BlueCross and BlueShield of Montana Medical Policy/Codes
Biventricular Pacing
Chapter: Medicine: Treatments
Current Effective Date: April 18, 2013
Original Effective Date: April 18, 2013
Publish Date: January 18, 2013
Description

It is estimated that 20–30% of patients with heart failure (HF) have intraventricular conduction disorders resulting in a discoordinate contraction pattern and a wide QRS interval on the electrocardiogram (ECG).  This abnormality appears to be associated with increased morbidity and mortality.  Biventricular pacing, also known as cardiac resynchronization therapy (CRT) is a treatment for HF that uses an implantable device to improve the pumping efficiency of the heart.  Biventricular pacemakers using three leads (one in the right atrium and one in each ventricle) have been investigated as a technique to coordinate the contraction of the ventricles, thus improving patients’ hemodynamic status. 

Two strategies are being explored:

  • Incorporating biventricular pacing into automatic implantable defibrillators, and
  • The development of stand alone biventricular pacemakers.

One stand-alone biventricular pacemaker (InSync® Biventricular Pacing System, Medtronic) has received approval by the U.S. Food and Drug Administration (FDA) for the treatment of patients with NYHA Class III or IV HF, on a stable pharmacologic regimen, who also have a QRS duration of 130 msec or longer and a left-ventricular ejection fraction of 35% or less.  Biventricular pacemakers have also been combined with automatic implantable cardiac defibrillators (AICDs).  Both Guidant (CONTAC CD® CRT-D System) and Medtronic (InSync® ICD Model 7272) have received FDA approval for combined resynchronization therapy defibrillators for patients at high risk of sudden death due to ventricular arrhythmias and who have NYHA Class III or IV HF with left ventricular ejection fraction of 35% or less, QRS duration of 130 msec or longer (120 msec for the Guidant device) and remain symptomatic despite a stable, optimal HF drug therapy.  This combined ventricular/AICD is additionally equipped to monitor intrathoracic fluid levels using bioimpedance technology, referred to as OptiVol™ Fluid Status monitoring. 

In 2005, the InSync Sentry system received FDA approval through the supplemental premarket approval (PMA) process.  This combined biventricular pacemaker/ICD is also equipped to monitor intrathoracic fluid levels using bioimpedance technology, referred to as OptiVol Fluid Status monitoring. Bioimpedance measures, defined as the electrical resistance of tissue to flow of current, are performed many times per day using a vector from the right ventricular coil on the lead in the right side of the heart to the implanted pacemaker devices; changes in bioimpedance reflect intrathoracic fluid status and are evaluated based on a computer algorithm.  For example, changes in a patient’s daily average intrathoracic bioimpedance can be monitored.  Differences in the daily average compared to a baseline are reported as the OptiVol™ Fluid Index.  It has been proposed that these data may be used as an early warning system of cardiac decompensation, or provide additional feedback enabling a physician to further tailor medical therapy. 

In September 2010, the FDA expanded the indications for CRT to include patients with class I and II HF.  In addition to NYHA class I/II HF, indications for CRT in mild HF include a left ventricular (LV) ejection fraction of less than 30% and a QRS duration of 130 msec or greater.

The Stages of Heart Failure – NYHA Classification

Class I: no limitation is experienced in any activities; there are no symptoms from ordinary activities.

Class II: slight, mild limitation of activity; the patient is comfortable at rest or with mild exertion.

Class III: marked limitation of any activity; the patient is comfortable only at rest.

Class IV: any physical activity brings on discomfort and symptoms occur at rest.

Galectin-3 Testing

Galectin-3 is a recently developed biomarker associated with fibrosis and inflammation, and it may play a role in cardiac remodeling in HF. Elevated galectin-3 levels identify a subset of patients with chronic heart failure who suffer from an inherently progressive form of heart failure due to galectin-3-mediated fibrosis and adverse remodeling.

Patients with elevated galectin-3 levels may have worse prognosis in terms of mortality or risk of hospitalization than comparable patients with low levels of galectin-3. It is noted that measuring galectin-3 in patients with heart failure may offer clinically useful information pertaining to risk of adverse outcomes and this information can be used in heart failure patient management

The BGM Galectin-3 blood test is the first novel cardiovascular in-vitro diagnostic to be cleared by the FDA in >5 years. It marks the first clinical application derived from the galectin-3 research and the first blood test indicating the prognosis of patients diagnosed with chronic heart failure that is due to underlying fibrosis resulting in adverse outcomes.  The BGM Galectin-3 blood test is based on the common ELISA format, using the standard microtiter plate presentation.

Policy

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions.  Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coverage

Biventricular pacemakers (with or without an accompanying implantable cardiac defibrillator, i.e., a combined biventricular pacemaker/ICD) may be considered medically necessary as a treatment of heart failure (HF) in patients who are NYHA class II - IV AND, who meet the following specific criteria listed under the NYHA class

NYHA classification III or IV:

  • Left ventricular ejection fraction ≤35%,
  • Sinus rhythm,
  • QRS duration of ≥120–130  msec*, and
  • Patients treated with a stable pharmacological medical regimen prior to implant, such as an angiotensin-converting enzyme (ACE) inhibitor (or an angiotensin receptor blocker) and a beta blocker, digoxin, and/or diuretics.

NYHA classification II:

  • Left ventricular ejection fraction ≤30%,
  • Sinus rhythm,
  • QRS duration of ≥120–130 msec*, and
  • Patients treated with a stable pharmacological medical regimen prior to implant, such as an angiotensin-converting enzyme (ACE) inhibitor (or an angiotensin receptor blocker) and a beta blocker, digoxin, and/or diuretics

Biventricular pacemakers, with or without an accompanying implantable cardiac defibrillator (i.e., a combined biventricular pacemaker/ICD) are considered experimental, investigational and unproven as a treatment for patients with NYHA class I HF.

* The Federal Drug Administration (FDA)-labeled indication for the InSinc® Biventricular Pacing System is limited to patients with a QRS duration of > (greater than) 130msec, while the FDA labeled indication for the CONTAK CD® CRT-D System is limited to patients with a QRS > (greater than) 120msec.0

Inclusion of an intrathoracic fluid monitoring sensor as a component of an implanted biventricular pacemaker is considered experimental, investigational and unproven. 

Galectin-3 testing is considered experimental, investigational and unproven for all indications including but not limited to, selection of individuals for biventricular testing and to determine prognosis of heart failure.

Rationale

The FDA approval for the InSync® Biventricular Pacing System was based on the results of a multi-institutional randomized controlled trial.  The results are presented in the FDA Summary of Safety and Effectiveness, and reviewed below:

A total of 275 patients were enrolled and underwent implantation of the biventricular pacing system.  Of these, 171 patients were assigned to the control group in whom the device was not activated, and 174 were assigned to the treatment group in whom the device was activated.  The study was a double blind study.  Patients were followed up for six months.

The primary outcomes included exercise capacity, as measured by a six minute walk; quality of life, as measured by the Minnesota Living with HF Questionnaire; and functional status, as measured by change in NYHA classification.  Secondary outcomes focused on cardiodynamic measures, including oxygen consumption, and a variety of echocardiographic measures, including among others left ventricular ejection fraction, mitral regurgitation, and left ventricular end diastolic dimension.

Compared to the control group, the active treatment group reported significant improvements in all outcomes measured.  For example, in the treatment group, 68% reported an improvement in NYHA class compared to only 38% in the control group.  While an improvement in quality of life was reported by both groups, there was a statistically significant difference in the improvement in favor of the treatment group.  Similarly in the six minute hall walk, the increase in the treatment group is significantly greater than in the control group.  The treatment group also reported increases in a variety of cardiodynamic measures, including peak oxygen consumption, left ventricular end diastolic dimension, and left ventricular ejection fraction.  Finally, the InSync® Biventricular Pacing System met the primary safety objectives of the study, including implant success rate and freedom from device-related complications.  There was no difference in mortality after six months, although as a condition of FDA approval the manufacturer will perform a 12 month mortality assessment.  The above results are similar to a smaller, single-blind crossover trial of similarly selected patients.

2005 Update

Biventricular Pacemakers

A review of the peer-reviewed literature on MedLine from the period of January 2001-January 2005 reveled several randomized clinical trials that found beneficial outcomes to support the use of biventricular pacemakers.  In 2004, the results of the COMPANION study were published, which for the first time demonstrated that cardiac resynchronization was associated with an improvement in morbidity (i.e., hospitalizations) and mortality.  Previous studies have focused on the shorter term outcomes of exercise performance and quality of life.  There appears to be research interest in broadening the patient selection criteria to those with mild symptoms of HF.  However, there are no published clinical trials in this population of patients.

Combined automatic implantable cardiac defibrillators/biventricular pacemakers

In 2002, the FDA approved two new AICD devices with cardiac resynchronization therapy: Guidant’s CONTAK CD® CRT_D System, and Medtronic’s InSync® ICD Model 7272.  The FDA approval for the Guidant device was based on the results of two studies: the Contact CD Study and the Focused Confirmatory Study.  The recently published COMPANION study also used a Guidant device.  The Medtronic device received FDA approval based on the results of the InSync ICD Study, which has now been published in the peer-reviewed literature.  Both the Contact CD and InSync® ICD studies used selection criteria similar to the labeled indications, although NYHA Class II patients were included in both the Contact CD and the InSync® ICD study.  The results of the Contact CD® study did not demonstrate benefit in Class II patients; therefore the Focused Confirmatory Study that followed did not include Class II patients in its patient selection criteria.  The InSync® ICD study did not report on Class II patient outcomes.  Effectiveness end points of these studies included quality of life, as measured by the Minnesota Living with HF Questionnaire, NYHA classification, and six minute walk.  Conditions of approval for both studies include a three year evaluation of mortality, device performance, and adverse clinical events on 1,000 patients to assess the long-term safety and effectiveness of the devices.  In addition, Medtronic must address safety concerns of the Attain model 4189 lead used in the InSync® ICD device.  The COMPANION study examined cardiac resynchronization with and without an additional ICD.  Similar to the resynchronization group alone, there were improvements in morbidity and more marked improvement in mortality.

At the present time, based on the results of randomized studies, patients with class IV CHF are not considered appropriate candidates for an AICD, while patients with Class III CHF have been found to benefit.  However the use of biventricular pacemaker is intended to improve the ejection fraction of patients with Class IV congestive HF.  Therefore, some of these patients may improve to the point that they would be considered appropriate candidates for an ICD.  To avoid two surgical procedures, and the replacement of a biventricular pacemaker with a combined biventricular/AICD, the policy statement is revised to indicate that patients who would meet the criteria for a biventricular pacemaker would also be a candidate for a combined device.

Combined automatic implantable defibrillators/biventricular pacemakers/intrathoracic fluid monitors

Adding intrathoracic fluid status monitoring has been proposed as a more sensitive monitoring technique of the fluid status leading to prompt identification of impending HF, permitting early intervention and it is hoped, a decreased rate of hospitalization.  Medtronic, the manufacturer of the OptiVol™ Fluid Status Monitoring feature of the InSync® Sentry System, has announced several ongoing clinical trials of the device as follows:

The Fluid Accumulation Status Trial (FAST) is a prospective trial investigating the use of the algorithm used to analyze the collected bioimpedance data.  The early results of this trial have been presented in an abstract.  Data regarding fluid is collected, but not available to the physician.  Monitored outcomes include symptoms of fluid overload and diuretic use with correlation with bioimpedance measurements.  This is an ongoing study, and the abstract only reported the results of the first 44 patients followed up for a mean of 21.95 days.

The MIDHeFT study was a retrospective study designed to investigate the feasibility of predicting HF hospitalization based on intrathoracic bioimpedance and to validate impedance measurements as a surrogate measure of pulmonary congestion based on pulmonary wedge pressure.  The device that was used was a modified pacemaker and thus was not incorporated into a biventricular pacemaker/ICD.  A total of nine abstracts are derived from this study.  The most recent abstract included 33 patients.  Among the 10 patients with 26 hospitalizations for congestive HF during an 18 month follow-up, thoracic bioimpedance gradually decreased prior to the hospitalization, in many instances before the onset of clinical symptoms.

The SENSE-HF study is designed to prospectively evaluate the sensitivity of the OptiVol™ fluid trends feature in predicting HF hospitalizations with signs and/or symptoms of pulmonary congestion, and then to define OptiVol™ clinical guidelines for patient management.  The SENSE-HF study is being conducted in Europe.

The PARTNERS-HF study is a prospective, non-randomized post-market study to be conducted in up to 100 U.S. centers.  The goal of the trial is to characterize the relationship between a variety of diagnostic data derived from the implanted biventricular/ICD devices.  One component of this study will focus on the relationship between the fluid status monitoring diagnostic data and clinically relevant healthcare utilization.

2008 Update

Literature searches were performed to inform both a clinical update in populations where the literature was previously considered insufficient (atrial fibrillation [AF], NYHA class II HF, and narrow QRS [≤120 msec]), and whether other methods to detect mechanical dyssynchrony, in particular echocardiographic parameters, represent an improvement over the QRS duration for identifying potential responders to CRT (cardiac resynchronization therapy).  No changes to the ACC (American College of Cardiology) or AHA (American Heart Association) guidelines for CRT patient selection have been published since 2005.

Regarding atrial fibrillation, the 2005 guidelines suggest that patients with AF and complete AV block may benefit from CRT.  Adding to this, a prospective cohort of 162 patients indicated for CRT with permanent AF found that CRT without AV ablation was associated with less favorable outcomes than CRT with AV ablation.  Response to pacing was defined as 85% biventricular capture at two months and 42% of patients responded; non-responders were those who underwent ablation.  Evidence of reverse remodeling (reduction of left ventricular end systolic volume (LVESV) of ≥10% from baseline at six and 12 months) was three times more likely in ablated compared to non ablated patients.  Controlled trials addressing this issue are underway and are needed before recommending the “ablate and pace” pathway that would render many patients pacemaker dependent.  The results of a registry study of NYHA Class II patients receiving CRT suggested that CRT may have a beneficial effect on disease progression.  Compared to baseline, patients (n=188) experienced improved measures of reverse modeling and significant, but smaller gains (compared to NYHA classes III and IV) in clinical symptoms. Randomized controlled trials of CRT in class II HF are ongoing (REVERSE, Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction, and MADIT-CRT, Multicenter Automatic Defibrillator Implantation – Cardiac Resynchronization Trial).  While these promising indications await randomized trials, a trial of CRT in narrow QRS patients was published.  The RethinQ study (Resynchronization Therapy in Normal QRS Trial) enrolled 172 patients with narrow QRS duration (≤130 msec), with echocardiographic evidence (Doppler and M-mode) of dyssynchrony were randomized to receive a CRT device turned on or not, and followed for six months.  CRT-treated patients were not more likely to have improvement than non-CRT patients (46 vs. 41% met endpoint of improvement in exercise capacity [peak VO2]).  A subset of patients with QRS duration greater than or equal to 120–130 ms showed improvement (p=0.02), where patients with QRS less than 120 ms did not (p=0.45).  These studies do not change existing policy with respect to indications for use.

Regarding the question of assessing dyssynchrony by means other than QRS duration in order to better identify patients who might respond to CRT, no controlled trials were identified in MEDLINE (other than the aforementioned RethinQ study which enrolled narrow QRS duration patients on the basis of echocardiographic evidence of dyssynchrony).  Results of the PROSPECT study have not yet been published.  Several epidemiologic studies comparing methods of echocardiographic assessment in wide QRS duration patients were identified.  Two studies found that Doppler-TDI assessment was superior to M-mode assessment.  The first found that dyssynchrony was assessable 59% and 96% of the time using M-mode and Doppler-TDI techniques respectively.  Sensitivity and specificity (with respect to detecting a ≥1 grade improvement in NYHA class) were superior with Doppler-TDI (sensitivity 90%, specificity 82%) compared to M-mode (sensitivity 66%, specificity 50%) as well.  The second found 67% and 96% of patients assessable by M-mode and Doppler (lateral wall post-systolic displacement) echocardiography, respectively.  Additionally, Doppler was a multivariate predictor of response (improvement of LVESV of ≥15%) to CRT, where M-mode was not. 

An additional search for published studies addressing the ability of intrathoracic impedance monitoring to improve upon existing outcomes of therapy with standard CRT or CRT-ICD was conducted.  No controlled trials were found.  One epidemiologic study of 115 patients using Medtronic products (CRT or CRT-ICD) found that the currently recommended threshold for the alarm indicating decompensated HF was sensitive but not specific for symptoms.  After 45 alerts with greater than 50% false positives, the authors recommended doubling the threshold value to obtain a sensitivity of 60% and a specificity of 73%.  The trials mentioned above are awaited, with the exception of FAST, which was a hypothesis-generating study, and MID-HeFT on which the newly cited study was based.

2011 Update

A search of peer reviewed literature was conducted through September 2011.  A 2011 Blue Cross Blue Shield Association ( BCBSA) Technology Evaluation Center (TEC) Assessment “Cardiac Resynchronization Therapy for Mild Heart Failure” was prompted by a new clinical trial (Resynchronization-Defibrillation for Ambulatory Heart Failure Trial or “RAFT”) published in December 2010 that showed a mortality benefit for NYHA class II HF patients treated with a CRT device.

The RAFT trial randomized 1,798 patients with class II/III HF to ICD-CRT or ICD alone, with a mean follow-up 40 +/- 20 months. Unlike most previous trials, this trial did not confine enrollment to patients with sinus rhythm, but allowed patients with atrial arrhythmias to participate. However, the number of patients who were not in sinus rhythm was only 12.8% (229/1798).

This trial met all quality indicators on formal quality assessment and was given a “good” quality rating. The primary outcome, death from any cause or hospitalization for HF, was reduced in the ICD-CRT group compared to the ICD-alone group (33.2% vs. 40.3%, p<0.001). There were significant reductions in both individual components of the primary outcome, overall mortality (20.8% vs. 26.1%, p=0.003) and hospitalizations (19.5% vs. 26.1%, p<0.001). When restricted to patients with NYHA class II HF, the improvements in the outcomes of mortality and hospitalizations remained significant. The mortality for class II patients in the ICD-CRT group was 15.5% versus 21.1% in the ICD-alone group (hazard ratio [HR] 0.71, 95% confidence interval [CI]: 0.56-0.91; p<0.006). Hospitalizations for class II patients occurred in 16.2% of patients in the ICD-CRT group compared to 21.1% in the ICD-alone group (HR 0.70, 95% CI: 0.55-0.89, p<0.003).

Subgroup analyses from the RAFT trial reported that female gender, QRS duration ≥150msec, LV ejection fraction <20% and QRS morphologic features were predictive of benefit. Of these factors, the QRS duration was the strongest factor. Patients with a QRS duration ≥150msec had a relative risk (RR) for the primary outcome of approximately 0.50, compared with a relative risk (RR) of approximately 1.0 for patients with a QRS duration <150msec (p=0.003 for difference between RR’s). There was a trend for greater improvement in patients with sinus rhythm compared to patients with atrial arrhythmias, but this difference did not reach statistical significance.

With the addition of the RAFT trial, there are now four randomized, controlled trials of CRT use in patients with mild HF. These four trials report benefits on some outcomes, but not on others. The most important outcomes of this treatment are mortality, functional status and quality of life. A mortality benefit was reported by one of the four trials, the RAFT trial. There was a fairly large difference in overall mortality, with a relative risk reduction of 20.3% and an absolute risk reduction of 5.3%.  This represents a number needed to treat of 19 over a 40-month period.

None of the other three available trials showed a mortality difference.  While two of the trials were underpowered to detect differences in mortality, the MADIT-CRT was approximately the same size as the RAFT trial and did not show any improvement in mortality.  Patients in the RAFT trial were more severely ill compared to MADIT-CRT, and the baseline annualized mortality was higher in the control group for RAFT compared to MADIT-CRT (7.9% per year vs. 3.3% per year).  It is possible that the sicker patient population and longer follow-up in RAFT accounted for the mortality difference.

Hospitalizations for HF showed consistent improvements across studies. Three of the four trials reported on hospitalizations, with all three reporting a reduction for the CRT group. For the outcomes of functional status and quality of life, two trials reported these outcomes, with neither reporting improvements for the CRT group.  Furthermore, the evidence does not demonstrate benefit on progression of clinical HF, although this outcome measure was only evaluated in one of the three trials.

A meta-analysis of 25 trials of CRT was published in February 2011 by Al-Majed et al. This study focused on the analysis of trials with class I/II HF patients, identifying six trials treating 4572 patients.  There was a significant mortality benefit associated with CRT on combined analysis (six trials, 4572 participants; RR 0.83 [95% CI: 0.72 to 0.96]).  This mortality benefit was driven largely by the results of the RAFT trial, which had the most number of events and was given the greatest weight in combined analysis.  There was also a significant reduction in HF hospitalizations associated with CRT use (four trials, 4349 participants; RR, 0.71 [CI: 0.57 to 0.87]).  There were no significant benefits reported for quality of life, functional status, or progression to more advanced stages of HF.

2012 Update - Galectin-3

Tang et al (2011) stated that increased galectin-3 levels are associated with poor long-term survival in HF.  (31)  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.

In a randomized clinical trial Lopez-Andrès et al measured serum levels of ECCM biomarkers [galectin-3 (Gal-3), N-terminal propeptides of type I and III procollagens (PINP and PIIINP), type I collagen telopeptide (ICTP), and matrix metalloproteinase 1 (MMP-1)] in 260 patients in a sub study of CARE-HF. (32) This trial which evaluated the effects of CRT in patients with left ventricular systolic dysfunction and cardiac dyssynchrony. ECCM biomarkers did not change throughout the 18-month follow-up period. In age- and gender-adjusted analyses, Gal-3 and PIIINP were associated with death or HF hospitalization. In a further multivariate model, Gal-3 >30 ng/mL was associated [OR (95% CI):2.98 (1.43-6.22), P = 0.004] with death or HF hospitalization, along with left ventricular end-systolic volume >200 mL [3.42 (OR: 1.65-7.10), P = 0.001]. The outcome death or left ventricular ejection fraction (LVEF) ≤35% was associated with MMP-1 [≤3 ng/mL: 3.04 (1.37-6.71), P = 0.006]. No significant interaction was observed between the tested biomarkers and the treatment group.  CONCLUSIONS:  Increased Gal-3 and PIIINP, and low MMP-1 are associated with adverse long-term cardiovascular outcomes but did not predict response to CRT. CRT did not favorably affect serum concentrations of ECCM markers."

Felker et al conducted a randomized, controlled trial of exercise training in patients with chronic heart failure caused by left ventricular systolic dysfunction (HF-ACTION). (33) Galectin-3 was assessed at baseline in this cohort of 895 HF-ACTION subjects with stored plasma samples available. The association between galectin-3 and clinical outcomes was assessed using a series of Cox proportional hazards models. Higher galectin-3 levels were associated with other measures of heart failure severity, including higher New York Heart Association class, lower systolic blood pressure, higher creatinine, higher amino-terminal proB-type natriuretic peptide (NTproBNP), and lower maximal oxygen consumption. In unadjusted analysis, there was a significant association between elevated galectin-3 levels and hospitalization-free survival (unadjusted hazard ratio, 1.14 per 3-ng/mL increase in galectin-3; P<0.0001). In multivariable modeling, the prognostic impact of galectin-3 was significantly attenuated by the inclusion of other known predictors, and galectin-3 was no longer a significant predictor after the inclusion of NTproBNP.  The authors note “Galectin-3 is elevated in ambulatory heart failure patients and is associated with poor functional capacity and other known measures of heart failure severity. In univariate analysis, galectin-3 was significantly predictive of long-term outcomes, but this association did not persist after adjustment for other predictors, especially NTproBNP.”

De Boer et al. studied 592 heart failure (HF) patients who had been hospitalized for HF and followed them for 18 months.(34)   The study’s primary end-point was a composite of all-cause mortality and HF hospitalization.  The results demonstrated that a doubling of galectin-3 levels was associated with a hazard ratio (HR) of 1.97 (1.62 – 2.42) for the primary outcome. After correction for age, gender, BNP, eGFR, and diabetes the HR was 1.38.  Galectin-3 levels were correlated with higher IL-6 and CRP levels. Changes of galectin-3 levels after 6 months did not add prognostic information to the base-line value; however, combining plasma galectin-3 and BNP levels increased prognostic value over either biomarker alone. The predictive value of galectin-3 was stronger in patients with preserved LVEF compared to patients with reduced LVEF.  The authors note: “We realize that the observation that galectin-3 may be particularly important in patients with HF with preserved ejection fraction (HFPEF) is limited by the small number of patients. The echocardiographic evaluation was not standardized to a protocol, and we have no other echo data than LVEF. Furthermore, new guidelines question the cut-off point of 40% to distinguish between HFPEF and HF with reduced ejection fraction (HFREF).  These findings should be regarded as exploratory and be confirmed in independent cohorts of patients with HF due to HFPEF. Finally, this analysis is underpowered to make decisive conclusions on the secondary end-points.  In this to date largest HF cohort, we confirm that Galectin-3 is a strong and independent prognostic factor. Inflammatory markers are positively correlated to galectin-3 levels. Repeated galectin-3 sampling has no incremental value over base-line sampling alone.  Finally, galectin-3 might be a promising biomarker in patients with HFPE conclude that  Galectin-3 is an independent marker for outcome in HF and appears to be particularly useful in HF patients with preserved LVEF.

Coding

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy.  They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers.  Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps. 

ICD-9 Codes

00.50, 00.51, 00.52, 00.53, 00.54, 428.00 – 429.00  

ICD-10 Codes
I50.20-I50.9, 02H63MA, 02H73MA, 02HK3MA, 02HL3MA, 02H63ME, 02H73ME, 02HK3ME, 02HL3ME, 0JH63P0, 0JH60P0, 0JH63P1, 0JH60P1, 0JH63P2, 0JH60P2, 0JH63P3, 0JH60P3, 0JH63P4, 0JH60P4, 0JH63P5, 0JH60P5, 0JH63PA, 0JH60PA, 0JH63PY, 0JH60PY, 0JH83P0, 0JH80P0, 0JH83P1, 0JH80P1, 0JH83P2, 0JH80P2, 0JH83P3, 0JH80P3, 0JH83P4, 0JH80P4, 0JH83P5, 0JH80P5, 0JH83PA, 0JH80PA, 0JH83PY, 0JH80PY            
Procedural Codes: 33211, 33213, 33224, 33225, 82777, 93640, 93641, 93642
References
  1. FDA Summary of Safety and Effectiveness for InSync® Biventricular Pacing System: www.fda.gov .
  2. FDA Summary of Safety and Effectiveness for CONTAK CD CRT-D: http://www.fda.gov .
  3. FDA Summary of Safety and Effectiveness for InSync ICD: http://www.fda.gov .
  4. Cazeau, S., Leclercq, C., et al.  Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay.  New England Journal of Medicine (May 2001) 334(12):873-80.
  5. Linde, C., Leclercq, C., et al.  Long-term benefits of biventricular pacing in congestive heart failure; results from the Multisite Stimulation in cardiomyopathy (MUSTIC) study.  Journal of the American College of Cardiology (2002) 40(1):111-8.
  6. Abraham, W.T., Fisher, W.G., et al.  Cardiac resynchronization in chronic heart failure.  New England Journal of Medicine (2002) 346(24):1845-53.
  7. Garrigue, S., Bordacher, P., et al.  Comparison of permanent left ventricular and biventricular pacing in patients with heart failure and chronic atrial fibrillation; prospective hemodynamic study.  Heart (2002) 87(6):529-34.
  8. Kalinchak, D.M., Schoenfeld, M.H., et al.  Cardiac resynchronization: a brief synopsis part 1: patient selection and results from clinical trials. Journal of Interventional Cardiac Electrophysiology (2003) 9(2):155-61.
  9. Young, J.B., Abraham, W.T., et al.  Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ACD trial.  Journal of the American Medical Association (2003) 289(20):2685-94.
  10. Foreman, B., Fishel, R.S., et al.  Intra-thoracic impedance: A surrogate measure of thoracic fluid – Fluid Accumulation Status Trial (FAST).  Journal of Cardiac Failure (2004) 10(suppl): abstract 251.
  11. Yu, C.M., Wang, L., at al.  Impedance-based prediction of CHF admission precedes symptoms in heart failure patients.  Pacing and Clinical Electrophysiology (2004) 1(suppl):S213.
  12. Bristow, M.R., Saxon, L.A., et al.  Cardiac resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. New England Journal of Medicine (2004) 350(21):2140-50.
  13. McAlister FA, Ezekowitz JA, Wiebe N et al. Systematic review: cardiac resynchronization in patients with symptomatic heart failure. Ann Intern Med 2004; 141(5):381-90.
  14. Strickberger, S.A., Conti, J., et al.  Patient selection for cardiac resynchronization therapy: from the Council on Clinical Cardiology Subcommittee on Electrocardiography and Arrhythmias and the Quality of Care and Outcomes Research Interdisciplinary Working Group, in Collaboration with the Heart Rhythm Society. Circulation (2005) 111(16):2146-50.
  15. Yu, C.M., Abraham, W.T., et al. Predictors of response to cardiac resynchronization therapy (PROSPECT)--study design. American Heart Journal (2005) 149(4):600-5.
  16. Gasparini, M., Auricchio, A., et al. Four-year efficacy of cardiac resynchronization therapy on exercise tolerance and disease progression: the importance of performing atrioventricular junction ablation in patients with atrial fibrillation. Journal of American College of Cardiology (2006) 48(4):734-43.
  17. Landolina, M., Lunati, M., et al. Comparison of the effects of cardiac resynchronization therapy in patients with class II versus class III and IV heart failure (from the InSync/InSync ICD Italian Registry). American Journal of Cardiology (2007) 100(6):1007-12.
  18. Beshai, J.F., Grimm, R.A., et al. Cardiac-resynchronization therapy in heart failure with narrow QRS complexes. New England Journal of Medicine (2007) 357(24): 2461-71.
  19. Bleeker, G.B., Schalij, M.J., et al. Relative merits of M-mode echocardiography and tissue Doppler imaging for prediction of response to cardiac resynchronization therapy in patients with heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. American Journal of Cardiology (2007) 99(1):68-74.
  20. Sassone, B., Capecchi, A., et al. Value of baseline left lateral wall postsystolic displacement assessed by M-mode to predict reverse remodeling by cardiac resynchronization therapy. American Journal of Cardiology (2007) 100(3):470-5.
  21. Ypenburg, C., Bax, J.J., et al. Intrathoracic impedance monitoring to predict decompensated heart failure. American Journal of Cardiology (2007) 99(4):554-7.
  22. Leclercq C, Gadler F, Kranig W et al. A randomized comparison of triple-site versus dual-site ventricular stimulation in patients with congestive heart failure.  J Am Coll Cardiol 2008; 51(15):1455-62.
  23. Chung ES, Leon AR, Tavazzi L et al. Results of the predictors of response to CRT (PROSPECT) trial. Circulation 2008; 117(20):2567-9.
  24. Perego GB, Landolina M, Vergara G et al. Implantable CRT device diagnostics identify patients with increased risk for heart failure hospitalization.  J Interv Card Electrophysiol 2008; 23(3):235-42.
  25. ClinicalTrials.gov web site.  PARTNERS HF: Program to Access and Review Trending Information and Evaluate Correlation to Symptoms in Patients With Heart Failure. Available online at: http://clinicaltrials.gov/ct2/show/results/NCT00279955 .  Last accessed February 2010.
  26. Tang AS, Wells GA, Talajic M et al; Resynchronization-Defibrillation for Ambulatory Heart Failure Trial Investigators.  Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med 2010; 363(25):2385-95.
  27. Al-Majed NS, McAlister FA, Bakal JA et al. Meta-analysis: cardiac resynchronization therapy for patients with less symptomatic heart failure.  Ann Intern Med 2011.
  28. Biventricular Pacemakers for the Treatment of Congestive Heart Failure.  Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2011 April) Medicine 2.02.10.
  29. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC).  Cardiac resynchronization therapy for mild congestive heart failure. TEC Assessments July 2011, Volume 26, No. 1.
  30. Tang AS, Wells GA, Talajic M, et al; Resynchronization-Defibrillation for Ambulatory Heart Failure Trial Investigators. Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med. 2010; 363(25):2385-2395.
  31. Lopez-Andrès, N, Rossignol, et al.   Association of galectin-3 and fibrosis markers with long-term cardiovascular outcomes in patients with heart failure, left ventricular dysfunction, and dyssynchrony: insights from the CARE-HF (Cardiac Resynchronization in Heart Failure) trial. Eur J Heart Fail. 2012 Jan; 14(1):74-81.
  32. Felker GM, Fiuzat M, et al.  Galectin-3 in ambulatory patients with heart failure: results from the HF-ACTION study. Circ Heart Fail. 2012 Jan; 5(1):72-8.
  33. De Boer, LOK D., et al.  Predictive value of plasma galectin-3 levels in heart failure with reduced and preserved ejection fraction – de Boer RA, et al Annals of Medicine, 2011; 43: 60–68
History
January 2013 

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