Cardiac Resynchronization Therapy and Other Pacing/Defibrillator Treatments for Heart Failure
Number: 0610
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Scope of Policy
This Clinical Policy Bulletin addresses cardiac resynchronization therapy and other pacing/defibrillator treatments for heart failure.
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Medical Necessity
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Aetna considers U.S. Food and Drug Administration (FDA)-approved biventricular pacemakers (cardiac resynchronization therapy) medically necessary for the treatment of members with congestive heart failure (CHF) who are in sinus rhythm when either of the following criteria is met (A or B):
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New York Heart Association (NYHA) classification of heart failure III or IV (see Appendix) and all of the following criteria are met:
- Left ventricular ejection fraction (LVEF) less than or equal to 35 %; and
- QRS duration greater than or equal to 150 msec; and
- Member is on an optimal pharmacologic regimen, defined as 3 months of maximally titrated doses as tolerated,before implantation, which may include any of the following, unless contraindicated:
- Angiotensin-converting enzyme inhibitor; or
- Angiotensin receptor blocker; or
- Beta blocker; or
- Digoxin; or
- Diuretics; or
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Member is at least 40 days post myocardial infarction (MI); or
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NYHA classification of heart failure II-IV (see Appendix) and all of the following criteria are met:
- LVEF less than or equal to 35 %; and
- Left bundle branch block with QRS duration greater than or equal to 130 msec; and
- Member is on an optimal pharmacologic regimen, defined as 3 months of maximally titrated doses as tolerated, before implantation, which may include any of the following, unless contraindicated:
- Angiotensin-converting enzyme inhibitor; or
- Angiotensin receptor blocker; or
- Beta blocker; or
- Digoxin; or
- Diuretics; or
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Member is at least 40 days post MI.
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Aetna considers FDA-approved combination resynchronization-defibrillator devices medically necessary for members who are at high-risk for sudden cardiac death when the afore-mentioned criteria are fulfilled and any of the criteria listed below is met:
- Members have at least 1 episode of cardiac arrest as a result of ventricular tachyarrhythmias; or
- Members have recurring, poorly tolerated sustained ventricular tachycardia; or
- Members have a prior heart attack and a documented episode of non-sustained ventricular tachycardia, with an inducible ventricular tachyarrhythmia; or
- Members have a prior heart attack and a LVEF of less than or equal to 30 %.
- Aetna considers the following not medically necessary:
- Adjunctive cardiac resynchronization therapy in individuals with a left ventricular assist device currently in place;
- Biventricular pacemakers (cardiac resynchronization therapy) or combination resynchronization-defibrillator devices for individuals whose heart failure or ventricular arrhythmias are reversible or temporary.
- The following interventions in persons with these contraindications:
- Asynchronous pacing is contraindicated in the presence (or likelihood) of competitive paced and intrinsic rhythms; or
- Unipolar pacing is contraindicated in individuals with an implanted defibrillator or cardioverter-defibrillator (ICD) because it may cause unwanted delivery or inhibition of defibrillator or ICD therapy.
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Experimental and Investigational
The following procedures are considered experimental and investigational because the effectiveness of these approaches has not been established:
- Biventricular pacemakers for all other indications not noted as medically necessary above (e.g., atrial fibrillation, mild heart failure/NYHA functional class I, and anti-bradycardia pacing)
- Cardiac resynchronization therapy with wireless left ventricular endocardial pacing for the treatment of heart failure
- Combination resynchronization-defibrillator devices for all other indications (except those listed as medically necessary above)
- Galectin-3 test for selecting individuals for cardiac resynchronization therapy and for all other indications (e.g., prediction of outcome in individuals with stable dilated cardiomyopathy, prognosis of aortic valve stenosis/heart failure, risk prediction of atrial fibrillation)
- His bundle pacing for cardiac resynchronization therapy
- Implantable diaphragmatic stimulation (e.g., VisCardia’s VisONE implantable system) for the treatment of heart failure.
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Related Policies
Background
Approximately 5 million Americans are currently diagnosed with heart failure (HF), and more than 500,000 new cases are diagnosed each year. Up to 50 % of patients with advanced HF exhibit inter-ventricular conduction delay (ventricular dysynchrony), which result in abnormal contraction of the heart. Furthermore, prolonged QRS duration in these patients causes abnormal septal wall motion, reduced cardiac contractility, decreased diastolic filling time and extended mitral regurgitation. These abnormalities have been reported to be associated with increased morbidity and mortality. Biventricular pacing has been examined as a technique to coordinate the contraction of the ventricles, thus improving the hemodynamic status of the patient. Two approaches are being studied:- incorporation of biventricular pacing into automatic implantable cardiac defibrillators; and
- development of stand-alone biventricular pacemakers.
Cardiac resynchronization therapy (CRT) refers to pacing techniques that alter the degree of atrial and ventricular electromechanical asynchrony in patients with severe atrial and ventricular conduction disorders. These devices provide electrical stimulation to both sides of the heart (left and right) thereby synchronizing atrioventricular contractions and coordinating (resynchronizing) ventricular contractions. Ventricular resynchronization has been shown to result in greater clinical value than atrial resynchronization.
Individuals with dyssynchrony (the right and left ventricles do not contract and empty simultaneously) and who are at risk for developing life threatening arrhythmias, may be considered for implantation of a cardiac resynchronization therapy/implantable cardioverter defibrillator (CRT-ICD), which provides the dual function of CRT and an implantable cardioverter defibrillator. The dual role allows for coordinating ventricular contractions and terminating life threatening arrhythmias.
In 1998, the American College of Cardiology and the American Heart Association issued a joint guideline for implantation of cardiac pacemakers and anti-arrhythmia devices. The joint guideline addressed New York Heart Association (NYHA) Class III and IV patients and stated that "Preliminary data suggest that simultaneous biventricular pacing may improve cardiac hemodynamics and lead to subjective and objective symptom improvement". Recent studies have reported that CRT with biventricular pacing to be beneficial for patients with congestive heart failure (CHF), improving both hemodynamic and clinical performance of these patients.
The InSync Biventricular Pacing System (Medtronic, Minneapolis, MN) is a stand-alone biventricular pacemaker that has been approved by the Food and Drug Administration (FDA) for the treatment of patients with NYHA Class III or IV heart failure, who are on a stable pharmacologic regimen, and who additionally have a QRS duration of greater than or equal to 130 msec and left ventricular ejection fraction (LVEF) of less than 35 %.
The Guidant Cardiac Resynchronization Therapy Defibrillator System -- the CONTAK RENEWAL -- is a combination resynchronization-defibrillator device that has been approved by the FDA. It is indicated for patients who are at high-risk of sudden death due to ventricular arrhythmias and who have moderate-to-severe HF (NYHA Class III/IV) including left ventricular dysfunction (LVEF less than or equal to 35 %) and QRS duration greater than or equal to 130 msec, and remain symptomatic despite stable, optimal heart failure drug therapy. Other combination resynchronization-defibrillator devices currently on the market include the Boston Scientific COGNIS and VIVIAN CRT with defibrillator (CRT-D) Systems, and the Medtronic InSync ICD Model 7272.
There is a lack of evidence that echocardiographic parameters can improve selection of patients for CRT. Chung and colleagues (2008) noted that data from single-center studies suggested that echocardiographic parameters of mechanical dyssynchrony may improve patient selection for CRT. In a prospective, multi-center setting, the Predictors of Response to CRT (PROSPECT) study, these researchers tested the performance of these parameters to predict CRT response. A total of 53 centers in Europe, Hong Kong, and the United States enrolled 498 patients with standard CRT indications (NYHA class III or IV heart failure, LVEF less than or equal to 35 %, QRS greater than or equal to 130 ms, stable medical regimen). Twelve echocardiographic parameters of dyssynchrony, based on both conventional and tissue Doppler-based methods, were evaluated after site training in acquisition methods and blinded core laboratory analysis. Indicators of positive CRT response were improved clinical composite score and greater than or equal to 15 % reduction in left ventricular end-systolic volume at 6 months. Clinical composite score was improved in 69 % of 426 patients, whereas left ventricular end-systolic volume decreased greater than or equal to 15 % in 56 % of 286 patients with paired data. The ability of the 12 echocardiographic parameters to predict clinical composite score response varied widely, with sensitivity ranging from 6 % to 74 % and specificity ranging from 35 % to 91 %; for predicting left ventricular end-systolic volume response, sensitivity ranged from 9 % to 77 % and specificity from 31 % to 93 %. For all the parameters, the area under the receiver-operating characteristics curve for positive clinical or volume response to CRT was less than or equal to 0.62. There was large variability in the analysis of the dyssynchrony parameters. The authors concluded that given the modest sensitivity and specificity in this multi-center setting despite training and central analysis, no single echocardiographic measure of dyssynchrony may be recommended to improve patient selection for CRT beyond current guidelines.
Anderson et al (2008) reviewed the status of proposed dyssynchrony indexes by echocardiography for patient selection in CRT. The authors concluded that despite the huge output of publications in this field, they do not presently advise incorporating echocardiographic dyssynchrony parameters for the selection of candidates for CRT for the following reasons:- no large published clinical trials exist to demonstrate benefit with a particular dyssynchrony index,
- conflicting results are emerging on the predictive value of dyssynchrony indexes,
- all the parameters described to date have either technical or theoretical limitations.
A practical parameter or index for selection of appropriate patients for CRT should be simple and preferably should not require offline analysis. Clinically, it will be more important to identify non-responders to CRT using various clinical, laboratory, and echocardiographic data with a very high accuracy. This ideal parameter has not been found.
Hawkins et al (2009) stated that international guidelines unanimously endorse QRS prolongation to identify candidates for CRT, based on over 4,000 patients randomized in landmark trials. Small, observational, non-randomized studies with surrogate end points have promoted echocardiography as a superior method of patient selection. Over 30 dyssynchrony parameters have been proposed. Most lack validation in appropriate clinical settings, including demonstration of short-term as well as long-term reproducibility and intra- and inter-observer variability. Prospective multi-center trials have proved informative in unexpected ways. In core laboratories, parameters exhibit striking variability, poor reproducibility, and limited predictive power. The authors are concerned that many centers today are using these techniques to select patients for CRT. Publication density and bias have mis-informed clinical decision making. These investigators stated that echocardiographic parameters have no place in denying potentially life-saving treatment or in exposing patients to unnecessary risks and draining health care resources. Such measures should not stray beyond the research environment unless validated in randomized trials with robust clinical end points. The electrocardiogram remains a simple, inexpensive, and reproducible tool that identifies patients likely to benefit from CRT. Patient selection must use the parameter prospectively validated in landmark clinical trials: the QRS duration.
Sanderson (2009) noted that after the publication of the PROSPECT trial, the use of echocardiography for the assessment of mechanical dyssynchrony and as a possible aid for selecting patients for CRT has been heavily criticized. Calls have been made to observe the current guidelines and implant according to the entry criteria of recent major trials. However, although this approach is currently to be recommended, the attempt to identify patients who will not receive the benefits of CRT and whose clinical condition may be worsened should continue. Professional resources and the costs to society are high and wasted if devices are implanted inappropriately; further work is needed to refine the techniques and new clinical trials performed. A combination of methods that include finding the site of latest mechanical activation, myocardial scar localization, and assessing venous anatomy pre-operatively may help to identify those who will not derive any benefit or be potentially worsened.
Stellbrink (2009) stated that CRT aims to correct the mechanical dyssynchrony in patients with heart failure and broad QRS complex. Until now, indication for CRT is based mainly on clinical and electrocardiographic criteria. Because QRS width is only weakly correlated to mechanical dyssynchrony, imaging techniques such as echocardiography and magnetic resonance tomography (MRT) seem suitable for analysis of dyssynchrony. Echocardiography has been studied in several studies for identification of suitable CRT candidates. Apart from conventional methods such as M mode-, 2 dimensional-, and Doppler-echocardiography, other techniques such as tissue Doppler echocardiography, have been used. Despite many positive results in individual studies no single echocardiographic parameter was able to predict positive CRT response in a prospective multi-center trial. Thus, QRS width remains the "gold standard" for CRT patient identification at present.
In a prospective, double-blind, multi-center study, Yu and associates (2009) examined if biventricular pacing is superior to right ventricular apical pacing in preventing deterioration of LV systolic function and cardiac remodeling in patients with bradycardia and a normal LVEF. These investigators randomly assigned 177 patients in whom a biventricular pacemaker had been successfully implanted to receive biventricular pacing (n = 89) or right ventricular apical pacing (n = 88). The primary end points were LVEF and left ventricular end-systolic volume (LVESV) at 12 months. At 12 months, the mean LVEF was significantly lower in the right-ventricular-pacing group than in the biventricular-pacing group (54.8 +/- 9.1 % versus 62.2 +/- 7.0 %, p < 0.001), with an absolute difference of 7.4 percentage points, whereas the LVESV was significantly higher in the right-ventricular-pacing group than in the biventricular-pacing group (35.7 +/- 16.3 ml versus 27.6 +/- 10.4 ml, p < 0.001), with a relative difference between the groups in the change from baseline of 25 % (p < 0.001). The deleterious effect of right ventricular apical pacing occurred in pre-specified subgroups, including patients with and patients without pre-existing LV diastolic dysfunction. Eight patients in the right-ventricular-pacing group (9 %) and 1 in the biventricular-pacing group (1 %) had LVEF of less than 45 % (p = 0.02). There was 1 death in the right-ventricular-pacing group, and 6 patients in the right-ventricular-pacing group and 5 in the biventricular-pacing group were hospitalized for HF (p = 0.74). The authors concluded that in patients with normal systolic function, conventional right ventricular apical pacing resulted in adverse LV remodeling and in a reduction in LVEF; these effects were prevented by biventricular pacing. Moreover, the authors stated that randomized trials with longer follow-up periods, larger samples, and sufficient power to assess clinical outcomes between these two pacing strategies are needed.
Daubert et al (2009) examined the long-term effects of CRT in the European cohort of patients enrolled in the REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) trial. These researchers randomly assigned 262 recipients of CRT pacemakers or defibrillators, with QRS greater than or equal to 120 ms and LVEF less than or equal to 40 % to active (CRT ON; n = 180) versus control (CRT OFF; n = 82) treatment, for 24 months. Mean baseline LVEF was 28.0 %. All patients were in sinus rhythm and receiving optimal medical therapy. The primary study end point was the proportion worsened by the heart failure (HF) clinical composite response. The main secondary study end point was LVESV index (LVESVi). In the CRT ON group, 19 % of patients were worsened versus 34 % in the CRT OFF group (p = 0.01). The LVESVi decreased by a mean of 27.5 +/- 31.8 ml/m(2) in the CRT ON group versus 2.7 +/- 25.8 ml/m(2) in the CRT OFF group (p < 0.0001). Time to first HF hospital stay or death (hazard ratio: 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 patient population in NYHA functional classes I or II. These findings suggested that CRT prevents the progression of disease in patients with asymptomatic or mildly symptomatic LV dysfunction.
In an editorial that accompanied the afore-mentioned article, Exner (2009) noted that the REVERSE trial demonstrated a 29 % reduction in the risk of the combined end point of death or HF events (p = 0.003). This outcome was purely driven by a reduction in HF events. The proportion of these events that were actual hospitalizations for HF is unclear. Furthermore, the average 6-min walk test distance of 361 +/- 108 m suggested that many of these patients would have been categorized as NYHA function al class III in past trials, based on a walk distance of less than 450 m. The author stated that it is premature to recommend CRT as a routine intervention to patients with asymptomatic LV dysfunction or those with mildly symptomatic HF today.
In September 2010, the FDA approved a new indication for 3 cardiac resynchronization therapy defibrillators (CRT-D) used to treat certain heart failure patients. The new use is for patients with left bundle branch block, which occurs when there is delayed activation and contraction of the left ventricle. The 3 devices, all manufactured by Boston Scientific Corp., are intended to treat patients with left bundle branch block who have either mild heart failure or heart failure with no apparent symptoms. CRT-Ds are to be used as an addition to, not a replacement for, heart failure drug therapy. The FDA based its approval on the results of the 1,820-patient Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) clinical study. The study, which followed 1,820 patients for an average of nearly 3 years at 110 centers in the Canada, Europe, Israel, and United States. It compared CRT-D therapy to implantable cardioverter-defibrillator (ICD)-only therapy in specific heart failure patients to determine whether it reduced the risk of death and heart failure. In patients with left bundle branch block, who represented 70 % of the study group, CRT-D showed a reduction in the risk of death and heart failure by 57 %, as compared to ICD alone. The rate of complications was considered to be acceptable by the FDA for this device, however, physicians should adequately inform patients about potential complications.
As a condition of FDA approval, Boston Scientific must conduct 2 post-approval studies. One study will evaluate complications and long-term mortality benefits of CRT-D in patients with left bundle branch block identified through the National Cardiovascular Data Registry. The other will follow patients from the original MADIT-CRT clinical study every 6 months for 5 years to assess long-term mortality benefits of CRT-D versus ICD.
The efficacy of CRT in patients with mild or moderate HF was confirmed by the Resynchronization–Defibrillation for Ambulatory Heart Failure Trial (RAFT trial). Tang, et al (2010) reported on a controlled clinical study that found that, among patients with NYHA class II or III heart failure, a wide QRS complex, and left ventricular systolic dysfunction, the addition of CRT to an ICD reduced rates of death and hospitalization for heart failure. The investigators randomly assigned 1,798 patients with NYHA class II or III HF, a LVEF of 30 % or less, and an intrinsic QRS duration of 120 msec or more or a paced QRS duration of 200 msec or more to receive either an ICD alone or an ICD plus CRT. The primary outcome was death from any cause or hospitalization for HF, and subjects were followed for a mean of 40 months. The primary outcome occurred in 297 of 894 patients (33.2 %) in the ICD–CRT group and 364 of 904 patients (40.3 %) in the ICD group (hazard ratio in the ICD–CRT group, 0.75; 95 % confidence interval [CI]: 0.64 to 0.87; p < 0.001). In the ICD–CRT group, 186 patients died, as compared with 236 in the ICD group (hazard ratio, 0.75; 95 % CI: 0.62 to 0.91; p = 0.003), and 174 patients were hospitalized for HF, as compared with 236 in the ICD group (hazard ratio, 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 patients in the ICD-CRT group, as compared with 58 in the ICD group (p < 0.001).
An assessment by the BlueCross BlueShield Association (BCBSA, 2011) Technology Evaluation Center (TEC) of cardiac resynchronization therapy for mild HF concluded that the use of cardiac resynchronization therapy for mild heart failure meets the TEC criteria for persons with NYHA class II heart failure who have a LVEF less than 30% and a QRS duration of greater than or equal to 130 msec. The use of cardiac resynchronization therapy for mild HF in other patient populations (e.g., NYHA class I HF) did not meet TEC criteria.
In a review on CRT in patients with NYHA class I and II HF, Linde and Daubert (2010) stated that a wider use of CRT in mildly symptomatic patients to prevent disease progression needs to be considered in the near future. First, however, whether mortality is influenced by CRT needs to be clarified, as well as the balance between the risks of CRT treatment and the potential benefits.
van Bommel et al (2011) noted that functional mitral regurgitation (MR) is a common finding in HF patients with dilated cardiomyopathy and has important prognostic implications. However, the increased operative risk of these patients may result in low-referral or high-denial rate for mitral valve surgery. Cardiac resynchronization therapy has been shown to have a favorable effect on MR. The aims of this study were to- evaluate CRT as a therapeutic option in HF patients with functional MR and high operative risk, and
- examine the effect of MR improvement after CRT on prognosis.
A total of 98 consecutive patients with moderate-severe functional MR and high operative risk underwent CRT according to current guidelines. Echocardiography was performed at baseline and 6-month follow-up; severity of MR was graded according to a multi-parametric approach. Significant improvement of MR was defined as a reduction greater than or equal to 1 grade. All-cause mortality was assessed during follow-up (median of 32 [range of 6.0 to 116] months). Thirteen patients (13 %) died before 6-months follow-up. In the remaining 85 patients, significant reduction in MR was observed in all evaluated parameters. In particular, 42 patients (49 %) improved greater than or equal to 1 grade of MR and were considered MR improvers. Survival was superior in MR improvers compared to MR non-improvers (log rank p < 0.001). Mitral regurgitation improvement was an independent prognostic factor for survival (hazard ratio 0.35, CI: 0.13 to 0.94; p = 0.043). The authors concluded that CRT is a potential therapeutic option in HF patients with moderate-severe functional MR and high-risk for surgery. Improvement in MR results in superior survival after CRT.
Stavrakis et al (2012) stated that atrio-ventricular junction (AVJ) ablation with permanent pacing improves symptoms in selected patients with atrial fibrillation (AF). The optimal pacing modality after AVJ ablation remains unclear. In a meta-analysis, these investigators examined if CRT is superior to right ventricular (RV) pacing in this patient population. They searched the MEDLINE and EMBASE databases for studies evaluating the effect of CRT versus RV pacing after AVJ ablation for AF. Pooled risk ratios (RRs) and mean differences with 95 % CIs were calculated for categorical and continuous outcomes, respectively, using a random effects model. A total of 5 trials involving 686 patients (413 in CRT and 273 in RV pacing group) were included in the analysis. On the basis of the pooled estimate across the studies, CRT resulted in a non-significant reduction in mortality (RR = 0.75, 95 % CI: 0.43 to 1.30; p= 0.30) and a significant reduction in hospitalizations for heart failure (RR = 0.38, 95 % CI: 0.17 to 0.85; p= 0.02) compared with RV pacing. Cardiac resynchronization therapy did not improve 6-min walk distance (mean difference 15.7, 95 % CI: -7.2 to 38.5 m; p = 0.18) and Minnesota Living with Heart Failure quality-of-life score (mean difference -3.0, 95 % CI: -8.6 to 2.6; p = 0.30) compared with RV pacing. The change in LVEF between baseline and 6 months favored CRT (mean change 2.0 %, 95 % CI: 1.5 to 2.4 %; p < 0.001). The authors concluded that CRT may be superior to RV pacing in patients undergoing AVJ ablation for AF. Moreover, they stated that further studies, adequately powered to detect clinical outcomes, are needed.
Curtis et al (2013) noted that RV pacing restores an adequate heart rate in patients with AV block, but high percentages of RV apical pacing may promote left ventricular systolic dysfunction. These researchers examined if biventricular pacing might reduce mortality, morbidity, and adverse left ventricular re-modeling in such patients. They enrolled patients who had indications for pacing with AV block; NYHA class I, II, or III HF; and a LVEF of 50 % or less. Patients received a cardiac-resynchronization pacemaker or ICD (the latter if the patient had an indication for defibrillation therapy) and were randomly assigned to standard RV pacing or biventricular pacing. The primary outcome was the time to death from any cause, an urgent care visit for HF that required intravenous therapy, or a 15 % or more increase in the left ventricular end-systolic volume index. Of 918 patients enrolled, 691 underwent randomization and were followed for an average of 37 months. The primary outcome occurred in 190 of 342 patients (55.6 %) in the RV-pacing group, as compared with 160 of 349 (45.8 %) in the biventricular-pacing group. Patients randomly assigned to biventricular pacing had a significantly lower incidence of the primary outcome over time than did those assigned to RV pacing (hazard ratio, 0.74; 95 % CI: 0.60 to 0.90); results were similar in the pacemaker and ICD groups. Left ventricular lead-related complications occurred in 6.4 % of patients. The authors concluded that biventricular pacing was superior to conventional RV pacing in patients with AV block and left ventricular systolic dysfunction with NYHA class I, II, or III HF.
Coburn and Frishman (2014) stated that HF is a major cause of morbidity and mortality in the United States; however, reliable biomarkers predicting outcomes of patients suffering from HF are still not available. Finding a prognostic indicator in patients with HF could ultimately help improve the quality of goal-directed care for these patients. A number of recent studies suggested that galectin-3, a peptide that has been repeatedly shown to be elevated in the setting of inflammatory processes, may provide information regarding the pathophysiologic process underlying HF. If this is the case, galectin-3 may independently be able to provide more information regarding prognosis in patients with HF than some of the more conventional indicators currently in use today (i.e., natriuretic peptide, C-reactive protein [CRP]). These researchers analyzed the most recent and comprehensive studies that have looked at the utility of galectin-3 as a prognostic marker in patients with HF. After a thorough review, they found that the evidence against the use of galectin-3 as a prognostic biomarker in HF was too strong to support its routine use in current clinical settings. However, many of the studies, both in support of and in opposition to the prognostic potential of galectin-3, were uniformly limited by undersized cohorts, and thus the need for further exploration is clearly warranted.
Atabakhshian et al (2014) examined the relationship between galectin-3 as a biomarker and ejection fraction and functional capacity in the patients with compensated systolic HF. In this study, serum levels of galectin-3 were measured in 76 patients with compensated HF with NYHA class I to IV and LVEF less than 45 %. Galectin-3 was measured by an ELISA kit. Besides, echocardiography was used to evaluate LVEF. Additionally, functional capacity was determined based on the patients' ability to perform a set of activities. After all, the data were analyzed used t-test, Kruskal-Wallis, 1-way ANOVA, and chi-square test; p < 0.05 was considered as statistically significant. The patients' age ranged from 45 to 75 years, with the mean age of 63.85 ± 9 years. In addition 57.9 % of the patients were male. The results revealed no significant correlation between galectin-3 and age, body mass index, and estimated glomerular filtration rate (eGFR). Also, no significant correlation was observed between galectin-3 levels and LVEF (p = 0.166) and functional capacity (p = 0.420). Yet, a significant difference was found between males and females regarding the mean of galectin-3 (p = 0.039). The authors concluded that the findings of this study suggested that galectin-3 could not be used as a marker of disease progression in the patients under treatment, which could probably be the result of medication use in these patients.
Srivatsan et al (2015) noted that HF continues to be an illness of daunting proportions with a 4-year mortality touching 50 %. Biomarkers for prognosticating patients with HF have generated immense interest. Several studies have been conducted on a novel biomarker, galectin-3 to assess its prognostic effect in HF populations. However, the studies have generated conflicting results. These investigators performed a systematic review to assess the utility of galectin-3 as a prognostic biomarker in HF. They carried out a literature search using terms “galectin-3 and heart” and “galectin-3 and heart failure” in Medline, Science Direct, Scopus, Springer Link, Cochrane Library and Google Scholar for original articles using a predefined inclusion/exclusion criteria. A total of 27 original articles were selected for the systematic review. Multi-variate analysis showed galectin-3 to be ineffective in predicting all-cause mortality and cardiovascular mortality especially under the influence of factors such as eGFR, LVEF, and N-terminal fragment of B-type natriuretic peptide (NT-proBNP). Galectin-3 was not found to be superior to NT-proBNP, serum levels of soluble ST2 (sST2), GDF-15 or CRP as a predictor of mortality. However the combination of natriuretic peptides and galectin-3 has been observed to be superior in predicting mortality compared to either of the biomarkers alone. The role of galectin-3 in re-modelling has not been conclusively proven as seen in earlier pre-clinical studies. The authors concluded that the current weight of evidence does not suggest galectin-3 to be a predictor of mortality. However, assessment of galectin-3 in a multi-biomarker panel may have a distinct advantage in prognosticating patients with HF.
Shah and colleagues (2015) stated that CRT reduces morbidity and mortality in patients with chronic systolic HF (SHF) and a wide QRS complex. It is unclear whether the same benefit extends to patients with QRS duration (QRSd) of less than 130 ms. These investigators performed a meta-analysis of all randomized controlled trials (RCTs) and evaluated the effect of implantable CRT defibrillator(CRTD) on all-cause mortality, HF mortality, and HF hospitalization in patients with QRSd of less than 130 ms. They performed a systematic literature search to identify all RCTs, comparing CRTD therapy with ICD therapy in patients with SHF (EF less than 35 %) and QRS less than or equal to 130 ms, published in PubMed, Medline, Embase, Cochrane library, and Google scholar from June 1980 through June 2013. The search terms included CRT, QRS duration, narrow QRS, clinical trial, RCT, biventricular pacing, heart failure, systolic dysfunction, dyssynchrony, left ventricular remodeling, readmission, mortality, survival, and various combinations of these terms. The authors studied the trends of overall mortality, SHF mortality, and hospitalizations due to SHF between the 2 groups. Heterogeneity of the studies was analyzed by Q statistic. A fixed-effect model was used to compute the RR of mortality due to SHF, while a random-effects model was used to compare hospitalization due to SHF. Out of a total of 12,100 citations, 4 RCTs comparing CRTD versus ICD therapy in patients with SHF and QRS of less than or equal to 130 ms fulfilled the inclusion criteria. The median follow-up was 12 months and the cumulative number of patients was 1,177. Relative risk for all-cause mortality in patients treated with CRTD was 1.66 with a 95 % CI of 1.096 to 2.515 (p = 0.017) while for SHF mortality was 1.29 with 9 5% CI of 0.68 to 2.45 (p = 0.42). Relative risk for HF hospitalization in patients treated with CRTD was 0.94 with 95 % CI of 0.50 to 1.74 (p = 0.84) in comparison to the ICD group. The authors concluded that CRT defibrillator has no impact on SHF mortality and SHF hospitalization in patients with systolic HF with QRS duration of less than or equal to 130 ms and is associated with higher all-cause mortality in comparison with ICD therapy.
Friedman and associates (2015) noted that patients with moderate-to-severe chronic kidney disease (CKD) are poorly represented in clinical trials of CRT. These researchers evaluated the real-world comparative effectiveness of CRT-D versus ICD alone in CRT-eligible patients with moderate-to-severe CKD. These investigators conducted an inverse probability-weighted analysis of 10,946 CRT-eligible patients (EF less than 35 %, QRS greater than 120 ms, NYHA functional class III/IV) with stage 3 to 5 CKD in the National Cardiovascular Data Registry (NCDR) ICD Registry, comparing outcomes between patients who received CRT-D (n = 9,525) versus ICD only (n = 1,421). Outcomes were obtained via Medicare claims and censored at 3 years. The primary end-point of HF hospitalization or death and the secondary end-point of death were assessed with Cox proportional hazards models; HF hospitalization, device explant, and progression to end-stage renal disease were assessed using Fine-Gray models. After risk adjustment, CRT-D use was associated with a reduction in HF hospitalization or death (hazard ratio [HR]: 0.84; 95 % CI: 0.78 to 0.91; p < 0.0001), death (HR: 0.85; 95 % CI: 0.77 to 0.93; p < 0.0004), and HF hospitalization alone (sub-distribution HR: 0.84; 95 % CI: 0.76 to 0.93; p < 0.009). Sub-group analyses suggested that CRT was associated with a reduced risk of HF hospitalization and death across CKD classes. The incidence of in-hospital, short-term, and mid-term device-related complications did not vary across CKD stages. The authors concluded that in a nationally representative population of HF and CRT-eligible patients, use of CRT-D was associated with a significantly lower risk of the composite end-point of HF hospitalization or death among patients with moderate-to-severe CKD in the setting of acceptable complication rates.
Rickard and colleagues (2016) determined predictors of response to CRT-D and CRT with pacemaker (CRT-P) utilizing the methods of systematic review. These investigators searched Medline, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) from January 1, 1995, as this is the date of first article reporting use of CRT through October 20, 2014. Paired investigators independently screened search results to assess eligibility. For inclusion, investigators abstracted data sequentially and assessed risk of bias independently. Investigators graded the strength of evidence as a group. They identified 13,015 unique citations of which 11,897 were excluded during the abstract screen. During the full-text screening, these researchers excluded 1,118 citations. 12 studies reported in 15 articles were included in this review. A left bundle branch (LBBB) morphology, non-ischemic cardiomyopathy (NICM), and female gender were generally associated with improved outcomes following CRT-D. Sinus rhythm (as compared to AF) and a wider QRS duration were associated with improved outcomes following CRT-D albeit with a lower strength of evidence. There was insufficient evidence to determine predictors of outcomes in patients undergoing CRT-P. The authors concluded that a native LBBB, NICM, female gender, sinus rhythm, and a wider QRS duration are associated with improved outcomes following CRT-D implant.
2012 ACCF/AHA/HRS focused update was incorporated into the 2008 guidelines for device-based therapy of cardiac rhythm abnormalities. This guideline outlines indications for cardiac resynchronization therapy:
- CRT can be useful for persons who have LVEF less than or equal to 35%, sinus rhythm, a non-LBBB pattern with a QRS duration greater than or equal to 150 ms, and NYHA class III/ambulatory class IV with symptoms on GDMT (LOE: A). (Note: the 2012 ACC/AHA/HRS guideline changed the QRS duration from 120 ms (2008 ACC/AHA/HRS guideline) to 150 ms).
- CRT is indicated for persons who have LVEF less than or equal to 35%, sinus rhythm, LBBB with a QRS duration greater than or equal to 150 ms, and NYHA class II, III, or ambulatory IV, and symptoms on while on guideline-directed medical therapy (GDMT) (LOE: A for NYHA class III/IV, LOE: B for NYHA class II).
- CRT can be useful for persons who have LVEF less than or equal to 35%, sinus rhythm, LBBB with a QRS duration 120 to 149 ms, and NYHA class II, III, or ambulatory IV with symptoms on GDMT (LOE: B).
- CRT is not recommended for patients with NYHA class I or II symptoms and non-LBBB pattern with QRS duration less than 150 ms (LOE: B).
An UpToDate review on “Cardiac resynchronization therapy in heart failure: Indications” (Adelstein and Saba, 2017) make the following CRT indication recommendations, which include persons who are in sinus rhythm and have an LVEF less than or equal to 35 percent, have optimal evidence-based medical therapy for at least three months after initial diagnosis (or for at least 40 days after myocardial infarction) and after treatment of any reversible causes of persistent HF, in addition to the following:
- QRS greater than or equal to 150 ms with LBBB and NYHA class II to ambulatory IV heart failure (HF); or
- QRS 130-149 ms with LBBB and NYHA class II to ambulatory class IV HF; or
- QRS greater than or equal to 150 ms with non-LBBB and NYHA class II or ambulatory IV HF.
In a meta-analysis, which included early crossover and 14 randomized trials with 4420 patients (nearly all with NYHA class III or IV symptoms, mean QRS range 155 to 209 ms), CRT increased the likelihood of improving by at least one NYHA class (59 versus 37 percent, RR 1.6, 95% CI 1.3-1.9). Hospitalizations for HF were reduced 37 percent, and all-cause mortality was reduced 22 percent, primarily because of a lower risk of HF-related death (RR 0.64, 95% CI 0.49-0.84) (Adelstein and Saba, 2017).
The Centers for Medicare & Medicaid Services (CMS) (2018) NCD decision memo for implantable cardioverter defibrillators states that while they reference CRT defibrillator devices in the document, there is no coverage determination made in an NCD. CRT devices are currently addressed by local Medicare contractors (LCD).
Cardiac Resynchronization Therapy plus Defibrillator for Patients with Mild Heart Failure
Biton and co-workers (2016) evaluated the long-term clinical outcomes of 537 non-LBB block patients with mild HF enrolled in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) study by QRS duration or morphology further stratified by PR interval. At 7 years of follow-up, the cumulative probability of HF hospitalization or death was 45 % versus 56 % among patients randomized to ICD and CRT-D, respectively (p = 0.209). Multivariable-adjusted subgroup analysis by QRS duration showed that patients from the lower quartile QRS duration group (less than or equal to 134 ms) experienced 2.4-fold (p = 0.015) increased risk for HF hospitalization or death with CRT-D versus ICD only therapy, whereas the effect of CRT-D in patients from the upper quartiles group (QRS greater than 134 ms) was neutral (H] =0.97, p = 0.86; p value for interaction = 0.024). In a second analysis incorporating PR interval (time from the onset of the P wave to the start of the QRS complex), patients with prolonged QRS (greater than 134 ms) and prolonged PR (greater than 230 ms) were protected with CRT-D (HR = 0.31, p = 0.003), whereas the association was neutral with prolonged QRS (greater than 134 ms) and shorter PR (less than or equal to 230 ms;, HR= 1.19, p = 0.386; p value for interaction = 0.002). The effect was neutral, regardless of morphology, right bundle branch block (HR = 1.01, p = 0.975), and intra-ventricular conduction delay (HR = 1.31, p = 0.172). The authors concluded that patients with mild HF but without LBB block morphology did not derive clinical benefit with CRT-D during long-term follow-up; relatively shorter QRS was associated with a significantly increased risk with CRT-D relative to ICD only.
Sun and associates (2016) noted that previous studies of CRT-D therapy used for primary prevention of sudden cardiac death have suggested that CRT-D therapy is less effective in patients with mild HF and a wide QRS complex. However, the long-term benefits are variable. These researchers performed a meta-analysis of randomized trials identified in systematic searches of Medline, Embase, and the Cochrane Database. A total of 3 studies (3,858 patients) with a mean follow-up of 66 months were included. Overall, CRT-D therapy was associated with significantly lower all-cause mortality than was ICD therapy (OR, 0.78; 95 % CI: 0.63 to 0.96; p = 0.02; I (2) = 19 %). However, the risk of cardiac mortality was comparable between 2 groups (OR, 0.74; 95 % CI: 0.53 to 1.01; p = 0.06); CRT-D treatment was associated with a significantly lower risk of hospitalization for HF (OR, 0.67; 95 % CI: 0.50 to 0.89; p = 0.005; I (2) = 55 %). The composite outcome of all-cause mortality and hospitalization for HF was also markedly lower with CRT-D therapy than with ICD treatment alone (OR, 0.67; 95 % CI: 0.57 to 0.77; p < 0.0001; I (2) = 0 %). The authors concluded that CRT-D therapy decreased the long-term risk of mortality and HF events in patients with mild HF with a wide QRS complex. However, long-term risk of cardiac mortality was similar between 2 groups. They stated that more randomized studies are needed to confirm these findings, especially in patients with NYHA class I HF or patients without LBBB.
Cardiac Resynchronization Therapy for the Treatment of Atrial Fibrillation
Gianni and colleagues (2017) stated that although CRT is an important treatment of symptomatic HF patients in sinus rhythm with low LVEF and ventricular dyssynchrony, its role is not well-defined in patients with AF. The authors stated that CRT is not as effective in patients with AF because of inadequate biventricular capture and loss of AV synchrony. Both can be addressed with catheter ablation of AF. It is still unclear if these therapies offer additive benefits in patients with ventricular dyssynchrony.
Xue and colleagues (2019) noted that CRT has been established to improve prognosis for patients with HF and sinus rhythm (SR). Whether the benefit observed with CRT on survival was similar in AF patients receiving atrio-ventricular junction ablation (AVJA) or not and patients in SR remains uncertain. These researchers examined the impact of CRT on the outcome of survival in AF patients with or without AVJA and patients in SR. Medline, Embase, and the Cochrane Library were searched for inception through June 31, 2018. Two reviewers independently evaluated and extracted data from 4 studies, including a total of 7,896 CRT recipients, composed of 554 AF with AVJA (CRT+AF+AVJA), 1,071 AF without AVJA (CRT+AF-AVJA), and 6,244 SR (CRT+SR). The benefit on survival was comparable between CRT+AF+AVJA and CRT+SR (HR = 1.00; 95 % CI: 0.73 to 1.40). CRT+AF+AVJA and CRT+SR both were associated with significantly higher survival compared with CRT+AF-AVJA, with HR of 0.64 (95 % CI: 0.46 to 0.91) and 0.63 (95 % CI: 0.53 to 0.75), respectively. The survival benefit was similar for patients with CRT+AF+AVJA and CRT+SR, while it was 36 to 37 % high as compared to CRT+AF-AVJA. The authors concluded that whether aggressive intervention with AVJA in AF should be routinely combined with CRT despite rate-slowing drug treatment is helpful deserves further studies.
Cardiac Resynchronization Therapy with Wireless Left Ventricular Endocardial Pacing for the Treatment of Heart Failure
Reddy and colleagues (2017) noted that a total of 30 % to 40 % of patients with CHF eligible for CRT either do not respond to conventional CRT or remain untreated due to an inability or impediment to coronary sinus (CS) lead implantation. The WiSE-CRT system (EBR Systems, Sunnyvale, CA) was developed to address this at-risk patient population by performing bi-ventricular pacing via a wireless LV endocardial pacing electrode. The SELECT-LV (Safety and Performance of Electrodes implanted in the Left Ventricle) study is a prospective, multi-center, non-randomized trial evaluating the safety and effectiveness of the WiSE-CRT system. A total of 35 patients indicated for CRT who had "failed" conventional CRT underwent implantation of an LV endocardial pacing electrode and a subcutaneous pulse generator. System performance, clinical efficacy, and safety events were assessed out to 6 months post-implant. The procedure was successful in 97.1 % (n = 34) of attempted implants. The most common indications for endocardial LV pacing were difficult CS anatomy (n = 12), failure to respond to conventional CRT (n = 10), and a high CS pacing threshold or phrenic nerve capture (n = 5). The primary performance end-point, bi-ventricular pacing on the 12-lead electrocardiogram (EKG) at 1 month, was achieved in 33 of 34 patients. A total of 28 patients (84.8 %) had improvement in the clinical composite score at 6 months, and 21 (66 %) demonstrated a positive echocardiographic CRT response (greater than or equal to 5 % absolute increase in LVEF). There were no peri-cardial effusions, but serious procedure/device-related events occurred in 3 patients (8.6 %) within 24 hours, and 8 patients (22.9 %) between 24 hours and 1 month. The authors concluded that the SELECT-LV study demonstrated the clinical feasibility of the WiSE-CRT system, and provided clinical benefits to a majority of patients within an otherwise "failed" CRT population. This clinical trial is still ongoing, but not recruiting subjects (Last updated September 27, 2016).
Santos et al (2022) noted that left ventricular endocardial pacing (LVEP) is an alternative technique used in CRT, when placement of a LV lead is not possible via the coronary sinus or in non-responders to conventional CRT. In a systematic review, these researchers examined the safety and effectiveness of LVEP. They carried out a systematic search on Medline (PubMed), ClinicalTrials.gov and Embase with the terms "endocardial left ventricular pacing", "biventricular pacing" or "endocardial left pacing" with the identification of 1,038 results. A total of 11 studies with LVEP patients were included, independent of the technique being applied to naive CRT patients or non-responders to conventional CRT. The endpoint of this analysis was the impact of LVEP techniques on NYHA functional classification, LVEF and QRS width, and the occurrence of complications; MD and CI were used as a measurement of treatment. A total of 560 patients were included, with different techniques used (trans-atrial septal technique, trans-ventricular septal technique and transapical technique). Significant improvement was registered in NYHA class (MD 0.73, CI: 0.48 to 0.98, p < 0.00001, I2 = 87 %), LVEF (MD -7.63, CI: -9.93 to -5.33, p < 0.00001, I2 = 69 %) and QRS width (MD 29.25, CI: 9.99 to 48.50, p < 0.00001, I2 = 91 %). Several complications were reported after the procedure, 11 pocket infections, 22 transient ischemic attacks (TIAs), 18 ischemic strokes, 41 thrombo-embolic events, among other complications. The mortality rate during the follow-up was 20.54 %. The authors concluded that LVEP is a feasible alternative to conventional CRT, with clinical, electrocardiographic and echocardiographic improvement; however, first data regarding this procedure was associated with significant complications rates.
Wijesuriya et al (2022) stated that leadless LVEP to achieve CRT is a novel procedure for treatment of patients with dyssynchronous HF. Current evidence is limited to observational studies with small patient numbers. In a systematic review and meta-analysis, these investigators examined the safety and effectiveness of leadless LVEP. They carried out a literature search through PubMed, Embase, and Cochrane databases. Mean differences (MDs) in NYHA functional class and LVEF from baseline to 6 months post-procedure were combined using a random effects model. Heterogeneity was evaluated using the Cochrane Q test, I2, meta-regression, and sensitivity analysis. Funnel plots were constructed to detect publication bias. A total of 5 studies with 181 patients were included in the final analysis. Procedural success rate was 90.6 %. Clinical response rate was 63 %, with mean improvement in NYHA functional class of 0.43 (MD -0.43; 95 % CI: -0.76 to -0.1; p = 0.01), with high heterogeneity (p < 0.001; I2 = 81.1 %). There was a mean increase in LVEF of 6.3 % (MD 6.3; 95 % CI: 4.35 to 8.19; p < 0.001, with low heterogeneity (p = 0.84; I2 < 0.001 %). The echocardiographic response rate was 54 %. Procedure-related complication and mortality rates were 23.8 % and 2.8 %, respectively. The authors concluded that the current meta-analysis showed a good effectiveness profile of leadless CRT with impressive clinical and echocardiographic response rates in a group of high-risk, “untreatable” patients. The procedural complication rate suggested improvements are needed to allow widespread uptake, and current practice should be limited to high-volume centers with experienced operators in order to optimize the technology and procedure techniques to minimize complication rates. These researchers stated that advances such as trans-septal access, image guidance, and leadless conduction system pacing may improve the overall safety and effectiveness profile, which may support leadless pacing as a viable 1st-line CRT therapy in years to come, with the potential to provide significant long-term benefits over traditional lead-based systems. They stated that significant heterogeneity for clinical outcomes was noted; suggesting that further investigation is needed to effectively select patients who are likely to have favorable outcomes. More robust data from randomized clinical trials would validate its use, and the SOLVE-CRT study results are awaited in that regard.
The authors stated that this review had several drawbacks. No RCTs were found during the literature search; thus, this meta-analysis comprised only observational, single-arm studies. The SOLVE-CRT (Stimulation Of the Left Ventricular Endocardium for Cardiac Resynchronization Therapy in non-responders and previously untreatable patients) study is an ongoing multi-center randomized study in Europe and North America that is close to finishing recruitment, and the results will provide RCT data that will examine the safety and effectiveness of this technology. Furthermore, the studies included in this meta-analysis inherently will have a degree of bias, and results should be interpreted with caution, especially when making comparisons with the current standard of care (SOC) -- conventional CRT. Because this is a relatively new technology, only a small number of studies met eligibility criteria, which limited the strength of the conclusions. There was heterogeneity in the inclusion criteria, and several important baseline characteristics such as presence of AF, diabetes, and underlying rhythm were not reported, which limited the scope of subgroup analysis and meta-regression. Endpoints also varied between studies (e.g., volumetric echocardiographic indices were not universally reported), and neither were electrocardiographic metrics such as baseline intrinsic QRS duration and morphology, which raised the possibility of publication bias and selective reporting.
Prognosis of Aortic Valve Stenosis
Arangalage and colleagues (2016) stated that myocardial fibrosis has been proposed as an outcome predictor in asymptomatic patients with severe aortic stenosis (AS) that may lead to consider prophylactic surgery. It can be detected using MRI but its widespread use is limited and development of substitute biomarkers is highly desirable. These researchers analyzed the determinants and prognostic value of galectin-3, one promising biomarker linked to myocardial fibrosis. Patients with at least mild degenerative AS enrolled between 2006 and 2013 in 2 ongoing studies, COFRASA/GENERAC (COhorte Française de Rétrécissement Aortique du Sujet Agé/GENEtique du Rétrécissement Aortique), aiming at assessing the determinants of AS occurrence and progression, constituted the study population. These investigators prospectively enrolled 583 patients. The mean galectin-3 value was 14.3 ± 5.6 ng/ml. There was no association between galectin-3 and functional status (p = 0.55) or AS severity (p = 0.58). Independent determinants of galectin-3 were age (p = 0.0008), female gender (p = 0.04), hypertension (p = 0.002), diabetes (p = 0.02), reduced LVEF (p = 0.01), diastolic dysfunction (E/e', p = 0.02) and creatinine clearance (p < 0.0001). Among 330 asymptomatic patients at baseline, galectin-3 was neither predictive of outcome in univariate analysis (p = 0.73), nor after adjustment for age, gender, rhythm, creatinine clearance and AS severity (p = 0.66). The authors concluded that in a prospective cohort of patients with a wide range of AS severity, galectin-3 was not associated with AS severity or functional status. Main determinants of galectin-3 were age, hypertension and renal function. They stated that galectin-3 did not provide prognostic information on the occurrence of AS-related events; and that these findings did not support the use of galectin-3 in the decision-making process of asymptomatic patients with AS.
Galectin-3 Test for the Prediction of Outcome in Individuals with Stable Dilated Cardiomyopathy
Wojciechowska and colleagues (2017) noted that dilated cardiomyopathy (DCM) is the 3rd cause of HF and the most frequent cause of heart transplantation (HT). The value of biomarkers in prognostic stratification may be important in identifying patients for more advanced treatment. Assessment of serum galectin-3 (Gal-3) and ST2 as biomarkers of unfavorable outcome (death and combined end-point: HT or death or left ventricular assist device [LVAD] implantation) in stable DCM patients. A total of 107 DCM patients aged 39 to 56 years were included into the study and followed-up for a mean of 4.8 years; Gal-3 and ST2 concentrations were measured using ELISA tests. Clinical data, treatment, laboratory parameters, NT-proBNP, Gal-3 and ST2 measured at time of inclusion were assessed as risk factors for reaching the study end-points using log rank test and Cox proportional-hazards model. During follow-up, 27 patients died, 40 achieved combined end-point; ROC curves indicated cut-off value of ST2 -- 17.53 ng/ml, AUC-0.65(0.53 to 0.76) and of NT-proBNP -- 669 pg/ml, AUC 0.61(0.50 to 0.73) for prediction of death. In multi-variate analysis, ST2 was predictor of death (HR per unit increase in log ST2 2.705, 95 % CI: 1.324 to 5.528, p = 0.006) and combined end-point (HR per unit increase in log ST2 2.753, 95 % CI: 1.542 to 4.914, p < 0.001). The authors concluded that NT-proBNP was predictive variable only for death in multi-variate analysis; Gal-3 concentration was not associated with adverse outcome; ST2 but not Gal-3 may be useful for predicting adverse outcome in stable DCM patients.
Adjunctive Cardiac Resynchronization Therapy in Individuals with Left Ventricular Assist Device
Gopinathannair and associates (2018) stated that many patients with HF continue CRT after continuous flow LVAD (CF-LVAD) implant. In a multi-center, non-randomized, observational study, these investigators reported the first study that examined the impact of CRT on clinical outcomes in CF-LVAD patients. Analysis was carried out on 488 patients (58 ± 13 years, 81 % men) with an implantable cardioverter defibrillator (ICD) (n = 223) or CRT-D (n = 265) who underwent CF-LVAD implantation at 5 centers from 2007 to 2015. Effects of CRT on mortality, hospitalizations, and ventricular arrhythmia incidence were compared against CF-LVAD patients with an ICD alone. Baseline differences were noted between the 2 groups in age (60 ± 12 years versus 55 ± 14 years, p < 0.001) and QRS duration (159 ± 29 ms versus 126 ± 34 ms, p = 0.001). Median biventricular pacing in the CRT group was 96 %. During a median follow-up of 478 days, Kaplan-Meier analysis showed no difference in survival between groups (log rank p = 0.28). Multi-variate Cox regression demonstrated no survival benefit with type of device (ICD versus CRT-D; p = 0.16), whereas use of amiodarone was associated with increased mortality (HR 1.77, 95 % CI: 1.1 to 2.8, p = 0.01). No differences were observed between CRT and ICD groups in all-cause (p = 0.06) and HF (p = 0.9) hospitalizations, ventricular arrhythmia incidence (43 % versus 39 %, p = 0.3), or ICD shocks (35 % versus 29 %, p = 0.2). During follow-up, 69 (26 %) patients underwent pulse generator replacement in the CRT-D group compared with 36 (15.5 %) in the ICD group (p = 0.003). The authors concluded that in this large, multi-center CF-LVAD cohort, continued CRT was not associated with improved survival, hospitalizations, incidence of ventricular arrhythmia and ICD therapies, and was related to a significantly higher number of pulse generator changes. These researchers stated that these findings supported discontinuing biventricular pacing following CF‐LVAD implant to preserve battery life and reduce generator replacements. They stated that large, prospective, randomized studies are needed to determine the role of CRT on ventricular remodeling and clinical outcomes in CF‐LVAD patients.
The authors stated that this study was limited by its observational, non-randomized design. Baseline characteristics and duration of follow‐up, however, were mostly similar between the ICD and CRT‐D groups. The proportion of patients who received CF‐LVADs for destination therapy or as bridge‐to‐transplant were equally represented in the ICD and CRT‐D groups. Moreover, the large sample size and multi-center data added validity to the results. These investigators did not follow a standard protocol for CRT programming. CRT‐D group patients were mostly continued on their pre‐LVAD biventricular pacing settings, and any programming changes were made on a case‐by‐case basis at the discretion of the patient's electrophysiologist. It was possible that a standardized CRT programming could have made a difference in outcomes in the CRT group, although no supporting evidence in this regard is available in the LVAD population. No accurate and consistent functional status or quality of life (QOL) data were available to report. Although no significant difference in survival was noted in the CRT group when stratified by LVAD indication and type of cardiomyopathy, further study is needed to identify specific subgroups of patients with CF‐LVAD who may benefit from, or conversely be harmed by, continued CRT.
Voruganti and colleagues (2019) stated that the impact of CRT on clinical outcome in patients with a CF-LVAD is currently not well-understood. These investigators carried out a systematic literature review and meta-analysis to summarize all published clinical evidence. They searched Medline and Embase data-bases through March 2018 for studies that compared the outcomes in patients with LVAD and CRT. Pooled OR and 95 % CI were calculated using a random-effects model, inverse variance method. The between-study heterogeneity was evaluated using the Q statistic and I2. A total of 7 studies that included 1,157 (575 CRT; 582 non-CRT) patients were identified. The meta-analysis did not demonstrate a significant difference in the risk of mortality (pooled OR = 1.21, 95 % CI: 0.90 to 1.63, p = 0.21), ventricular arrhythmia incidence (pooled OR = 1.36, 95 % CI: 0.99 to 1.86, p = 0.06), hospitalization (pooled OR = 1.36, 95 % CI: 0.59 to 3.14, p = 0.48), or ICD therapies (pooled OR = 1.08, 95 % CI: 0.51 to 2.30, p = 0.84) among the CRT group compared with the non-CRT group. There was high heterogeneity with an I2 of 75 % for ICD therapies. The authors concluded that among LVAD patients, CRT did not significantly affect mortality, re-hospitalization, ventricular arrhythmia incidence, and ICD therapies.
Cardiac Resynchronization Therapy with Defibrillation for the Treatment of Non-Ischemic Cardiomyopathy
Patel and colleagues (2021) noted that CRT represents a major medical advance in patients with HF with electrical dysschrony to improve symptoms, reduce hospitalization, and increase survival both in the presence and absence of ICD therapy. However, among CRT-eligible patients with non-ischemic cardiomyopathy (NICM), the benefit of defibrillator therapy in addition to CRT remains unclear. In a systematic review and meta-analysis, these researchers compared outcomes of patients with NICM and HF who underwent CRT with ICD (CRT-D) versus CRT only (CRT-P). They carried out a literature search from inception through February 2020 in PubMed and Cochrane Review Databases for all studies reporting outcomes of CRT-D versus CRT-P in CRT-eligible patients with NICM. Studies reporting non-stratified outcomes including patients with ischemic cardiomyopathy were excluded. The primary endpoint of interest was all-cause mortality (ACM). A random effects model using HR was utilized to calculate a cumulative HR for all-cause mortality. The GRADE approach assessed the certainty of evidence across outcomes. Of a total of 1,478 potential citations, the search yielded 8 citations that met inclusion and exclusion criteria. There was 1 RCT that included a sub-group of 645 CRT-eligible NICM patients (322 with CRT-D and 323 with CRT-P); 7 observational studies representing 9,944 CRT-eligible patients with NICM (6,865 CRT-D implantation and 3,079 with CRT-P) were included in a pooled meta-analysis. The cumulative adjusted HR for ACM for CRT-D versus CRT-P was 0.92 (95 % CI: 0.83 to 1.03); I2 = 0; although with low certainty of evidence. There may be little difference in infection and cardiac mortality between CRT-D versus CRT-P devices (HR: 0.82; 95 % CI: 0.29 to 2.20; moderate certainty of evidence, and HR: 0.68; 95 % CI: 0.37 to 1.25; low certainty of evidence, respectively). The authors concluded that in this meta-analysis, the addition of defibrillator therapy was not significantly associated with a reduction in ACM in CRT-eligible patients with NICM.
Doran and associates (2021) stated that it is uncertain whether CRT-D compared to CRT-P is associated with a survival benefit in patients with non-ischemic etiologies of heart failure with reduced ejection fraction (HFrEF). In the COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure) Trial, these researchers examined if patients with HFrEF due to non-ischemic etiology eligible for CRT would benefit from an ICD. Analyses of the COMPANION Trial were carried out, using Cox proportional hazards modeling stratified by HFrEF etiology of NICM or ICM. The primary outcome was ACM; secondary outcomes were the combination of cardiovascular mortality or HF hospitalization and sudden cardiac death (SCD). Among patients randomized to CRT (n = 1,212), 236 (19.5 %) died, resulting in 131 and 105 in the CRT-P and CRT-D arms, respectively. The unadjusted and adjusted HRs for CRT-D versus CRT-P were both 0.84 (95 % CI: 0.65 to 1.09) for ACM, with a significant device-etiology interaction (p interaction = 0.015 adjusted; p interaction = 0.040 unadjusted). In patients with NICM (n = 555), CRT-D versus CRT-P was associated with reduced ACM (adjusted HR: 0.54; 95 % CI: 0.34 to 0.86), while patients with ICM (n = 657) did not exhibit a between-device reduction in ACM (adjusted HR: 1.05; 95 % CI: 0.77 to 1.44). The effects of CRT-D versus CRT-P on SCD (advantage CRT-D) and cardiovascular mortality or HF hospitalization (no difference between CRT-P and CRT-D) were similar between the 2 HFrEF etiologies. The authors concluded that patients with NICM in the COMPANION Trail exhibited a decrease in ACM associated with CRT-D but not CRT-P treatment, whereas patients with ICM did not. They stated that these findings support the use of CRT-D in patients with advanced HFrEF with NICM etiology who are CRT eligible and illuminate the need for more investigation in this area to provide more precision for ICD recommendations. However, these findings cannot be extended to support the use of ICDs in patients with NICM who do not meet criteria for CRT. Also of importance is that in patients with ICM with advanced HFrEF and co-morbidities, risks for non-cardiac mortality may reduce the impact of ICD prevention of SCD to the point of compromising ACM reduction, an issue that clearly needs further investigation.
However, the finding of this trial (The COMPANION Trial) differed from those of the and DANISH NICM Trial (Kober et al, 2016). Trial design and patient population differences between the DANISH and COMPANION Trials may contribute to the disparity in ACM effects among these trials’ patients with NICM. Compared with DANISH, COMPANION patients had more advanced clinical HF and structural plus functional left ventricular (LV) remodeling with lower LVEFs. Whereas the majority of DANISH patients were in NYHA functional class II, COMPANION randomized only patients with HFrEF in functional class III or IV. COMPANION patients with NICM also had a mean baseline LVEF of 20 %, compared with 25 % in DANISH. Furthermore, COMPANION entry criteria included LV dilatation and QRS delay requirements, with 2/3 of subjects having left bundle branch block. These factors alone would have contributed to the marked difference in annualized mortality of 11.2 % in COMPANION patients with NICM and 4.0 % in DANISH. Therefore, patients in COMPANION had a greater severity of HFrEF and LV remodeling that may have influenced ICD effectiveness, in part because DANISH patients were at much lower mortality risk, which would lower the ACM signal-to-noise ratio but potentially also because brady-arrhythmic arrest might have been more prevalent in COMPANION. A recent post-hoc analysis of DANISH supported this hypothesis, in which patients with NICM with more advanced HFrEF had a statistically significant ICD-related reduction in ACM. Another difference between the 2 Trials was a much longer follow-up period in DANISH, more than 5 years compared with approximately 1.4 years in COMPANION. However, in DANISH, drop-outs in the ICD-arm and ICD drop-in rates in the control-arm were relatively low (both less than 10 %), so length of follow-up did not affect integrity of the Trial. Neither did CRT-P drop-in or CRT-D drop-out rate affected COMPANION results, as both were less than or equal to 5 %. However, inspection of the DANISH time-to-event curves showed the ACM treatment associated effect waning after 5 years, so duration of disease could have affected the outcome. The reason for the convergence of the survival curves appeared to be a declining event rate in the control group, which might be a survivor effect of decreasing risk over time. Patients with NICM in the COMPANION Trial were more likely to be women compared with those with ICM or the DANISH study population, but there was no evidence that ICD or CRT-P mortality effects were influenced by sex. Finally, there was a difference in the percentage of patients receiving beta-blocker therapy in the COMPANION Trial (73 % among patients with NICM) compared with DANISH (92 %). However, the present analysis confined only to COMPANION’s beta-blocker-treated patients yielded ACM results that were, if anything, more favorable to NICM CRT-D versus CRT-P results (unadjusted HR: 0.49; 95 % CI: 0.025 to 0.96) compared with ICM of (HR: 1.01; 95 % CI: 0.65 to 1.55). These researchers believed that the most likely explanation for the differences between the DANISH and COMPANION Trials regarding the benefit of an ICD in CRT-eligible patients with NICM was differences in the severity of HFrEF, resulting in a patient population with much higher SCD risk among COMPANION patients with NICM.
The authors stated that this study had several drawbacks. The COMPANION Trial was an older study; thus, certain medications, including sacubitril/valsartan and sodium-glucose cotransporter-2 inhibitors, were not available for management of HF. However, recent trials have shown that even in contemporary practice, less than 2 % of patients with co-morbid diabetes mellitus and HFrEF received sodium-glucose cotransporter-2 inhibitor therapy, and 2.3 % of patients hospitalized with HFrEF were receiving sacubitril/valsartan. The DANISH Trial was also conducted before the regulatory approval of sodium-glucose cotransporter-2 inhibitors and sacubitril/valsartan, and differences in background therapy did not explain the disparate results between the COMPANION and DANISH Trials inasmuch as the use of other HF therapies was similar. These investigators stated that further research is needed to examine the impact of CRT-D versus CRT-P among patients on contemporary medications. The COMPANION Trial was post-hoc and relatively under-powered and had the inherent unblinded device trial limitations of treatment arm cross-over for device arm drop-ins from the control group. However, these limitations were shared with the DANISH Trial, to which the drop-in rate compared favorably. Nevertheless, because of the robust difference between CRT-D- and CRT-P-associated treatment effects on ACM and SCD, these researchers were able to detect a benefit of the addition of an ICD in patients with NICM. Unfortunately, because of sample size limitations, these investigators were unable to examine other possible mediating factors for the findings, such as age, sex, race, duration of HF, and degree of LV remodeling.
In a systematic review, Teimourizad and colleagues (2021) examined the cost-effectiveness of CRT-D versus ICD alone in patients with HF. These researchers employed 5 databases (NHS Economic Evaluation Database, Cochrane Library, Medline, PubMed, and Scopus) to examine studies published in the English language on the cost-effectiveness of CRT-D versus ICD alone in patients with HF from 2000 to 2020. Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist was used to evaluate the quality of the selected studies. A total of 5 studies reporting the cost-effectiveness of CRT-D versus ICD were finally identified. The results revealed that time horizon, direct medical costs, type of model, discount rate, and sensitivity analysis obviously mentioned in almost all studies. All studies used quality-adjusted life years (QALYs) as an effectiveness measurement. The highest and the lowest incremental cost-effectiveness ratio (ICER) were reported in the U.S. ($138,649 per QALY) and the U.K. ($41,787 per QALY), respectively. The authors concluded that the findings of this systematic review showed that CRT-D compared to ICD alone was the most cost-effective treatment in patients with HF.
His Bundle Pacing for Cardiac Resynchronization Therapy
Qi and colleagues (2020) noted that permanent His bundle pacing (HBP) has been described as an alternative for patients with CRT indications; and more recently has been examined for feasibility as a 1st-line strategy. Data on His (HBP for CRT are largely limited to small single-center reports, and clinical benefits and risks have not been systematically examined. In a systematic review, these researchers examined published studies of HBP for CRT and evaluated the feasibility and efficacy of the therapy. PubMed, Cochrane Library, Embase, CNKI, and WanFang databases were searched up to December 2019 to identify relevant studies. Clinical outcomes of interest included implant success rate; Q wave, R wave, and S wave QRS duration; pacing thresholds; LVEF; left ventricular end-diastolic dimension (LVEDD); and NYHA status, complications, and mortality. These investigators extracted and summarized the data; using Revman5.3 software to carry out the meta-analysis. A total of 13 studies involving 503 patients were included. The average implant success rate was 79.8 % (95 % CI: 72.4 to 87.2 %). Permanent HBP resulted in a significant narrow of mean QRS duration from 165.5 ± 8.7 to 122.9 ± 12.0 ms (MD = 43.5, 95 % Cl: 36.34 ~ 50.56, p < 0.001). A trend of increase was observed in capture thresholds at follow-up compared with that in the baseline threshold (MD = - 0.24, 95 % Cl: - 0.38 ~ - 0.10, p = 0.001). Average NYHA functional class (MD = 1.2, 95 % CI: 1.09 ~ 1.31, p < 0.001), LVEF (MD = - 12.60, 95 % Cl: - 14.32 ~ - 10.87, p < 0.001), LVEDD (MD = 4.30, 95 % Cl: 3.05 ~ 5.55, p < 0.001) significantly improved at greater than 3 months follow-up compared with that of the baseline (p < 0.001); 10 studies reported safety information and the most commonly reported complication was the increase in HB capture threshold. The authors concluded that HBP was feasible with a reasonable success rate in patients requiring CRT. HBP could achieve significant narrow of QRS duration and improve LV function during follow-up. Moreover, these researchers stated that RCTs are needed to further examine the efficacy of HBP compared with that of biventricular pacing (BVP) in achieving CRT.
Furthermore, an UpToDate review on “Cardiac resynchronization therapy in heart failure: Implantation and other considerations” Cantillon (, 2021) states that “His bundle pacing is an emerging alternative to CRT”.
Qu et al (2021) noted that His-Purkinje conduction system pacing (HPCSP) has emerged as an effective alternative to overcome the limitations of right ventricular pacing (RVP) via physiological left ventricular activation; however, there remains a paucity of comparative information for His bundle pacing (HBP) and left bundle branch pacing (LBBP). These investigators carried out a Bayesian random-effects network analysis to compare the relative effects of HBP, LBBP, and RVP in patients with bradycardia and conduction disorders. PubMed, Embase, Cochrane Library, and Web of Science were systematically searched from database inception until September 21, 2021. A total of 28 studies involving 4,160 patients were included in this meta-analysis. LBBP significantly improved success rate, pacing threshold, pacing impedance, and R-wave amplitude compared with HBP. LBBP also demonstrated a non-significant trend towards superior outcomes of lead complications, HF hospitalization, AF, and all-cause death. However, HBP was associated with significantly shorter paced QRS duration relative to LBBP. Despite higher success rates, shorter procedure/fluoroscopy duration, and fewer lead complications, patients receiving RVP were more likely to experience LVEF, longer paced QRS duration, and higher rates of HF hospitalization than those receiving HPCSP. No statistical differences were observed in the remaining outcome measures. The authors concluded that this network meta-analysis demonstrated the safety and effectiveness of HPCSP for the treatment of bradycardia and conduction disorders, with differences in pacing parameters, electrophysiology characteristics, and clinical outcomes between HBP and LBBP. Moreover, these researchers stated that larger-scale, long-term comparative studies are needed for further verification.
Peng et al (2021) stated that recent studies have demonstrated that RVP has deleterious effects on non-synchronized ventricular contraction, while HBP or left bundle branch pacing (LBBP) contribute to improvements in patients' mid- and long-term outcomes. In a meta-analysis, these researchers compared the safety and effectiveness of physiologic pacing (HBP/LBBP) versus those of RVP. They carried out a systematic search of PubMed, Cochrane Library, and Embase for studies that compared the effects of physiologic pacing and RVP. All eligible studies were published before January 1, 2021 and were conducted in humans. STATA software version 15.0 was used for all the data analyses. A total of 20 articles (n = 2,787 patients) were included in this meta-analysis. Compared to RVP, physiologic pacing was associated with a significantly shorter QRS duration and better cardiac function. Physiologic pacing was also correlated with lower rates of MR, pacing-induced cardiomyopathy, death, HF hospitalization, and AF, although the afore-mentioned results were not statistically significant. Furthermore, RVP led to the achievement of higher success rates than physiologic pacing, a shorter fluoroscopic time and mean procedure duration, a lower pacing threshold: the results were statistically significant. Compared with HBP, LBBP appeared to have some advantages in R wave amplitudes, pacing threshold, fluoroscopic time, procedure time, and success rate, with statistically significant differences. Whereas HBP was associated with fewer surgical complications and shorter QRS duration, the results were not statistically significant. The authors concluded that physiologic pacing (HBP/LBBP) might be a better strategy than RVP and improved long-term clinical outcomes like cardiac function. Although LBBP appeared to have some advantages over HBP, the long-term benefits are still controversial. These researchers stated that more double-blinded, large-scale, multi-center RCTs are needed for further verification.
The authors stated that this study had several drawbacks. First, It included a small sample size and did not include any multi-center study. As LBBP is a relatively new pacing technique, some of the included studies had a short follow-up period; a larger number of studies with longer follow-up durations are needed to provide evidence pertaining to long-term clinical outcomes and myocardial performance. Second, many of the experiments in this meta-analysis had a cross-over design, and the influence of the placebo and nocebo effects originating from the first-phase experiment on patients may have affected the results. Third, owing to a lack of adequate clinical studies, only 1 RCT was included.
Gui et al (2022) noted that His-Purkinje system pacing (HPSP) has recently emerged as an alternative to bi-ventricular pacing (BIVP) in CRT. In a meta-analysis, these researchers compared the clinical outcomes associated with HPSP versus BIVP in patients with HF. There was also a comparison of clinical outcomes of HBP and LBBP in the His-Purkinje system. They searched the Cochrane Library, Embase, and PubMed, for studies published between January 2010 and October 2021 that compared the clinical outcomes associated with HPSP versus BIVP and HBP versus LBBP in HPSP in patients who underwent CRT. The pacing threshold, R-wave amplitudes, QRS duration, NYHA, LVEF, and LVEDD of HF, at follow-up, were extracted and summarized for meta-analysis. A total of 18 studies and 1,517 patients were included in this analysis. After a follow-up period of 9.3 ± 5.4 months, the HPSP was found to be associated with shorter QRS duration in the CRT population compared to that in the BIVP (standard mean difference [SMD], -1.17; 95 % CI: -1.56 to -0.78; p < 0.00001; I2 = 74 %). No statistical difference was verified between HBP and LBBP on QRS duration (SMD, 0.04; 95 % CI: -0.32 to 0.40; p = 0.82; I2 = 84 %). In the comparison of HPSP and BIVP, the LBBP subgroup showed improved LVEF (SMD, 0.67; 95 % CI: 0.42 to 0.91; p < 0.00001; I2 = 0 %), shorter LVEDD (SMD, 0.59; 95 % CI: 0.93 to 0.26; p = 0.0005; I2 = 0 %), and higher NYHA functional class (SMD, -0.65; 95 % CI: -0.86 to -0.43; p < 0.00001; I2 = 45 %). In terms of pacing threshold and R-wave amplitude clinical outcomes, LBBP has a lower pacing threshold (SMD, 1.25; 95 % CI: 1.12 to 1.39; p < 0.00001; I2 = 47 %) and higher R-wave amplitude (MD, -7.88; 95 % CI: -8.46 to -7.31; p < 0.00001; I2 = 8 %) performance compared to HBP. The authors concluded that the findings of this meta-analysis showed that the HPSP produced higher LVEF, shorter QRS duration, and higher NYHA functional class in the CRT population than the BIVP as observed on follow-up. LBBP has a lower pacing threshold and higher R-wave amplitude. These researchers stated that HPSP may be a new and promising alternative to BIVP in the future.
The authors stated that this meta-analysis had several drawbacks. First was a bias due to the small number of included relevant RCTs and the fact that most studies were post-hoc analyses. This bias may have influenced the conclusions of this study. Second, the length of follow-up in the included literature took longer to justify the results. Third, this meta-analysis did not include data on mortality or cardiovascular hospitalization. Fourth, the complications following different pacing procedures were not discussed.
Implantable Diaphragmatic Stimulation (VisCardia’s VisONE implantable system) for the Treatment for Heart failure
Roos and co-workers (2009) noted that pharmacological conditioning of the phrenic nerve can positively influence systolic performance, and diaphragm activation improves ventilatory function. These investigators examined if pacing-induced diaphragmatic stimulation (PIDS) may improve LV systolic function. They studied a total of 35 patients (4 women, mean age of 67 +/- 9 years, ejection fraction of 61 +/- 14 %) within 7 days following open heart surgery. The hemodynamic impact of different PIDS and ventricular pacing configurations and coupling intervals was tested in 132 episodes. Success of PIDS was evaluated using fluoroscopy and palpation. Left ventricular systolic performance was recorded using the electromechanical activation time (EMAT) obtained via acoustic cardiography; 18 subjects were tested in the catheter laboratory and 17 in the intensive care unit (ICU). For both groups, EMAT significantly improved when the diaphragm was stimulated 20 ms after the onset of ventricular pacing. In all instances, PIDS could be induced with or without causing patient symptoms, and LV systolic performance improvement was comparable in symptomatic and asymptomatic modes. No desensitization of the diaphragm was observed following PIDS delivery 4 to 6 and 24 hours following open heart surgery. The authors concluded that pacing-induced diaphragmatic stimulation, if synchronized to the onset of ventricular contraction with a fixed, non-zero coupling delay, could improve LV systolic function reproducibly for at least 1 hour without causing patient symptoms. The absence of diaphragm desensitization enhanced the potential of PIDS as a practical therapeutic approach in device-based HF management.
These investigators stated that this study was designed to examine the effect of PIDS on LV systolic function. The patients selected following open heart surgery were neither pacemaker-dependent nor in HF. The number of patients in the various study phases was small, and the results should be confirmed in a larger group of patients. Continuous PIDS was limited to a maximum of 1 hour in the supine position, and the hemodynamic effect of PIDS in various positions over days and weeks needs to be examined in further studies.
In a pilot study, Beeler and colleagues (2014) stated that device-based PIDS may have therapeutic potential for patients with chronic HF. These researchers examined the effects of PIDS on cardiac function and functional outcomes. In 24 chronic HF patients with CRT, an additional electrode was attached to the left diaphragm. Subjects were randomized into 2 groups; patients received the following PIDS modes for 3 weeks in a different sequence: PIDS off (control group); PIDS 0 ms mode (PIDS simultaneously with ventricular CRT pulse); or PIDS optimized mode (PIDS with optimized delay to ventricular CRT pulse). For PIDS optimization, acoustic cardiography was used. Effects of each PIDS mode on dyspnea, power during exercise testing, and LVEF were evaluated. Dyspnea improved with the PIDS 0 ms mode (p = 0.057) and the PIDS optimized mode (p = 0.034) as compared with the control group. Maximal power increased from median 100.5 W in the control group to 104.0 W in the PIDS 0 ms mode (p = 0.092) and 109.5 W in the PIDS optimized mode (p = 0.022). Median LVEF was 33.5 % in the control group, 33.0 % in the PIDS 0 ms mode, and 37.0 % in the PIDS optimized mode (p = 0.763 and p = 0.009 as compared with the control group, respectively). PIDS was asymptomatic in all patients. The authors concluded that PIDS improved dyspnea, working capacity, and LVEF in chronic HF patients over a 3-week period in addition to CRT. These researchers stated that the findings of this pilot study demonstrated proof-of principle of an innovative technology that should be confirmed in a larger sample.
The authors stated that this study had several drawbacks. First, generalizability of this study's findings was limited, given the small sample size of 24 patients at 1 center. However, this study did demonstrate proof-of-principle, suggesting that PIDS should continue to be examined in different settings. Second, some of the outcomes with high inter- and intra-individual variability (e.g., 6 min walk test [6MWT]) probably require a higher number of patients because the present study was not powered for that. Third, complete blinding was not possible in this study because researchers were involved in the programming of the PIDS settings. Fourth, the subjects enrolled in this study were not necessarily pacemaker-dependent nor did they had evidence of electrical LV dyssynchrony; hence, the results presented could not be compared in absolute terms with results from previous CRT studies. Fifth, due to the fact that PIDS delay was changed concomitantly with AV delay, the beneficial effects of PIDS on cardiac function might also be in part the result of the AV delay optimization. However, the additional analysis at 9-week follow-up showed that the outcomes were worse again in the PIDS off mode though AV delay remained optimized.
Spiesshoefer and associates (2019) stated that in HF with reduced ejection fraction (HFrEF), diaphragmatic dysfunction likely contributes to exercise intolerance, dyspnea and impaired overall prognosis, beyond what can be explained from indices of heart function and neurohormonal derangement alone. However, much remains unknown regarding the pathophysiology underlying diaphragm dysfunction in HF, especially in HFpEF. Diaphragm dysfunction in HF is either just a “by-product” (if it occurred only due to hypoperfusion) or could also be related to systemic inflammation. Therefore, future research needs to focus on accurate and comprehensive measurement of diaphragm function and its association with pro-inflammatory cytokines in patient with HFrEF and HF with preserved ejection fraction (HFpEF). This may be a mechanism that could be targeted to preserve diaphragmatic function and potentially improve exercise intolerance in HFrEF and HFpEF.
In April 2020, VisCardia received breakthrough device designation from the FDA for its implantable VisONE system to treat moderate-to-severe HF with reduced ejection fraction and preserved ventricular synchrony. The FDA breakthrough device program is a 2-phase process, which is designed to support patients to attain timely access to breakthrough technologies. VisCardia has completed the 1st phase of the program for the system. The FDA will advance re-market reviews of VisCardia’s IDE(s) and the subsequent pre-market approval (PMA) application to request approval to commercialize the device in the United States, during the 2nd phase of the program. VisONE technology is said to engage the diaphragm by employing stimuli synchronously with the cardiac cycle, aiding in improving the blood flow via weak heart by modulating the pressures within the chest. Transient intra-thoracic pressures synchronized to cardiac activity are modulated by electrically stimulating the diaphragm in an imperceptible manner, helping to improve both cardiac filling and output.
UpToDate reviews on “Overview of the management of heart failure with reduced ejection fraction in adults” (Colucci, 2021a), “Treatment of acute decompensated heart failure: Specific therapies” (Colucci, 2021b), “Management of refractory heart failure with reduced ejection fraction” (Dunlay and Colucci, 2021) and “Treatment and prognosis of heart failure with preserved ejection fraction” (Borlaug and Colucci, 2021) do not mention diaphragmatic stimulation as a management / therapeutic option.Cardiac Magnetic Resonance in Identifying Appropriate Candidates for Cardiac Resynchronization Therapy
Bazoukis et al (2022) stated that despite the strict indications for CRT implantation, a significant proportion of patients will fail to adequately respond to the treatment. In a systematic review, these investigators examined the available evidence on the role of cardiac magnetic resonance (CMR) in identifying patients who are likely to respond better to the CRT. Two independent investigators carried out a systematic search in the MedLine database and Cochrane Library from their inception to August 2021, without any limitations. They considered eligible observational studies or RCTs that enrolled patients 18 years of age or older with HF of ischemic or non-ischemic etiology and provided data regarding the association of baseline CMR variables with clinical or echocardiographic (ECG) response to CRT for at least 3 months. This systematic review was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Following their search strategy, a total of 47 studies were finally included in this review. CMR appeared to have an additive role in identifying the subgroup of patients who will respond better to CRT. Specifically, the presence and the extent of myocardial scar were associated with increased non-response rates, while those with no scar respond better. In addition, existing data showed that scar location could be associated with CRT response rates. CMR-derived markers of mechanical desynchrony could also be used as predictors of CRT response. CMR data can be used to optimize the position of the left ventricular lead during the CRT implantation procedure. Specifically, positioning the left ventricular lead in a branch of the coronary sinus that feeds an area with transmural scar was associated with poorer response to CRT. The authors concluded that CMR can be used as a non-invasive optimization tool to identify patients who are more likely to achieve better clinical and ECG response following CRT implantation.
Mehta et al (2022) noted that positioning the left ventricular (LV) lead at the optimal myocardial segment has been proposed to improve CRT response. In a systematic review and meta-analysis, these investigators examined ECG and clinical response delivered with different guidance modalities compared to conventional fluoroscopic positioning. Randomized trials with 6 months or longer follow-up comparing any combination of imaging, electrical, hemodynamic, or fluoroscopic guidance were included. Imaging modalities were split whether one modality was used: CMR, speckle-tracking echocardiography (STE), single-photon emission computed tomography (SPECT), cardiac computed tomography (CT), or a combination of these, defined as "multi-modality imaging". A total of 12 studies were included (n = 1,864). Pair-wise meta-analysis resulted in significant odds of reduction in LV end-systolic volume (LVESV) of greater than 15 % (odds ratio [OR] 1.50, 95 % CI: 1.05 to 2.13, p = 0.025) and absolute reduction in LVESV (SMD -0.25, 95 % CI: -0.43 to -0.08, p = 0.005) with guidance. CMR (OR 55.3, 95 % CI: 4.7 to 656.9, p = 0.002), electrical (OR 17.0, 95 % CI: 2.9 to 100, p = 0.002), multi-modality imaging (OR 4.47, 95 % CI: 1.36 to 14.7, p = 0.014), and hemodynamic guidance (OR 1.29 to 28.0, p = 0.02) were significant in reducing LVESV of greater than 15 %. Only STE showed a significant reduction in absolute LVESV (SMD -0.38, 95 % CI: -0.68 to -0.09, p = 0.011]. CMR had the highest probability of improving clinical response (OR 17.9, 95 % CI: 5.14 to 62.5, p < 0.001). The authors concluded that overall, guidance improved CRT outcomes; STE and multi-modality imaging provided the most reliable evidence of effectiveness. Wide CIs observed for results of CMR guidance suggested more powered studies are needed before a clear ranking is possible. Moreover, these researchers stated that further evidence in the form of large, randomized studies will allow a more nuanced evaluation of which modality is best placed to guide optimal LV lead delivery, especially in advanced imaging modalities such as CMR.
The authors stated that this meta-analysis had several drawbacks. First, multiple different measures of CRT outcome and follow-up duration were not consistent across studies; thus, the most common outcome markers were evaluated. Second, patients and outcome assessors were not uniformly masked to whether they were in the intervention group, which may have introduced treatment and observer bias. Third, not all studies were 1:1 randomized. In some of the network arms there was 1 study with smaller numbers of patients included, notably evaluating CMR only. This accounted for the wide CIs observed and suggested further clinical trials will increase confidence of their effectiveness. Fourth, specific patient populations were only recruited in some of the studies, which may have reduced the reproducibility of these results in a general dyssynchronous HF population. Two studies did not present fully published results; however, the inclusion of “gray literature” was to avoid selection and publication bias. Sensitivity analyses were carried out to mitigate this risk, and these results showed the robustness of the inclusion of these studies. Fifth, only 4 studies specified what proportion of quadripolar or bipolar lead was implanted; 3 used both, with no significant differences between the guidance and fluoroscopic group. In addition, only 5 studies identified type of programming specified post-implant and whether the device was optimized. The lack of consistency in programming and lead technology may have affected the interpretation of these findings. Sixth, the data used were derived data published by the study authors; thus, patient-level data were not used for the meta-analysis.
In a systematic review and meta-analysis, LaPointe et al (2022) examined available evidence for an image-guided approach for CRT that targets left ventricular (LV) lead placement at the segment of latest mechanical activation. These investigators carried out a systematic review of Embase and PubMed for RCTs and prospective observational studies from October 2008 through October 2020 that compared an image-guided CRT approach with a non-image-guided approach for LV lead placement. Meta-analyses were conducted to evaluate the association between the image-guided approach and NYHA class improvement or changes in LVESV, LV end-diastolic volume (LVEDV), and LVEF. From 5,897 citations, 5 RCTs including 818 patients (426 image-guided and 392 non-image-guided) were identified. The mean age ranged from 66 to 71 years, 76 % were men, and 53 % had ischemic cardiomyopathy. STE was the primary image-guided method in all studies. LV lead placement within the segment of the latest mechanical activation (concordant) was achieved in the image-guided arm in 45 % of the evaluable patients. There was a statistically significant improvement in the NYHA class at 6 months (OR 1.66; 95 % CI: 1.02 to 2.69) with the image-guided approach, but no statistically significant change in LVESV (MD -7.1 %; 95 % CI: -16.0 to 1.8), LVEDV (MD -5.2 %; 95 % CI: -15.8 to 5.4), or LVEF (MD 0.68; 95 % CI: -4.36 to 5.73) versus the non-image-guided approach. The authors concluded that image-guided CRT approach was associated with improvement in the NYHA class but not ECG measures, possibly due to the small sample size and a low rate of concordant LV lead placement despite using the image-guided approach. Therefore, this meta-analysis was not able to identify consistent improvement in CRT outcomes with an image-guided approach. Moreover, these researchers stated that other factors such as device optimization, percentage of bi-ventricular pacing, and arrhythmia burden may also need to be considered and integrated into any future strategic approach for CRT.
The authors stated that this study had several drawbacks, including the relatively small number of studies (5 RCTs) eligible for inclusion and the small number of total patients (n = 818). All but 1 study was a single-center study; however, the included multi-center study only included 2 sites. Thus, performance of the intervention and the results may not be generalizable. There was also considerable heterogeneity identified in the analyses for LVEF and LVESV. Changes in guideline recommendations and technology over time resulted in potentially significant differences in study populations and/or LV lead implantation techniques, resulting in heterogeneity across studies and/or within studies. Finally, the study by Borgquest et al (2020) was terminated early due to equivocal results between study arms, potentially introducing bias
Furthermore, an UpToDate review on “Cardiac resynchronization therapy in heart failure: Implantation and other considerations” (Knight, 2023) states that “Some experts consider the site of greatest mechanical delay as a factor ancillary to the site of greatest electrical delay when identifying the site for LV pacing. Targeting the site of greatest mechanical delay for pacing stimulation has been associated with improved CRT outcomes in some studies. Echocardiographic-based imaging and magnetic resonance imaging have been utilized to evaluate the value of placing the LV pacing lead at or near the area of maximal mechanical delay”. However, cardiac MRI is not mentioned in the “Summary and Recommendations” section of this UTD review.
Leadless Cardiac Pacing
Hua et al (2022) noted that CRT via bi-ventricular pacing (BVP) improves morbidity, mortality, and QOL, especially in subsets of patients with impaired cardiac function and wide QRS. However, the rate of unsuccessful or complicated LV lead placement via coronary sinus is 5 % to 7 %, and the rate of "CRT non-response" is approximately 30 %. These reasons have pushed physicians and engineers to collaborate to overcome the challenges of LV lead implantation; therefore, various alternatives to BVP have been proposed to improve CRT effectiveness. His bundle pacing (HBP) has been increasingly used by activating the His-Purkinje system; however, this approach is constrained by challenging implantation, low success rates, high and often unstable thresholds, and low perception. Thus, the concept of pacing a specialized conduction system distal to the His bundle to bypass the block region was proposed. Multiple clinical studies have shown that left bundle branch area pacing (LBBAP) has comparable electrical resynchronization with HBP but is superior in terms of simpler operation, higher success rates, lower and stable capture thresholds, and higher perception. Despite their well-demonstrated effectiveness, the transvenous lead-related complications remain major limitations. Recently, leadless LV pacing has been developed and demonstrated effective for these challenging patient cohorts. The authors concluded that HBP, LBBAP, and leadless LV pacing have been demonstrated as potential alternatives for optimal CRT when conventional CRT fails. Each technique has its advantages and disadvantages. HBP and LBBAP have shown more effective electrical resynchronization than conventional BVP. Accordingly, they provided equivalent or even superior clinical outcomes in some challenging cohorts. However, transvenous leads remain a major limitation of these pacing modalities. Therefore, leadless LV pacing has been developed and demonstrated to provide more physiological LV endocardial activation coupled with clinical benefits. In addition, the advantage of leadless LV pacing would become more pronounced in cases of venous occlusion or lead infection. These researchers stated that with a better understanding of HBP, LBBAP, leadless LV pacing, and their appropriate candidates, it is more likely that the most suitable alternative will be chosen when conventional CRT is impossible or ineffective.
The authors stated that the findings of this review supported the effectiveness of leadless LV pacing as an alternative in patients in whom CRT is impossible or ineffective. It significantly reduced diaphragm stimulation, avoided mitral regurgitation, and could be performed at multiple physiological pacing positions. Furthermore, the receiver electrode was completely endothelialized for approximately 4 weeks; thus, long-term anti-coagulation was not required. However, leadless LV pacing has several drawbacks. First, it is challenging to choose a suitable acoustic window (distance of less than 10 cm and angulation of less than 30°) to effectively transmit ultrasound. Second, some regions of the left lateral free wall of the enlarged LV may be difficult to reach owing to the current delivery sheath. Third, the battery life projections averaged 18 months (range of 9 to 42 months), which is often over-estimated and should be improved. Moreover, the procedure is complex and has a relatively high complication rate. However, security issues are a common problem in the early stages of any novel technique. Improvements in the safety profile, such as different delivery sheaths, increased operator experience, and practice modifications, would reduce its complication rates and increase its widespread use. Furthermore, pre-procedural cardiac computed tomography (CT) can be used to identify the optimal positioning of the receiver electrode based on indicators such as scar burden, simulated latest activation, and hemodynamic assessment.
Strocchi et al (2022) stated that bi-ventricular endocardial (BIV-endo) pacing and left bundle pacing (LBP) are novel delivery methods for CRT. Both pacing methods can be delivered via leadless pacing, to avoid risks associated with endocardial or transvenous leads. These researchers employed computational modelling to quantify synchrony induced by BIV-endo pacing and LBP via a leadless pacing system; and examined how the right-left ventricle (RV-LV) delay, RV lead location and type of left bundle capture would affect response. They simulated ventricular activation on 24 4-chamber heart meshes inclusive of His-Purkinje networks with left bundle branch block (LBBB). Leadless bi-ventricular (BIV) pacing was simulated by adding an RV apical stimulus and an LV lateral wall stimulus (BIV-endo lateral) or targeting the left bundle (BIV-LBP), with an RV-LV delay set to 5 ms. To test effect of prolonged RV-LV delays and RV pacing location, the RV-LV delay was increased to 35 ms and/or the RV stimulus was moved to the RV septum. BIV-endo lateral pacing was less sensitive to increased RV-LV delays, while RV septal pacing worsened response compared to RV apical pacing, especially for long RV-LV delays. To examine how left bundle capture would affect response, these researchers computed 90 % BIV activation times (BIVAT-90) during BIV-LBP with selective and non-selective capture, and left bundle branch area pacing (LBBAP), simulated by pacing 1 cm below the left bundle. Non-selective LBP was comparable to selective LBP. LBBAP was worse than selective LBP (BIVAT-90: 54.2 ± 5.7 ms versus 62.7 ± 6.5, p < 0.01), but it still significantly reduced activation times from baseline. Lastly, these researchers compared leadless LBP with RV pacing against optimal LBP delivery via a standard lead system by simulating BIV-LBP and selective LBP alone with and without optimized atrio-ventricular delay (AVD). Although LBP alone with optimized AVD was better than BIV-LBP, when AVD optimization was not possible BIV-LBP outperformed LBP alone, because the RV pacing stimulus shortened RV activation (BIVAT-90: 54.2 ± 5.7 ms versus 66.9 ± 5.1 ms, p < 0.01). The authors concluded that BIV-endo lateral pacing or LBP delivered via a leadless system could potentially become an alternative to standard CRT. RV-LV delay, RV lead location and type of left bundle capture affect leadless pacing efficacy and should be considered in future trial designs. Moreover, these researchers stated that the results they presented laid the foundation for clinical trial design examining the safety and effectiveness of leadless pacing.
Malaczynska-Rajpold et al (2023) noted that since the introduction of transvenous cardiac pacing leads, pacemaker system design has remained similar for several decades. Progressive miniaturization of electronic circuitry and batteries has enabled a smaller, single pacing unit comprising the intra-cardiac electrodes, generator and computer. These researchers examined the development of leadless pacing, the clinical trials comparing leadless to transvenous pacing in addition to the future developments of multi-chamber leadless pacing. They stated that demonstration of the feasibility and reliability of leadless RV pacing devices was the 1st important step in a long journey for leadless technology. There have been ongoing efforts towards achieving AV synchrony using leadless pacing, and it will be exciting to follow the trajectory of this over the next 10 years. Advances in subcutaneous ICD (S-ICD) technology, leadless LV endocardial pacing, and the possibility of a leadless device providing anti-tachycardia pacing (ATP) would enable a completely leadless system with a full array of CRT-defibrillator (CRT-D) functionality. While this is an extremely attractive concept, especially in younger patients who are currently exposed to a lifetime of lead-related complications, several challenges must be overcome for this to be translatable in a real-world setting: these include miniaturization of technology to allow complex programming within leadless units; enabling communication between devices from different manufacturers; and how to manage devices at the end of battery life. Indeed, battery drain as well as finite capacity is one limitation that surrounds both transvenous and leadless devices. Wireless charging which now exists with smartphones may be possible with pacemaker batteries in the future. Other concepts include complete disruption of the battery concept; harvesting of the kinetic energy generated by the cardiac movement to drive electrical current and pace the heart; feasibility models have been tested and will inevitably undergo numerous further iterations over the coming years. The authors concluded that with the indications for device therapy increasing in recent years, leadless pacing has the potential to provide safe long-term therapeutic options for a large cohort of patients with cardiovascular disease. If rapid innovation and development continue at their current trajectory, it is plausible that leadless technology may become a 1st-line therapeutic option in decades to come.
Appendix
The NYHA classification of HF is a 4-tier system that categorizes patients based on subjective impression of the degree of functional compromise. The 4 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 or 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 (i.e., mild exertion) 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 cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased.
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