et al 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 (Brignole, 2018). 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=0.013). For the individual outcome measures, no significant difference in all-cause mortality was observed. Worsening heart failure was not significantly difference between groups, but hospitalizations for heart failure were reduced with CRT. Completion of the APAF-CRT mortality trial is expected in July 2021.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Brignole et al published the results of the APAF-CRT mortality trial (Brignole, 2021). 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).
A RCT comparing outcomes of triple-site CRT and conventional CRT consisting of 96 participants found +31.2 outcome for 6 minute walk test and +6.4% ejection fracture for triple-site CRT compared to -29.9 outcome for 6 minute walk test and +7.3% ejection fracture for standard CRT (Gould, 2021).
The ACC, American Heart Association, and Heart Failure Society of America published guidelines on the management of heart failure (2022) to replace the 2013 guidelines (Heidenreich, 2022). The most recent recommendations on CRT for heart failure from the guidelines are included below:
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Other meta-analyses of the association between QRS interval and outcomes 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 (Sipahi, 2011; Bryant, 2013; Stavrakis, 2012; Sipahi, 2012; Kang, 2015; Shah, 2015; Friedman, 2023).,In 1 of these studies, the benefit of CRT was confined to patients with LBBB (Sipahi, 2012). 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.
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