Clinical UM Guideline

This document addresses biventricular cardiac pacing to deliver cardiac resynchronization therapy (CRT) to alleviate the symptoms of moderate to severe congestive heart failure associated with left ventricular dyssynchrony. It also addresses a hybrid device that combines CRT with an implantable cardioverter defibrillator (ICD). In the combined device (CRT/ICD), the CRT component promotes coordinated contraction of both ventricles, while the ICD portion detects dangerous arrhythmias and shocks the heart back into a normal rhythm. Biventricular pacemakers, also known as CRT devices, have three leads – one connected to the right atrium, one to the left ventricle, and one to the right ventricle. In contrast, dual-chamber pacemakers have two leads, one connected to the right atrium and the right ventricle. This document does not address wireless CRT.

Note: For further information, see:

• CG-SURG-97 Cardioverter Defibrillators
• SURG.00152 Wireless Cardiac Resynchronization Therapy for Left Ventricular Pacing

Medically Necessary:

Biventricular pacemakers for cardiac resynchronization therapy (CRT) are considered medically necessary for individuals who meet all of the following criteria:

1. NYHA functional Class II, III, or ambulatory Class IV symptoms* secondary to heart failure who remain symptomatic despite recommended, Guideline-directed medical therapy (GDMT);** and
2. Have either:
   1. Left bundle branch block (LBBB) morphology and QRS duration of 120 to 149 ms; or
   2. Any QRS morphology and QRS duration greater than or equal to 150 ms; and
3. Left ventricular ejection fraction (LVEF) less than or equal to 35%; and
4. In either:
   1. Sinus rhythm; or
   2. Atrial fibrillation when AV nodal ablation or pharmacologic rate control will allow near 100% ventricular pacing.

*See Definition section for further information on New York Heart Association (NYHA) functional class.

**Optimal medical therapy, which is now referred to as “Guideline-directed medical therapy” (GDMT), may include use of the following medications either individually or in combination, unless contraindicated: angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, beta-blockers, digoxin, diuretics, and aldosterone antagonists, when appropriate.

GDMT would include a trial period of prior medical management for at least 3 months.

The use of an ICD, in combination with cardiac resynchronization therapy (CRT/ICD), is considered medically necessary when the criteria listed above for CRT therapy AND the criteria within CG-SURG-97 Cardioverter Defibrillators are met.

Not Medically Necessary:

Biventricular pacemakers CRT, or combined biventricular pacemaker-defibrillator devices (CRT/ICD), are considered not medically necessary for all other indications.

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

When services are Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met, for all other diagnosis, or for situations designated in the Clinical Indications section as not medically necessary.

When services may also be Medically Necessary when criteria are met for services associated with biventricular pacemakers for CRT and CRT/ICDs:

When services are Not Medically Necessary:
For the procedure codes listed above when criteria are not met for biventricular pacemakers for CRT or CRT/ICD.

There are a number of biventricular pacemakers designed to provide cardiac resynchronization therapy (CRT). Individuals meeting selection criteria for CRT therapy frequently are also considered candidates for an implantable cardioverter defibrillator (ICD). These persons may receive combined therapy with a combined CRT/ICD device. A biventricular pacemaker is designed to resynchronize the pumping action of the left ventricle. This type of pacing is called cardiac resynchronization therapy (CRT). Standard pacemakers pace the right side of the heart. In contrast, biventricular pacemakers pace both the right and left sides of the heart enabling the left ventricle to pump blood more efficiently. Biventricular pacemakers use three leads (one in the right atrium, and one in each ventricle) and have been investigated as a technique to coordinate the contraction of the ventricles, thus, improving the individual’s hemodynamic status.

The Multi-Center InSync Randomized Clinical Evaluation (MIRACLE) trial showed symptomatic improvement and improvement in cardiac function. In this trial, all subjects received a CRT device, but were then randomized to either active (device-on) or inactive (device-off) groups. Overall, 68% of those in the active treatment group versus 35% of those in the inactive treatment group, demonstrated improvement in primary endpoints, including quality of life, 6-minute hall walk, and NYHA functional class. The active treatment group also reported increases in a variety of cardiodynamic measures, including peak oxygen consumption, left ventricular (LV) end diastolic dimension, and left ventricular ejection fraction (LVEF) (Abraham, 2002). The subsequent Cardiac Resynchronization – Heart Failure (CARE-HF) trial focused on the final health outcomes of morbidity and mortality (Cleland 2005). A total of 813 subjects with left ventricular systolic dysfunction, cardiac dyssynchrony, and symptomatic heart failure (HF) were randomized to receive either CRT or standard medical care and followed for a mean of 29.4 months. The primary endpoint, a composite of death from any cause or an unplanned hospitalization for a major cardiovascular event, was reached by 159 subjects in the CRT group, as compared with 224 in the medical therapy group (39% vs. 55%; hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.51 to 0.77; p<0.001). The authors concluded that CRT substantially reduced the risk of complications and death among those subjects with moderate or severe HF, due to left ventricular systolic dysfunction and cardiac dyssynchrony. Cleland and colleagues published another article in 2009 regarding the effects of CRT on long-term quality of life with data analysis taken from the CARE-HF trial. Quality of life (QoL) was measured at baseline and at 3 months using generic European QoL-5 Dimensions and disease-specific (Minnesota Living with Heart Failure) questionnaires and at 18 months and study-end using the latter instrument. Median follow-up was 29.6 (interquartile range 23.6-34.6) months. The authors concluded that CRT improves long-term QoL and survival in individuals with moderate to severe HF, adding that the effects appeared to be sustained, and therefore, the gain in quality of life with CRT should be even greater during longer-term follow-up (Cleland, 2009).

The COMPANION trial was a multicenter, randomized controlled trial to investigate whether prophylactic CRT with a biventricular pacemaker or a CRT/ICD would reduce the risk of death and hospitalization among individuals with advanced chronic HF and intra-ventricular conduction delays. A total of 1520 subjects who had advanced HF (NYHA Class III or IV), due to ischemic or non-ischemic cardiomyopathies and a QRS interval of at least 120 ms (milliseconds), were randomly assigned in a 1:2:2 ratio to receive optimal pharmacologic therapy (for example, diuretics, angiotensin-converting enzyme inhibitors, beta-blockers and spironolactone) alone or in combination with CRT or CRT/ICD. The primary composite endpoint was the time-to-death from, or hospitalization for, any cause. The results showed that, compared to optimal pharmacological therapy alone, CRT with a pacemaker decreased the risk of the primary endpoint (HR, -0.81; p=0.014), as did CRT/ICD (HR, -0.80; p=0.01). The risk of the combined endpoint of death from, or hospitalization for, HF was reduced by 34% in the pacemaker group (p<0.002) and by 40% in the pacemaker-defibrillator group (p<0.001 for the comparison with the pharmacological therapy group). CRT therapy reduced the risk of the secondary endpoint of death from any cause by 24% (p=0.059), and CRT/ICD therapy reduced the risk by 36% (p=0.003). The researchers concluded that in individuals with advanced HF and a prolonged QRS interval, CRT decreases the combined risk of death from any cause or of first hospitalization and, when combined with an ICD, significantly reduces mortality (Anand, 2009; Bristow, 2004).

Other studies examined the hypothesis that early use of CRT before the development of Class III HF symptoms may prevent or reverse remodeling, caused by prolonged ventricular conduction, thus preventing the progression of HF. The REVERSE trial (REsynchronization reVErse Remodeling in Systolic left vEntricular dysfunction) was double blinded and enrolled 610 subjects with NYHA class I or II HF and a QRS interval greater than or equal to 120 ms with a LVEF of less than 40% (Linde, 2008). All trial participants received a CRT device with or without an ICD. Trial participants were then randomized to active CRT (device-on) or control CRT (device-off) for 12 months. The primary endpoint was a HF clinical composite score consisting of any incidence of death, hospitalization due to worsening HF, or worsening symptoms. Subjects were classified as, “Worsened” if any of the above criteria were met. Subjects were classified as, “Improved” if there was an improvement in the NYHA class score or an improvement in symptoms. The remaining subjects were classified as, “Unchanged.” This composite outcome was chosen because those who were mildly symptomatic were unlikely to have an event rate for any individual parameter that was sufficiently high to show a treatment effect from CRT, thus requiring a more sensitive composite outcome to detect any beneficial treatment effect.

Of the 419 subjects assigned to the CRT-on group, 16% worsened, compared to 21% of the 191 subjects assigned to the CRT-off group, a difference that was not statistically significant (p=0.10). Therefore, the trial results did not meet the primary outcome. There was no significant difference in the number of hospitalizations between the two groups, but the time-to-first hospitalization was significantly delayed in the CRT-on group (HR, 0.47, p=0.03). Left ventricular end-systolic volume index was evaluated as a measure of left ventricular remodeling. Trial participants assigned to the CRT-on group experienced a greater improvement in this outcome. These results suggest that, while CRT can improve left ventricular remodeling, this improvement did not result in a significant improvement in clinical symptoms at 1 year. Other studies have reported that left ventricular remodeling precedes symptomatic improvement in those with advanced HF (Yu 2005), so the authors suggest that the 1-year follow-up in the REVERSE study was not long enough to detect clinical improvement (Sipahi, 2011).

Information has been published regarding the long-term effects of CRT in the European cohort enrolled in the REVERSE study. A total of 262 recipients (with QRS greater than or equal to 120 ms and LVEF less than or equal to 40%) were randomly assigned to either CRT or CRT-ICD and were designated either to the active arm (CRT-ON; n=180) or the control arm (CRT-OFF; n=82) for 24 months. Mean baseline LVEF was 28.0%. All subjects were in normal sinus rhythm (NSR) and receiving optimal medical therapy. The primary study endpoint was the proportion worsened by the HF clinical composite response. The main secondary study endpoint was the left ventricular end-systolic volume index (LVESVi). In the active treatment group, 19% worsened versus 34% in the control group (p=0.01). The LVESVi decreased by a mean of 27.5 ± 31.8 ml/m₂ in the active treatment group versus 2.7 ± 25.8 ml/m₂ in the control group (p<0.0001). Time to first hospital stay (for HF) or death (HR, 0.38; p=0.003) was significantly delayed by CRT. The authors concluded that after 24 months of CRT and compared with those of control subjects, clinical outcomes and LV function were improved and LV dimensions were decreased in this population in NYHA functional Classes I or II. These observations suggest that CRT prevents the progression of disease in those with asymptomatic or mildly symptomatic LV dysfunction (Daubert, 2009). However, in 2010 another article was published regarding the 2-year outcomes of the REVERSE trial which showed no differences in ventricular tachycardia/ventricular fibrillation (VT/VF) episodes or VT storm between groups. Specifically, in the CRT-ON group, the estimated event rate was 18.7% at 2 years compared with 21.9% in the CRT-OFF group (HR, 1.05, p=0.84). However, among CRT-ON subjects, those with reverse remodeling had a reduced incidence of VT/VF compared with those without remodeling (5.6% vs. 16.3%; HR, 0.31, p=0.001). These authors concluded that CRT for up to 2 years does not impact VT/VF in mild HF despite the marked clinical and remodeling effects of pacing. This neutral effect may be due to competing antiarrhythmic effects of reverse remodeling and the proarrhythmic effect of pacing (Gold, 2011, 2012).

Other trials also addressed this issue and were powered to measure morbidity and mortality rates. The RAFT trial (Resynchronization/Defibrillation for Ambulatory Heart Failure Trial) was a multi-center, double-blind, randomized controlled trial that was designed to determine if the addition of CRT to optimal pharmacological therapy and ICD is effective in reducing mortality and morbidity in individuals with mild to moderate HF symptoms. Initially those with NYHA Class II and III symptoms were included; this was changed to Class II symptoms only in 2006, due to the observation that Class III symptoms improve from CRT alone without ICD. This finding was also in alignment with updated specialty society guideline recommendations (NLM Identifier: NCT00251251). Results of the RAFT trial were published in 2010 which investigated a total of 1798 subjects in 34 centers in multiple countries for a mean follow-up period of 40 ± 20 months. The primary outcome occurred in 297 of 894 subjects (33.2%) in the ICD–CRT group and 364 of 904 subjects (40.3%) in the ICD group (HR in the ICD–CRT group, -0.75; 95% CI, 0.64 to 0.87; p<0.001). In the ICD–CRT group, 186 subjects died, as compared with 236 in the ICD group (HR, -0.75; 95% CI, 0.62 to 0.91; p=0.003), and 174 were hospitalized for HF, as compared with 236 in the ICD group (HR, -0.68; 95% CI, 0.56 to 0.83; p<0.001). However, at 30 days after device implantation, adverse events had occurred in 124 subjects in the ICD-CRT group, as compared with 58 in the ICD group (p<0.001). The authors concluded that among subjects with NYHA Class II or III HF, a wide QRS complex, and left ventricular systolic dysfunction, the addition of CRT to an ICD reduced rates of death and hospitalization for HF. This improvement was accompanied by more adverse events but is thought to provide convincing evidence in support of CRT for appropriately selected subjects with less severe HF disease (Class II and III symptoms, left ventricular systolic dysfunction and a wide QRS complex). These findings are consistent with the findings of two other major recent trials, the REVERSE and the MADIT-CRT (Moss, 2010; Tang, 2010).

The Multicenter Automatic Defibrillator Implantation Trial – Cardiac Resynchronization Trial (MADIT-CRT) was a randomized controlled trial of subjects with NYHA Class I and II symptoms that was similarly designed to determine if CRT combined with an ICD would reduce the risk of mortality and HF events. A total of 1820 subjects were enrolled (NLM Identifier: NCT00180271; 2008). Results of the MADIT-CRT were reported in 2009 as follows: during an average follow-up of 2.4 years, the primary endpoint occurred in 187 of 1089 subjects in the CRT-ICD group (17.2%) and 185 of 731 subjects in the ICD-only group (25.3%) (HR in the CRT-ICD group was 0.66; 95% CI, 0.52 to 0.84; p=0.001). The benefit did not differ significantly between those subjects with ischemic cardiomyopathy and those with nonischemic cardiomyopathy. The superiority of CRT was driven by a 41% reduction in the risk of HF events, a finding that was evident primarily in a prespecified subgroup with a QRS duration of 150 ms or more. CRT was associated with a significant reduction in left ventricular volumes and improvement in the LVEF. There was no significant difference between the 2 groups in the overall risk of death, with a 3% annual mortality rate in each treatment group. Serious adverse events were infrequent in the two groups. The authors concluded that CRT combined with ICD decreased the risk of HF events in relatively asymptomatic subjects with a low LVEF and wide QRS complex (Moss, 2009).  

In 2010, Solomon reported further on the results of the MADIT-CRT trial using echocardiographic changes to evaluate whether the improvement in outcomes with CRT plus an ICD was associated with favorable alterations in cardiac size and function. Echocardiographic studies were obtained at baseline and 12 months later in 1372 of the MADIT-CRT subjects. Changes in cardiac size and performance between treatment groups were compared, and the relationship between these changes was assessed over the first year, as well as subsequent outcomes. Compared with the ICD-only group, the CRT-plus-ICD group had greater improvement in left ventricular end-diastolic volume index (-26.2 versus -7.4 mL/m₂), left ventricular end-systolic volume index (-28.7 versus -9.1 mL/m₂), LVEF (11% versus 3%), left atrial volume index (-11.9 versus -4.7 mL/m₂), and right ventricular fractional area change (8% versus 5%; p<0.001 for all). Improvement in end-diastolic volume at 1 year was predictive of subsequent death or HF, with adjustment for baseline covariates and treatment group; each 10% decrease in end- diastolic volume was associated with a 40% reduction in risk (p<0.001). The authors of this analysis concluded that CRT resulted in significant improvement in cardiac size and performance compared with an ICD-only strategy in those subjects with mildly symptomatic HF. Improvement in these measures accounted for the outcomes benefit (Solomon, 2010).

In 2011, Sipahi published results of meta-analysis of five randomized controlled trials that reported outcomes according to QRS ranges (n=5813). The objective was to determine if the impact of CRT on clinical endpoints is affected by the degree of baseline QRS. The five previously reported trials that were included in this meta-analysis were the COMPANION, CARE-HF, REVERSE, MADIT-CRT and the RAFT trials. Results of the Sipahi analysis showed the following:

• No statistically significant benefit in those with moderately prolonged QRS in this meta-analysis of the included trials regardless of enrollment criteria for functional class;
• When directly compared with heterogeneity analysis, the overall effect of CRT on clinical events was significantly different for those with moderate vs. severely prolonged QRS (p<0.001);
• There was a statistically significant relationship between QRS duration and log risk ratio (slope -0.07; 95%, CI -0.10 to -0.04; z = −4.60; p<0.001); groups with QRS durations less than 150 milliseconds not showing benefit from CRT;
• Beneficial effects of CRT on reduction of clinical events became evident when cases with QRS intervals of 150 milliseconds or greater were included, and the magnitude of benefit became more prominent with further increases in QRS duration;
• (Sensitivity): When the analysis was limited to NYHA III and IV cases (COMPANION and CARE-HF), there was still a highly significant benefit of CRT in subjects with severely prolonged QRS and no statistically significant benefit in subjects with moderately prolonged QRS; the same was observed for NYHA Class I and II cases;
• When the analysis was limited to trials with nearly universal use of ICDs in both arms of the trials, statistically significant benefit with CRT was seen only in the subjects with severely prolonged QRS and not in those with moderately prolonged QRS; when the analysis was limited to trials without background ICD therapy, again the benefit of CRT was observed only in those with severely prolonged QRS;
• In each sensitivity analysis performed, using the 1-study-out method, there remained a significant difference in the impact of CRT on clinical events according to the degree of QRS prolongation; when analysis was limited to trials uniformly reporting hazard ratios (that is, when REVERSE was left out), there was again benefit in the subjects with severely prolonged QRS and not in those with moderately prolonged QRS.

The authors concluded that the degree of QRS prolongation is more important than the level of functional impairment for selection of subjects for CRT. However, multiple limitations to these findings were acknowledged including use of summary, (versus individual), data in this meta-analysis; use of heterogeneous enrollment criteria by the five included trials with variable composite outcome measures; unknown morphology of the QRS complex in participants with a QRS duration less than 150 msec; and unknown percentages of study participants with RBBB (right bundle branch block). It was noted that further analysis of individual subject-specific data from all relevant clinical trials can further refine the QRS cutoffs for different types of conduction abnormalities (Sipahi, 2011).

In 2018, Hernandez and colleagues published the results of a systematic review and meta-analysis with the aim to assess outcomes after CRT in inotrope-dependent individuals with HF. The systematic literature search yielded 8 studies with a total of 151 individuals, most of who were in NYHA Class IV (80.1%). All included individuals had severe systolic HF, LVEF less than 30%, and QRS complex duration greater than 130 ms. The results of the meta-analysis showed that 93% of the individuals were weaned from inotropic support after CRT (95% confidence interval [CI]: 86% to 100%). In addition, improvement in NYHA functional Class was noted [2% improved to NYHA Class I (95% CI: 2% to 6%), 36% improved to NYHA Class II (95% CI: 15% to 57%), 43% improved to NYHA Class III (95% CI: 10% to 76%), and 10% stayed in NYHA Class IV (95% CI: 3% to 18%)]. Study limitations include non-controlled, retrospective design of the included studies, and non-uniform, unspecified enrollment criteria.

Kutyifa and colleagues (2019) reported on a post-hoc analysis of MADIT-CRT (carried out from December 22, 2004 through June 22, 2009) that aimed to evaluate the long-term mortality benefit from CRT-D in mild HF defined as LVEF greater than 30%. Individuals who were excluded from MADIT-CRT due to central echocardiographic analysis in the core study laboratory identifying the LVEF as being greater than 30% were eligible for this post-hoc analysis. Of those eligible, individuals were excluded if they had a non-LBBB electrocardiographic morphology (n=537), or if they had no baseline LVEF measurement available (n=10). A total of 1274 individuals were identified for the post-hoc analysis with 824 (65%) individuals with LVEF of less than or equal to 30% and 450 (35%) individuals with LVEF greater than 30%. The primary outcome of the analysis was long-term all-cause mortality and the secondary outcome was HF alone. The median long-term follow-up was 5.6 years. Analysis results showed CRT-D versus ICD was associated with reduction in all-cause mortality in both individuals with LVEF greater than 30% and LVEF less than or equal to 30% (HR 0.47; 95% CI, 0.25-0.85; p=0.036 versus HR 0.69; 95% CI, 0.49-0.98; p=0.013; interaction p=0.261), and showed similar outcomes in the efficacy of CRT-D versus ICD only to reduce HF in individuals with LVEF greater than 30% and LVEF less than or equal to 30% (HR 0.36; 95% CI, 0.35-0.61; p<0.001 versus HR 0.46; 95% CI, 0.35-0.61; p<0.001; interaction p=0.342). While these results suggest LBBB individuals with LVEF greater than 30% may benefit from CRT-D, it remains unclear as to how many individuals included in the analysis had a LVEF greater than 35%. The authors note that the majority of individuals had a LVEF of 30% to 40% (mean LVEF of 32.2% with a narrow standard deviation for LVEF of 1.9%, meaning that nearly 70% of the individuals had a baseline LVEF greater than 30%, but less than 35%, and over 95% had a LVEF of 36% or less). Furthermore, longitudinal echocardiography data in MADIT-CRT was not available, and LVEF measurement at baseline may not be indicative of LVEF throughout the follow-up period. Due to this and the retrospective design of the study, large prospective studies are needed to better characterize long-term mortality benefit from CRT-D in mild HF individuals by LVEF greater than 35%.

In 2012, the American College of Cardiology Foundation/American Heart Association/Heart Rhythm Society (ACCF/AHA/HRS) published a focused update to the Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities (Tracy, 2012), in which the former Class I recommendation for CRT was expanded to include those in NYHA Class II and also specified subjects with left bundle branch block (LBBB) morphology and a QRS duration of ≥ 150 ms; (LVEF ≤ 35%, NSR and NYHA Class III and IV symptoms were unchanged in this recommendation) (Level of evidence: A for NYHA Class III/IV and B for NYHA Class II; based on CARE-HF and COMPANION) (Bristow, 2004; Cleland, 2005, 2009; Stavrakis, 2012).

Additional new Class IIa recommendations were added as follows:

• CRT “can be useful” for individuals with a LVEF ≤ 35%, in NSR, with LBBB and a QRS duration of 120 to 149 ms in NYHA class II, III, or ambulatory IV symptoms while on GDMT (Guideline-Directed Medical Therapy); (Level B evidence; Richard, 2011).
• CRT “can be useful” for individuals with a LVEF ≤ 35%, in NSR, a non-LBBB pattern with a QRS duration ≥ 150 ms, and NYHA class III/ambulatory class IV symptoms on GDMT; (Level A evidence; based on RAFT; Sipahi, 2011; Tang, 2010).

This ACCF/AHA/HRS guideline concluded that, “The congruence of results from the totality of CRT trials with regard to remodeling and HF events provides evidence supporting a common threshold of 35% for benefit from CRT in NYHA Class II through IV HF symptoms” (Tracy, 2012).

In 2013, the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) issued an updated Guideline for the Management of Heart Failure, in which several updated recommendations for use of CRT are provided and have been revised to now align with the Tracy guideline, as well as provide a new classification system for the definitions of HF which aligns with the NYHA classifications for HF severity (Yancy, 2013). The following is excerpted:

Class I:

CRT “is indicated” for patients who have LVEF of 35% or less, sinus rhythm, left bundle-branch block (LBBB) with a QRS duration of 150 ms or greater, and NYHA Class II, III, or ambulatory IV symptoms on GDMT; (Level of Evidence A for NYHA Class III/IV; Level of Evidence B for NYHA Class II – this recommendation was expanded to include those in NYHA Class II HF, also added LBBB and increased the QRS to 150 and above; based on Abraham, 2002; Bristow, 2004; Cleland, 2005; Hunt, 2009; Moss, 2009; Tang, 2010).

Class IIa:

• CRT “can be useful” for patients who have LVEF of 35% or less, sinus rhythm, a non-LBBB pattern with a QRS duration of 150 ms or greater, and NYHA Class III/ambulatory Class IV symptoms on GDMT; (Level of Evidence A – this recommendation was revised to address non-LBBB; based on Abraham, 2002; Bristow, 2004; Cleland, 2005; Tang, 2010).
• CRT “can be useful” for patients who have LVEF of 35% or less, sinus rhythm, LBBB with a QRS duration of 120 to 149 ms, and NYHA Class II, III, or ambulatory IV symptoms on GDMT; (Level of Evidence B – this NEW recommendation is based on Abraham, 2002; Bristow, 2004; Cleland, 2005; Linde, 2008; Moss, 2009; Tang, 2010).
• CRT “can be useful” for patients on GDMT who have LVEF of 35% or less and are undergoing placement of a new or replacement device with anticipated requirement for significant (> 40%) ventricular pacing; (Level of Evidence C – this recommendation was revised to address new or replacement devices; based on Adelstein, 2011; Doshi, 2005; Vatankulu, 2009; Wilkoff, 2002).

The above ACCF/AHA recommendations for CRT therapy were based on the results of the RAFT and MADIT-CRT trials (Moss, 2009; Tang, 2010), as well as trials attempting to predict optimum candidate selection criteria related to AV optimization techniques and echocardiographic parameters, such as the Predictors of Response to CRT (PROSPECT) trial (Chung, 2008) and the SmartDelay determined AV optimization: a comparison to other AV delay methods used in cardiac resynchronization therapy (SMART-AV) trial (Ellenbogen, 2010). Also, results of the ESCAPE trial (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) were reviewed which evaluated whether the use of pulmonary artery catheters (PAC) affected overall mortality in the management of HF (Binanay, 2005). The results of the ESCAPE trial indicated that use of PACs did not affect overall mortality and hospitalization but did increase adverse events. Additional trials cited in the ACCF/AHA recommendations for CRT therapy were related to the impact of different management strategies, such as noninvasive ventilation in acute cardiogenic pulmonary edema (Masip, 2005) and use of percutaneous left ventricular assist devices vs. intra-aortic balloon pumps in cardiogenic shock (Cheng, 2009; Kar, 2011).

The following is excerpted (Yancy, 2013):

New evidence supports extension of CRT to patients with milder symptoms. LV remodeling was consistently reversed or halted, with benefit also in reduction of HF hospitalizations. In this population with low 1-year mortality, reduction of HF hospitalization dominated the composite primary endpoints, but a mortality benefit was subsequently observed in a 2-year extended follow-up study (REVERSE trial) and in a meta-analysis of 5 trials of CRT in mild HF that included 4213 patients with Class II symptoms (Sipahi, 2011). Overall benefits in Class II HF were noted only in patients with QRS ≥ 150 ms and LBBB, with an adverse impact with shorter QRS duration or non-LBBB…

In 2016, The European Society of Cardiology (ESC) reported on guidelines created by The Task Force for the diagnosis and treatment of acute and chronic heart failure. The ESC made the following recommendations for CRT in individuals with HF:

• CRT is recommended for symptomatic patients with HF in sinus rhythm with a QRS duration ≥150 msec and LBBB QRS morphology and with LVEF ≤35% despite optimal medical therapy (OMT) in order to improve symptoms and reduce morbidity and mortality (Class I; Level A).
• CRT should be considered for symptomatic patients with HF in sinus rhythm with a QRS duration ≥150 msec and non-LBBB QRS morphology and with LVEF ≤35% despite OMT in order to improve symptoms and reduce morbidity and mortality (Class IIa; Level B).
• CRT is recommended for symptomatic patients with HF in sinus rhythm with a QRS duration of 130–149 msec and LBBB QRS morphology and with LVEF ≤35% despite OMT in order to improve symptoms and reduce morbidity and mortality (Class I; Level B).
• CRT may be considered for symptomatic patients with HF in sinus rhythm with a QRS duration of 130–149 msec and non-LBBB QRS morphology and with LVEF ≤35% despite OMT in order to improve symptoms and reduce morbidity and mortality (Class IIb; Level A).
• CRT rather than RV pacing is recommended for patients with heart failure with reduced ejection fraction (HFrEF) regardless of NYHA class who have an indication for ventricular pacing and high degree AV block in order to reduce morbidity. This includes patients with AF (Class I; Level A).
• CRT should be considered for patients with LVEF ≤35% in NYHA Class III–IV despite OMT in order to improve symptoms and reduce morbidity and mortality, if they are in AF and have a QRS duration ≥130 msec provided a strategy to ensure bi-ventricular capture is in place or the patient is expected to return to sinus rhythm (Class IIa; Level B).
• Patients with HFrEF who have received a conventional pacemaker or an ICD and subsequently develop worsening HF despite OMT and who have a high proportion of RV pacing may be considered for upgrade to CRT. This does not apply to patients with stable HF (Class IIb; Level B).
• CRT is contra-indicated in patients with a QRS duration < 130 msec (Class III; Level A).

The ACC, AHA, and HRS released a joint guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay (Kusumoto, 2018) with the following recommendations:

• In patients with atrioventricular block who have an indication for permanent pacing with a LVEF between 36% and 50% and are expected to require ventricular pacing more than 40% of the time, it is reasonable to choose pacing methods that maintain physiologic ventricular activation (e.g., cardiac resynchronization therapy [CRT] or His bundle pacing) over right ventricular pacing (Strength of Recommendation: Moderate; Level of Evidence: Moderate)
• In patients with atrioventricular block who have an indication for permanent pacing with a LVEF between 36% and 50% and are expected to require ventricular pacing less than 40% of the time, it is reasonable to choose right ventricular pacing over pacing methods that maintain physiologic ventricular activation (e.g., CRT or His bundle pacing) (Strength of Recommendation: Moderate; Level of Evidence: Moderate)
• In patients with heart failure, a mildly to moderately reduced LVEF (36%-50%), and LBBB (QRS ≥150 ms), CRT may be considered (Strength of Recommendation: Weak; Level of Evidence: Limited data)

Regarding the timeframe for prior conservative GDMT before consideration for CRT therapy, the general consensus in the practice community for prior GDMT is 3 to 6 months. In 2013, a report of the American College of Cardiology Foundation (ACCF) Appropriate Use Criteria Task Force, Heart Rhythm Society (HRS), American Heart Association (AHA), American Society of Echocardiography (ASE), Heart Failure Society of America (HFSA), Society for Cardiovascular Angiography and Interventions (SCAI), Society of Cardiovascular Computed Tomography (SCCT), and Society for Cardiovascular Magnetic Resonance (SCMR) was issued, in which the following is noted regarding the timeframe for GDMT:

Patients who are going to receive substantial benefit from medical treatment alone usually show some clinical improvement during the first 3 to 6 months. Medical therapy is also assumed to include adequate rate control for tachyarrhythmias, including atrial fibrillation. Therefore, it is recommended that GDMT be provided for at least 3 months before planned reassessment of LV function to consider device implantation. If LV function improves to the point where primary prevention indications no longer apply, then device implantation is not indicated (Russo, 2013).

Comparison of ACCF/AHA Stages of HF and NYHA Functional Classifications:

*NYHA Classifications (New York Heart Association): See Definitions section for further information.

CRT in Atrial Fibrillation (AF):

The majority of studies of CRT have excluded individuals with atrial arrhythmias, which commonly occur in persons who would otherwise be considered candidates for CRT. Therefore, there has been interest in evaluating CRT in this group. For example, in the MUltisite STimulation In Cardiomyopathy (MUSTIC) study, 64 of the 131 enrolled subjects had atrial fibrillation (AF), in addition to HF and ventricular dyssynchrony (Cazeau, 2001). All subjects received a biventricular implant, but during the initial 3 months of the trial, the participants were randomized to either active or inactive pacing, followed by cross over to the other arm for an additional 3 months (Linde, 2002). Thirty-three of the participants with AF were followed up at 9 and 12 months to evaluate 6 minute walking distance, peak oxygen uptake and quality of life. A total of 42 of the 67 subjects in NSR were similarly evaluated. Trial subjects with AF showed similar improvements compared to those with NSR.

In 2005, Doshi and colleagues reported on the Left Ventricular-Based Cardiac Stimulation Post AV Nodal Ablation Evaluation (PAVE) Study, which was a prospective, individual-blinded, randomized, multicenter clinical trial comparing chronic biventricular (n=103) to right ventricular pacing (n=81) in individuals with chronic AF undergoing AV nodal ablation regardless of their EF, NYHA class, or duration of their baseline QRS. The study assessed this comparison through the primary endpoint of the degree of change in the distance walked during the 6-minute walk test performed prior to AV nodal ablation (baseline) compared to 6 months postablation. Results showed:

At 6 months postablation, patients treated with cardiac resynchronization had a significant improvement in 6-minute walk distance, (31%) above baseline (82.9 ± 94.7 m), compared to patients receiving right ventricular pacing, (24%) above baseline (61.2 ± 90.0 m) (p=0.04). There were no significant differences in the quality-of-life parameters. At 6 months postablation, the ejection fraction in the biventricular group (0.46 ± 0.13) was significantly greater in comparison to patients receiving right ventricular pacing (0.41 ± 0.13, p=0.03) (Doshi, 2005).

However, the differences found in the EF and walking distance between both groups was due to a decline in the outcomes for the right ventricular pacing group and not an increase in the biventricular pacing group. This suggests that biventricular pacing can avoid adverse effects of cardiac dyssynchrony created by pacing only from the right ventricle, and leads to reason that a “biventricular pacing device should be considered for patients who require AV node ablation for management of atrial fibrillation and who have a left ventricular ejection fraction ≤ 45% or who have NYHA Class II or III symptoms” (Doshi, 2005).  

Upadhyay and colleagues (2008) conducted a meta-analysis of prospective cohort studies of CRT in subjects with AF and those in NSR. A total of 5 studies enrolling 1164 subjects met the study selection criteria. The authors concluded that both groups benefited from CRT. The NYHA classification improved similarly in both groups. While those in NSR reported greater improvement in the 6 minute walk test, compared to those with AF, the AF group had greater improvement in the LVEF.

A systematic review and meta-analysis was conducted in 2011 by Wilton and colleagues which included 23 observational studies and followed a total of 7495 CRT recipients, 25.5% of whom had AF, for a mean duration of 33 months. The purpose of this analysis was to compare outcomes in subjects with and without AF receiving CRT. A secondary objective was to evaluate the effects of atrioventricular nodal ablation (AVN) on outcomes in subjects with AF. All of the included studies were observational cohort studies, and most reported significant differences in the baseline characteristics of the study participants between those with and without AF. The results showed that presence of AF is associated with an increased risk of non-response to CRT (34.5% vs. 26.7%; pooled relative risk [RR], 1.32; 95% CI, 1.12, 1.55; p=0.001) and all-cause mortality (10.8% vs. 7.1% per year; pooled RR, 1.50; 95% CI, 1.08, 2.09; p=0.015). The presence of AF was also associated with less improvement in quality of life measures, 6-minute hall walk distance, and LV end-systolic volume but not LVEF. Among study subjects with AF, AVN ablation appeared favorable with a lower risk of clinical non-response (RR 0.40; 95% CI 0.28, 0.58; P<0.001) and a reduced risk of death. There was insufficient data to permit meta-analysis of hospitalization rates in those with, versus without, AF. The authors concluded that the benefits of CRT appear to be attenuated in AF, although AF is associated with increased risk for clinical non-response and death when compared to outcomes from CRT in those without AF. It was also noted that AVN ablation may improve CRT outcomes in individuals with AF but randomized trials are needed to confirm these findings (Wilton, 2011b).

The 2012 ACCF/AHA/HRS focused update to the Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities (Tracy, 2012) included the following recommendation specific to individuals with AF:

CRT “can be useful” for individuals with AF and LVEF ≤ 35% on GDMT if: a) the patient requires ventricular pacing or otherwise meets CRT criteria and b) AV nodal ablation or pharmacologic rate control will allow near 100% ventricular pacing with CRT; (Class IIa; Level of Evidence B).

The level of evidence for this recommendation changed from C to B, based on MUSTIC (Brignole, 2011; Doshi, 2005; Gasparini, 2006; Linde, 2003).

The 2013 ACCF/AHA updated Guideline for the Management of Heart Failure (Yancy, 2013) included the exact same recommendation for individuals with AF which had been previously issued in the 2012 ACCF/AHA/HRS document (Tracy, 2012) with the same Class IIa, Level of Evidence B.

The following is excerpted from Yancy, 2013:

…The weight of the evidence has been accumulated from patients with sinus rhythm, with meta-analyses indicating substantially less clinical benefit in patients with permanent AF. Because effective CRT requires a high rate of ventricular pacing, the benefit for patients with AF is most evident in patients who have undergone atrioventricular nodal ablation, which ensures obligate ventricular pacing.

In 2013, a focused update to the 2012 ACCF/AHA/HRS guideline (Tracy, 2012) was incorporated into the ACCF/AHA/HRS 2008 Guidelines for Device-based Therapy of Cardiac Rhythm Abnormalities which provided:

• Limitation of the Class I indication to patients with QRS duration ≥ 150 ms with LBBB pattern;
• Expansion of Class I indications to NYHA class II HF with LBBB and QRS duration ≥ 150 ms;
• Addition of a Class IIb recommendation for patients who have LVEF ≤ 30%, ischemic etiology of HF, SR, LBBB with a QRS duration ≥ 150 ms, and NYHA class I symptoms (Epstein, 2013).

Evidence to support use of CRT in selected individuals with LVEF > 35% and < 50% is limited. The rationale for CRT in this setting is based upon indirect evidence from trials in individuals with LVEF ≤ 35% as well as the results of the BLOCK-HF trial which demonstrated that in HF individuals (NYHA class I, II, and III symptoms and an LVEF between 30% and 50%) with AV block, CRT was superior to conventional RV pacing for a composite end point (death, HF event requiring intervention, or ventricular remodeling [45.8 versus 55.6 percent; HR 0.74, 95% CI 0.60-0.90]), but failed to show a significant difference in the risk of death (St John Sutton, 2015). In 2019, an Agency for Healthcare Research and Quality Technology Assessment on the use of CRT affirmed that the evidence for effectiveness and harms in individuals with LVEF > 35% and < 50% is limited (Michtalik, 2019).

CRT Devices Overview

The InSync^® Biventricular Pacing System (Medtronic Inc., Minneapolis, MN) is an example of a biventricular pacemaker. It’s FDA labeling states that it is indicated for:

The treatment of individuals with NYHA functional class III or IV HF, who remain symptomatic despite stable, optimal medical therapy, who additionally have a QRS duration of greater than or equal to 130 milliseconds, and a LVEF of less than or equal to 35%. (See additional information below).

The FDA approval was based on data collected in the Multi-Center InSync Randomized Clinical Evaluation (MIRACLE) trial (FDA, 2001).

In May of 2002, the FDA approved the first hybrid device that combines CRT with an ICD, the CONTAK CD^® (Guidant Corp., St. Paul, MN). The device is indicated for:

Individuals at high-risk of sudden death due to ventricular arrhythmias and who have moderate to severe HF (NYHA Class III/IV), including a LVEF less than or equal to 35% and a QRS duration greater than or equal to 120 milliseconds, and who remain symptomatic despite stable, optimal HF drug therapy.

In June of 2004, the FDA approved additional devices, the Epic^™ HF and Atlas^® + HF Dual Chamber Implantable Cardioverter Defibrillator Systems with Cardiac Resynchronization Therapy (St Jude Medical^® Inc., Sunnyvale, CA) for ventricular antitachycardia pacing and ventricular defibrillation for automated treatment of life-threatening ventricular arrhythmias. This device has similar criteria to the others with a QRS duration equal to or greater than 150 milliseconds (FDA, 2004).

On April 29, 2005, the St. Jude Medical Frontier™ Model 5508L and Frontier™ II Model 5586 Cardiac Resynchronization Therapy Pacemakers (St Jude Medical Inc., Sylmar, CA) received additional approval for two more indications:

• Maintaining synchrony of the left and right ventricles in patients who have undergone an AV nodal ablation for chronic atrial fibrillation and have NYHA Class II or III heart failure
• The reduction of the symptoms of moderate to severe heart failure (NYHA Class III or IV) in those patients who remain symptomatic despite stable, optimal medical therapy, and have a left ventricular ejection fraction ≤35% and a prolonged QRS duration (FDA, 2005)

On September 16, 2010 the FDA approved expanded indications for three CRT devices (the Cognis^® CRT-D, Livian^™ CRT-D and Contak Renewal^® 3 RF HE CRT-D, Boston Scientific Corp., St. Paul, MN), based on the results of the MADIT-CRT trial as follows:

These CRT-D devices are indicated for individuals with HF who receive stable optimal pharmacologic therapy for HF and who meet any one of the following classifications:
1)   Moderate to severe HF (NYHA Class III-IV) with EF less than or equal to 35% and QRS duration greater than or equal to 120 ms; or
2)   LBBB with QRS greater than or equal to 130 ms, EF less than or equal to 30%, and mild (NYHA Class II) ischemic or nonischemic HF or asymptomatic (NYHA Class I) ischemic HF (FDA, 2010).

In 2014, additional CRT devices manufactured by Medtronics, Inc. were cleared for expanded indications to include:

Individuals with NYHA functional class I, II, or III HF, who have a LVEF of 50% or less on stable, optimal HF medical therapy, if indicated, and who have AV block that is expected to require a high percentage of ventricular pacing that cannot be managed with algorithms to minimize right ventricular pacing (FDA, 2014).

These Medtronics devices go by multiple trade names; most are combination CRT/D devices, and one of the new devices is a combination CRT/pacemaker device (CRT-P), the Consulta^® CRT-P System which has an adaptive pacing function intended for individuals who may benefit from maintenance of AV synchrony. Additional detailed information on the Medtronics devices is available at: http://www.accessdata.fda.gov/cdrh_docs/pdf/P010015S205b.pdf (FDA, April 10, 2014; accessed on July 9, 2020).

In May 2017, Boston Scientific received FDA clearance for the Resonate^™ family of ICD and CRT-D systems. The approval includes new features in the Resonate devices, including SmartCRT^™ technology with multisite pacing capability for multi-electrode pacing and compatibility with the HeartLogic^™ Heart Failure Diagnostic Services, intended to help physicians improve HF management.

Arrhythmia: An irregular heartbeat which can be either an atrial or ventricular arrhythmia depending on which part of the heart the abnormal rhythm originates from.

Atrial fibrillation (AF): This abnormal rhythm disorder involves an irregular and often rapid heart rate that emanates from the heart's two upper chambers (the atria) resulting in chaotic beating of the atria. This fibrillation of the atria is out of coordination with the two lower chambers (the ventricles) of the heart causing inefficient pumping of the heart and diminished blood flow throughout the body. AF symptoms often include heart palpitations, shortness of breath and weakness.

CRT-D: A cardiac resynchronization therapy device that performs biventricular cardiac pacing and has a cardioverter-defibrillator.

CRT-P: A cardiac resynchronization therapy device without a cardioverter-defibrillator that performs biventricular cardiac pacing.

Congestive heart failure (CHF) or heart failure: A condition in which the heart no longer adequately functions as a pump. As blood flow out of the heart slows, blood returning to the heart through the veins backs up, causing congestion in the lungs and other organs.

Defibrillation: A process in which an electronic device (a defibrillator) gives the heart an electric shock, helping reestablish normal contraction rhythms in a heart that is not properly beating. This may be done using an external device or by a device implanted in the body, an implantable cardioverter defibrillator (ICD).

Guideline-directed medical therapy (GDMT): This term was adopted by the writing groups for the major specialty medical societies, (such as found in Tracy, 2012 and Yancy, 2013) in 2012; the term replaces and is synonymous with “Optimal medical therapy.”

Left ventricular ejection fraction (LVEF): The measurement of the heart's ability to pump blood through the body. Normal LVEF readings would be in the 58-70% range.

Myocardial infarction (MI): The medical term for heart attack. A heart attack occurs when the blood supply to part of the heart muscle (the myocardium) is severely reduced or blocked.

New York Heart Association (NYHA) Definitions:
The NYHA classification of heart failure is a 4-tier system that categorizes subjects based on subjective impression of the degree of functional compromise; the four NYHA functional classes are as follows:

• Class I - patients with cardiac disease but without resulting limitation of physical activity; ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain; symptoms only occur on severe exertion.
• Class II - patients with cardiac disease resulting in slight limitation of physical activity; they are comfortable at rest; ordinary physical activity (e.g., moderate physical exertion such as carrying shopping bags up several flights of stairs) results in fatigue, palpitation, dyspnea, or anginal pain.
• Class III - patients with cardiac disease resulting in marked limitation of physical activity; they are comfortable at rest; less than ordinary activity causes fatigue, palpitation, dyspnea or anginal pain.
• Class IV - patients with cardiac disease resulting in inability to carry on any physical activity without discomfort; symptoms of heart failure or the anginal syndrome may be present even at rest; if any physical activity is undertaken, discomfort is increased.

QRS complex: Refers to a portion of a tracing within an electrocardiogram that represents the spread of the electrical impulse through the ventricles. A prolonged QRS interval indicates a dyssynchrony of the right and left ventricle and is an important selection criterion for a biventricular pacemaker.  

Sudden cardiac death: Death resulting from an abrupt loss of heart function (also known as cardiac arrest).

Ventricular tachyarrhythmias: A medical term for a rapid heartbeat that may be regular or irregular arising from the ventricle or pumping chamber of the heart. Two common tachyarrhythmias are ventricular tachycardia and ventricular fibrillation.

Ventricular fibrillation (Vfib or VF): A condition in which the heart's electrical activity becomes disordered. When this happens, the heart's lower (pumping) chambers contract in a rapid, unsynchronized fashion (the ventricles "quiver" rather than beat) and the heart pumps little or no blood.

Ventricular tachycardia (Vtach or VT): A fast regular heart rate that starts in the lower chambers (ventricles). VT may result from serious heart disease and usually requires prompt treatment.

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69. Miller RJH, Howlett JG, Exner DV, et al. Baseline functional class and therapeutic efficacy of common heart failure interventions: a systematic review and meta-analysis. Can J Cardiol. 2015; 31:792-799.
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73. Moss AJ. Preventing heart failure and improving survival. N Engl J Med. 2010; 363(25):2456-2457.
74. Nery PB, Keren A, Birnie DH. Cardiac resynchronization therapy: expanding clinical indications and refining patient selection. Curr Opin Cardiol. 2012; 27(2):137-142.
75. Ouellet G, Huang DT, Moss AJ, et al. Effect of cardiac resynchronization therapy on the risk of first and recurrent ventricular tachyarrhythmic events in MADIT-CRT. J Am Coll Cardiol. 2012; 60(18):1809-1816.
76. Peterson PN, Greiner MA, Qualls LG, et al. QRS duration, bundle-branch block morphology, and outcomes among older patients with heart failure receiving cardiac resynchronization therapy. JAMA. 2013; 310(6):617-626.
77. Peterson PN, Varosy PD, Heidenreich PA, et al. Association of single- vs dual-chamber ICDs with mortality, readmissions, and complications among patients receiving an ICD for primary prevention. JAMA. 2013; 309(19):2025-2034.
78. Rickard J, Bassiouny M, Cronin EM, et al. Predictors of response to cardiac resynchronization therapy in patients with a non-left bundle branch block morphology. Am J Cardiol. 2011; 108(11):1576-1580.
79. Rogers DP, Lambiase PD, Lowe MD, Chow AW. A randomized double-blind crossover trial of triventricular versus biventricular pacing in heart failure. Eur J Heart Fail. 2012; 14(5):495-505.
80. Ruschitzka F, Abraham WT, Singh JP, et al. Cardiac-resynchronization therapy in heart failure with a narrow QRS complex. N Engl J Med. 2013; 369(15):1395-1405.
81. Saxon LA, Boehmer JP, Hummel J, et al.; The VIGOR CHF and VENTAK CHF investigators. Biventricular pacing in patients with congestive heart failure; two prospective randomized trials. Am J Cardiol. 1999; 83(5B):120D-123D.
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83. Shah RM, Patel D, Molnar J, et al. Cardiac-resynchronization therapy in patients with systolic heart failure and QRS interval ≤ 130 ms: Insights from a meta-analysis. Europace. 2015; 17(2):267-273.
84. Singh JP, Klein HU, Huang DT, et al. Left ventricular lead position and clinical outcome in the multicenter automatic defibrillator implantation trial-cardiac resynchronization therapy (MADIT-CRT) trial. Circulation. 2011; 123(11):1159-1166.
85. Sipahi I, Carrigan TP, Rowland DY, et al. Impact of QRS duration on clinical event reduction with cardiac resynchronization therapy: meta-analysis of randomized controlled trials. Arch Intern Med. 2011; 171(16):1454-1462.
86. Sipahi I, Chou JC, Hyden M, et al. Effect of QRS morphology on clinical event reduction with cardiac resynchronization therapy: meta-analysis of randomized controlled trials. Am Heart J. 2012; 163(2):260-267.
87. Solomon SD, Foster E, Bourgoun M, et al. Effect of cardiac resynchronization therapy on reverse remodeling and relation to outcome: multicenter automatic defibrillator implantation trial: cardiac resynchronization therapy. Circulation. 2010; 122(10):985-992.
88. Stavrakis S, Lazzara R, Thadani U. The benefit of cardiac resynchronization therapy and QRS duration: a meta-analysis. J Cardiovasc Electrophysiol. 2012; 23(2):163-168.
89. St John Sutton M, Ghio S, Plappert T, et al. Cardiac resynchronization induces major structural and functional reverse remodeling in patients with New York Heart Association class I/II heart failure. Circulation. 2009; 120(19):1858-1865.
90. St John Sutton MG, Plappert T, Abraham WT, et al. Effect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure. Circulation. 2003; 107(15):1985-1900.
91. St John Sutton MG, Plappert T, Adamson PB, et al. Left ventricular reverse remodeling with biventricular versus right ventricular pacing in patients with atrioventricular block and heart failure in the BLOCK HF trial. Circ Heart Fail. 2015; 8:510-518.
92. St John Sutton MG, Plappert T, Hilpisch KE, et al. Sustained reverse left ventricular structural remodeling with cardiac resynchronization at one year is a function of etiology: quantitative Doppler echocardiographic evidence from the Multicenter InSync Randomized Clinical Evaluation (MIRACLE). Circulation. 2006; 113(2):266-272.
93. Sweeney MO, Ellenbogen KA, Casavant D, et al. Multicenter prospective randomized safety and efficacy study of a new atrial-based managed ventricular pacing mode (MVP) in dual chamber ICDs. J Cardiovasc Electrophysiol. 2005; 16(8):811-817.
94. Tang AS, Wells GA, Talajic M, et al. Cardiac resynchronization therapy for mild to moderate heart failure. N Engl J Med. 2010; 363(25):2385-2395.
95. Thibault B, Harel F, Ducharme A, et al.; LESSER EARTH Investigators. Cardiac resynchronization therapy in patients with heart failure and a QRS complex < 120 milliseconds: the Evaluation of Resynchronization Therapy for Heart Failure (LESSER-EARTH) trial. Circulation. 2013; 127(8):873-881.
96. Upadhyay GA, Choudhry NK, Auricchio A, et al. Cardiac resynchronization in patients with atrial fibrillation: a meta-analysis of prospective cohort studies. J Am Coll Cardiol. 2008; 52(15):1239-1246.
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98. Vatankulu MA, Goktekin O, Kaya MG, et al. Effect of long-term resynchronization therapy on left ventricular remodeling in pacemaker patients upgraded to biventricular devices. Am J Cardiol. 2009; 103(9):1280-1284.
99. Whellan DJ, Ousdigian KT, Al-Khatib SM, et al. Combined heart failure device diagnostics identify patients at higher risk of subsequent heart failure hospitalizations: results from PARTNERS HF (Program to Access and Review Trending Information and Evaluate Correlation to Symptoms in Patients With Heart Failure) study. J Am Coll Cardiol. 2010; 55(17):1803-1810.
100. Wikstrom G, Blomström-Lundqvist C, Andren B, et al. The effects of etiology on outcome in patients treated with cardiac resynchronization therapy in the CARE-HF trial. Eur Heart J. 2009; 30(7):782-788.
101. Wilkoff BL, Cook JR, Epstein AE, et al. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA. 2002; 288(24):3115-3123.
102. Wilton SB, Kavanagh KM, Aggarwal SG, et al. Association of rate-controlled persistent atrial fibrillation with clinical outcome and ventricular remodeling in recipients of cardiac resynchronization therapy. Can J Cardiol. 2011a; 27(6):787-793.
103. Wilton SB, Leung AA, Ghali WA, et al. Outcomes of cardiac resynchronization therapy in patients with versus those without atrial fibrillation: a systematic review and meta-analysis. Heart Rhythm. 2011b; 8(7):1088-1094.
104. Yancy CW, Fonarow GC, Albert NM, et al. Influence of patient age and sex on delivery of guideline-recommended heart failure care in the outpatient cardiology practice setting: findings from IMPROVE HF. Am Heart J. 2009; 157(4):754-762.
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Government Agency, Medical Society, and Other Authoritative Publications:

1. Boston Scientific Corporation, University of Rochester. MADIT-CRT Automatic defibrillator implantation with cardiac resynchronization therapy. NLM Identifier: NCT00180271. Last updated on December 18, 2018. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00180271?term=MADIT+CRT&rank=1. Accessed on July 9, 2020.
2. Brignole M, Auricchio A, Baron-Esquivias G, et al. 2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: The Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Eur Heart J. 2013; 34(29):2281-2329.
3. Centers for Medicare and Medicaid Services. National Coverage Determination for Cardiac Pacemakers. NCD#20.8. Effective August 13, 2013. Available at: https://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=238&ncdver=3&DocID=20.8&generalError=Thank+you+for+your+interest+in+the+Medicare+Coverage+Database.
   +You+may+only+view+the+page+you+attempted+to+access+via+normal+usage+of+the+Medicare+Coverage+Database.&bc=
   gAAAABAAAAAAAA%3d%3d&. Accessed on July 9, 2020.
4. Centers for Medicare and Medicaid Services. Proposed National Decision Memo for Implantable Cardioverter Defibrillators. CAG-00157R3. January 27, 2005. Available at: http://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=148&NCDId=110&ncdver=3&NcaName=Implantable+Defibrillators&IsPopup=y&bc=AAAAAAAAEAAA&,#Top. Accessed on July .
5. Dickstein K, Vardas PE, Auricchio A, et al. 2010 Focused Update of ESC Guidelines on device therapy in heart failure: an update of the 2008 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure and the 2007 ESC Guidelines for cardiac and resynchronization therapy. Developed with the special contribution of the Heart Failure Association and the European Heart Rhythm Association. Eur Heart J. 2010; 31(21):2677-2687.
6. Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices) developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. J Am Coll Cardiol. 2008; 51(21):e1-62.
7. Epstein AE, DiMarco JP, Ellenbogen KA, et al.; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines; Heart Rhythm Society. 2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2013; 61(3):e6-75.
8. Gorcsan J 3rd, Abraham T, Agler DA, et al. American Society of Echocardiography Dyssynchrony Writing Group. Echocardiography for cardiac resynchronization therapy: recommendations for performance and reporting--a report from the American Society of Echocardiography Dyssynchrony Writing Group endorsed by the Heart Rhythm Society. J Am Soc Echocardiogr. 2008; 21(3):191-213.
9. Hunt SA, Abraham WT, Chin MH, et al. 2009 Focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the International Society for Heart and Lung Transplantation. J Am Coll Cardiol. 2009; 53(15):e1-90.
10. Khairy P, Van Hare GF, Balaji S, et al. PACES/HRS expert consensus statement on the recognition and management of arrhythmias in adult congenital heart disease: developed in partnership between the Pediatric and Congenital Electrophysiology Society (PACES) and the Heart Rhythm Society (HRS). Endorsed by the governing bodies of PACES, HRS, the American College of Cardiology (ACC), the American Heart Association (AHA), the European Heart Rhythm Association (EHRA), the Canadian Heart Rhythm Society (CHRS), and the International Society for Adult Congenital Heart Disease (ISACHD). Can J Cardiol. 2014; 30(10):e1-e63.
11. Kusumoto FM, Schoenfeld MH, Barrett C, et al. 2018 ACC/AHA/HRS guideline on the evaluation and management of patients with bradycardia and cardiac conduction delay. J Am Coll Cardiol. 2019; 74(7):e51-e156.
12. Lindenfeld J, Albert NM, Boehmer JP, et al.; Heart Failure Society of America. HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail. 2010; 16(6):e1-e194.
13. Medtronic Cardiac Rhythm Disease Management. Medtronic, Inc. REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction (REVERSE). NLM Identifier: NCT00271154. Last updated on January 30, 2012. Available at: http://clinicaltrials.gov/ct2/show/NCT00271154?term=NCT00271154&rank=1. Accessed on July 9, 2020.
14. Michtalik HJ, Sinha SK, Sharma R, et al. Use of cardiac resynchronization therapy. Technology Assessment. (Prepared by Johns Hopkins University Evidence-based Practice Center under Contract No. HHSA290201500006I) Rockville, MD: Agency for Healthcare Research and Quality (AHRQ). November 2019.
15. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016; 37(27):2129-2200.
16.  Russo AM, Stainback RF, Bailey SR, et al. ACCF/HRS/AHA/ASE/HFSA/SCAI/SCCT/SCMR 2013 appropriate use criteria for implantable cardioverter-defibrillators and cardiac resynchronization therapy: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, Heart Rhythm Society, American Heart Association, American Society of Echocardiography, Heart Failure Society of America, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance. J Am Coll Cardiol. 2013; 61(12):1318-1368.
17. Tracy CM, Epstein AE, Darbar D, et al. 2012 ACCF/AHA/HRS focused update of the 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2012; 60(14):1297-1313.
18. Uhlig K, Balk EM, Earley A, et al. Assessment on implantable defibrillators and the evidence for primary prevention of sudden cardiac death. Evidence Report/Technology Assessment. (Prepared by the Tufts Evidence-based Practice Center under Contract No. 290-2007-10055-I.) Rockville, MD: Agency for Healthcare Research and Quality (AHRQ). June 2013.
19. University of Ottowa Heart Institute, Canadian Institutes of Health Research (CIHR), Medtronic, Inc. Resynchronization/Defibrillation for Ambulatory Heart Failure Trial (RAFT). NLM Identifier: NCT00251251. Last updated on June 18, 2012. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00251251?term=Resynchronization%2Fdefibrillation&rank=1 Accessed on July 9, 2020.
20. U.S. Food and Drug Administration (FDA). Center for Devices and Radiological Health. Boston Scientific Corporation. Cognis CRT-D, Livian CRT-D and Contak Renewal 3 RF HE CRT-D. P010012/S230. September 16, 2010.
21. U.S. Food and Drug Administration (FDA). Center for Devices and Radiological Health. Premarket Approval (PMA) Database. Ela Medical, Inc., (Plymouth, MN) Ovatio CRT-D System. PMA number P060027. May 15, 2008. Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf6/P060027a.pdf. Accessed on July 9, 2020.
22. U.S. Food and Drug Administration (FDA). Center for Devices and Radiological Health. Premarket Approval (PMA) Database. St. Jude Medical^® Frontier and Frontier II biventricular pacing systems. PMA number P030035. Original PMA date: May 13, 2004. Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf3/P030035A.pdf. Accessed on July 9, 2020.
23. U.S. Food and Drug Administration (FDA). Center for Devices and Radiological Health. Premarket Approval (PMA) Database. St. Jude Medical Frontier™ Model 5508L and Frontier™ II Model 5586 Cardiac Resynchronization Therapy Pacemakers. PMA number P030035/S3. April 29, 2005. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf3/P030035S003B.pdf. Accessed on July 9, 2020.
24. U.S. Food and Drug Administration (FDA). Center for Devices and Radiological Health. St. Jude Medical^® Epic^™ HF dual chamber implantable cardioverter defibrillator systems with cardiac resynchronization therapy. P030054. June 30, 2004. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=p030054. Accessed on July 9, 2020.
25. U.S. Food and Drug Administration (FDA). Center for Devices and Radiological Health. Summary of Safety and Effectiveness for Medtronic InSync^® Biventricular Pacing System. P010015. Original PMA date: August 28, 2001. Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf/P010015A.pdf. Accessed on July 9, 2020.
26. U.S. Food and Drug Administration (FDA). Center for Devices and Radiological Health. Expanded indications for use of CRT-P and CRT-D devices. P010015/S205. April 10, 2014. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf/p010015s205a.pdf. Accessed on July 9, 2020.
27. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013; 62(16):e147-239.
28. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2017; 70:776–803.

1. National Heart, Lung and Blood Institute. Heart failure. Available at: http://www.nhlbi.nih.gov/health/dci/Diseases/Hf/HF_WhatIs.html. Accessed on July 9, 2020.

Atlas + HF
Biventricular Pacemaker
Consulta CRT-P System
Consulta CRT-D System
CONTAK RENEWAL
Epic HF
InSync Biventricular Pacing System
InSync ICD Dual Chamber ICD with CRT
Resonate CRT-D System

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.