1. Aetna considers 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):

   1. New York Heart Association (NYHA) classification of heart failure III or IV (see Appendix) and all of the following criteria are met: 
      
      1. Left ventricular ejection fraction (LVEF) less than or equal to 35 %; and
      2. QRS duration greater than or equal to 120 msec; and
      3. Member is on a stable pharmacologic regimen before implantation, which may include any of the following, unless contraindicated: 
         
         
         1. Angiotensin-converting enzyme inhibitor; or
         2. Angiotensin receptor blocker; or
         3. Beta blocker; or
         4. Digoxin; or
         5. Diuretics. 
             

   2. NYHA classification of heart failure II (see Appendix) and all of the following criteria are met:

      1. LVEF less than or equal to 30 %; and
      2. Left bundle branch block with QRS duration greater than or equal to 130 msec; and
      3. Member is on a stable pharmacologic regimen before implantation, which may include any of the following, unless contraindicated.
         
         
         1. Angiotensin-converting enzyme inhibitor; or
         2. Angiotensin receptor blocker; or
         3. Beta blocker; or
         4. Digoxin; or
         5. Diuretics. 
             

2. Aetna considers biventricular pacemakers experimental and investigational for all other indications (e.g., atrial fibrillation, mild heart failure/NYHA functional class I, and anti-bradycardia pacing) because their effectiveness for these indications has not been estanlished. 

3. 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:

   1. Members have at least 1 episode of cardiac arrest as a result of ventricular tachyarrhythmias; or
   2. Members have recurring, poorly tolerated sustained ventricular tachycardia; or
   3. Members have a prior heart attack and a documented episode of non-sustained ventricular tachycardia, with an inducible ventricular tachyarrhythmia; or
   4. Members have a prior heart attack and a LVEF of less than or equal to 30 %.
       
4. Aetna considers combination resynchronization-defibrillator devices experimental and investigational for all other indications because their effectiveness for these indications has not been estanlished.
    
5. Aetna considers the galectin-3 test experimental and investigational for selection of individuals for cardiac resynchronization therapy and all other indications (e.g., prognosis of heart failure) because its effectiveness has not been estanlished.

Note: Biventricular pacemakers (cardiac resynchronization therapy) or combination resynchronization-defibrillator devices are not considered medically necessary for individuals whose heart failures or ventricular arrhythmias are reversible or temporary.

Contraindications:

The following approaches are considered not medically necessary 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.

See also CPB 0585 - Cardioverter-Defibrillators. 

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: (i) incorporation of biventricular pacing into automatic implantable cardiac defibrillators; and (ii) 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.  Ventricular resynchronization has been shown to result in greater clinical value than atrial resynchronization.

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 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-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: (i) no large published clinical trials exist to demonstrate benefit with a particular dyssynchrony index, (ii) conflicting results are emerging on the predictive value of dyssynchrony indexes, (iii) 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.

Galectin-3 is a member of the galectin family, which consists of animal lectins that bind beta-galactosides.  It plays an important role in fibroblast activation and fibrosis in animal models; and a role for galectin-3 in the pathophysiology of heart failure has been suggested.

Gupta and co-workers (2009) described some promising newer biomarkers that have contributed to a better understanding of pathophysiologic mechanisms involved in HF but for which less data are currently available: osteoprotegerin, galectin-3, cystatin C, chromogranin A, and the adipokines adiponectin, leptin, and resistin.  Despite the intriguing early information from these newer markers, none is ready for routine clinical use.  The authors concluded that much additional study is needed to determine how these biomarkers will fit into diagnostic and treatment algorithms for patients who have HF.

Lok and associates (2010) stated that biomarkers are increasingly being used in the management of patients with CHF.  Galectin-3 is a recently developed biomarker associated with fibrosis and inflammation, and it may play a role in cardiac remodeling in HF.  These researchers determined its prognostic value in patients with CHF.  Patients with CHF (NYHA functional class III or IV) who participated in the Deventer-Alkmaar heart failure study were studied.  Galectin-3 levels were determined at baseline using a novel optimized enzyme-linked immunosorbent assay.  Uni-variate and multi-variate analyses were used to determine the prognostic value of this biomarker.  These investigators studied 232 patients; their mean age was 71 +/- 10 years, 72 % were male, and 96 % were in NYHA class III.  During a follow-up period of 6.5 years, 98 patients died.  Galectin-3 was a significant predictor of mortality risk after adjustment for age and sex, and severity of HF and renal dysfunction, as assessed by N-terminal B-type natriuretic peptide (NT-proBNP) and estimated glomerular filtration rate, respectively (hazard ratio per standard deviation 1.24, 95 % CI: 1.03 to 1.50, p = 0.026).  The authors concluded that plasma galectin-3 is a novel prognostic marker in patients with CHF.  Its prognostic value is independent of severity of HF, as assessed by NT-proBNP levels, and it may potentially be used in the management of such patients.

de Boer et al (2010) noted that galectin-3 is specifically up-regulated in decompensated HF compared with compensated HF in animal models of HF.  This has been associated with activation of fibroblasts and macrophages, which are a hallmark of cardiac remodeling.  Thus, galectin-3 may be a culprit biomarker in HF.  Initial clinical observations indicate that galectin-3 may be a useful biomarker for decompensated HF, with incremental value over well-used "pressure-dependent" biomarkers, such as B-type natriuretic peptide.  The authors concluded that future studies should focus on galectin-3 biology to better address the usefulness of galectin-3 as a biomarker and probe the usefulness of anti-galectin-3 therapy in treating HF.

de Couto et al (2010) stated that early identification of cardiac dysfunction would allow implementation of early intervention strategies to delay the progression or to prevent the onset of HF altogether.  Although screening methods for asymptomatic cardiac dysfunction have yet to be optimized, a staged approach for patients with predisposing risk factors using serological biomarkers followed by non-invasive imaging techniques may be useful.  Existing biomarkers for cardiac dysfunction include B-type natriuretic peptide, troponins, and C-reactive protein.  Novel markers such as protein ST2, galectin-3, and various prohormones are emerging and may provide prognostic information that is incremental to conventional clinical evaluation.

Tang et al (2011) stated that increased galectin-3 levels are associated with poor long-term survival in HF.  These researchers examined the relation between plasma galectin-3 levels and myocardial indexes of systolic HF.  They measured plasma galectin-3 in 133 subjects with CHF and 45 with advanced decompensated HF using echocardiographic and hemodynamic evaluations.  In the CHF cohort, median plasma galectin-3 level was 13.9 ng/ml (inter-quartile range of 12.1 to 16.9).  Higher galectin-3 was associated with more advanced age (r = 0.22, p = 0.010), poor renal function (estimated glomerular filtration rate, r = -0.24, p = 0.007; cystatin C, r = 0.38, p < 0.0001) and predicted all-cause mortality (hazard ratio 1.86, 95 % CI: 1.36 to 2.54, p < 0.001).  In multi-variate analysis, galectin-3 remained an independent predictor of all-cause mortality after adjusting for age, estimated glomerular filtration rate, LVEF, and mitral early diastolic myocardial relaxation velocity at septal mitral annulus (hazard ratio 1.94, 95 % CI: 1.30 to 2.91, p = 0.001).  However, galectin-3 did not predict the combined end point of all-cause mortality, cardiac transplantation, or HF hospitalization (p > 0.05).  Furthermore, there were no relations between galectin-3 and LV end-diastolic volume index (r = -0.05, p = 0.61), LV EF (r = 0.10, p = 0.25), or LV diastolic function (mitral early diastolic myocardial relaxation velocity at septal mitral annulus, r = 0.06, p = 0.52; left atrial volume index, r = 0.08, p = 0.41).  In the advanced decompensated HF cohort, these investigators did not observe any relation between galectin-3 and echocardiographic or hemodynamic indexes.  The authors concluded that high plasma galectin-3 levels were associated with renal insufficiency and poorer survival in patients with chronic systolic HF.  However, a relation between galectin-3 and echocardiographic or hemodynamic indexes was not observed.

Yanavitski and Givertz (2011) discussed some novel biomarkers that may aid in diagnosis, treatment, and prognosis of acute HF, specifically focusing on ST2, endoglin, galectin-3, cystatin C, neutrophil gelatinase-associated lipocalin, midregional pro-adrenomedullin, chromogranin A, adiponectin, resistin, and leptin and their emerging clinical roles.

Gaggin and Januzzi (2013) stated that HF biomarkers have dramatically impacted the way HF patients are evaluated and managed.  B-type natriuretic peptide and NT-proBNP are the gold standard biomarkers in determining the diagnosis and prognosis of HF, and studies on natriuretic peptide-guided HF management look promising.  An array of additional biomarkers has emerged, each reflecting different pathophysiological processes in the development and progression of HF: myocardial insult, inflammation and remodeling.  Novel biomarkers, such as mid-regional pro atrial natriuretic peptide (MR-proANP), mid-regional pro adrenomedullin (MR-proADM), highly sensitive troponins, soluble ST2 (sST2), growth differentiation factor (GDF)-15 and galectin-3, show potential in determining prognosis beyond the established natriuretic peptides, but their role in the clinical care of the patient is still partially defined and more studies are needed. 

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 (i) evaluate CRT as a therapeutic option in HF patients with functional MR and high operative risk, and (ii) 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.

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.