This document addresses biventricular cardiac pacing to deliver cardiac resynchronization therapy (CRT) to alleviate the symptoms of moderate to severe congestive heart failure associated with left ventricular dyssynchrony.  It also addresses a hybrid device that combines CRT with an implantable cardioverter defibrillator (ICD).  In the combined device (CRT/ICD), the CRT component promotes coordinated contraction of both ventricles, while the ICD portion detects dangerous arrhythmias and shocks the heart back into a normal rhythm.

Medically Necessary:

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

1. NYHA functional Class III or ambulatory Class IV symptoms, secondary to heart failure who remain symptomatic despite recommended, optimal medical therapy;* and
2. Who have cardiac dyssynchrony, (which is currently defined as a QRS duration greater than 120 ms); and
3. Left ventricular ejection fraction (LVEF) less than or equal to 35%; and
4. Are in sinus rhythm. 

The use of an FDA-approved ICD, in combination with cardiac resynchronization therapy (CRT/ICD), is considered medically necessary when the criteria listed above for CRT therapy AND the criteria within SURG.00033  Implantable Cardioverter-Defibrillator (ICD) are met.

*See definition section for further information on NYHA functional class.  Optimal drug therapy may include use of the following medications either individually or in combination, unless contraindicated: angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, beta-blockers, digoxin, diuretics, and aldosterone antagonists, when appropriate.

Investigational and Not Medically Necessary:

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

There are a number of FDA approved biventricular pacemakers designed to provide cardiac resynchronization therapy (CRT).  Patients meeting selection criteria for CRT therapy frequently are also considered candidates for an implantable cardiac defibrillator (ICD).  These patients may receive combined therapy with a combined CRT/ICD device.  

The InSync^® Biventricular Pacing System (Medtronic, Minneapolis, MN) is an example of a biventricular pacemaker.  Its FDA labeling states that it is indicated for the treatment of patients with New York Heart Association (NYHA) functional class III or IV heart failure, who remain symptomatic despite stable, optimal medical therapy, who additionally have a QRS duration of greater than or equal to 130 milliseconds, and a left ventricular ejection fraction (LVEF) of less than or equal to 35%.  The FDA approval was based on data collected in the Multi-Center InSync Randomized Clinical Evaluation (MIRACLE) trial.  In this trial, all patients received a CRT device, but patients were then randomized to either active (device-on) or inactive (device-off) groups.  Overall, 68% of those in the active treatment group versus 35% of those in the inactive treatment group, demonstrated improvement in primary endpoints, including quality of life, 6-minute hall walk, and NYHA functional class.  The active treatment group also reported increases in a variety of cardiodynamic measures, including peak oxygen consumption, LV end diastolic dimension, and left ventricular ejection fraction (Abraham, 2002).

While the MIRACLE trial showed symptomatic improvement and improvement in cardiac function, the subsequent Cardiac Resynchronization – Heart Failure (CARE-HF) trial focused on the final health outcomes of morbidity and mortality (Cleland 2005).  A total of 813 patients with left ventricular systolic dysfunction, cardiac dyssynchrony, and symptomatic heart failure were randomized to receive either CRT or standard medical care and followed for a mean of 29.4 months.  The primary endpoint, a composite of death from any cause or an unplanned hospitalization for a major cardiovascular event, was reached by 159 patients in the CRT group, as compared with 224 patients in the medical therapy group (39% vs. 55%; hazard ratio 0.63; 95% CI, 0.51 to 0.77; p < 0.001).  The authors concluded that CRT substantially reduced the risk of complications and death among patients with moderate or severe heart failure, due to left ventricular systolic dysfunction and cardiac dyssynchrony.  Cleland and colleagues published another article in 2009 regarding the effects of CRT on long-term quality of life with data analysis taken from the CARE-HF trial.  Quality of life (QoL) was measured at baseline and 3 months using generic European QoL-5 Dimensions and disease-specific (Minnesota Living with Heart Failure) questionnaires and at 18 months and study-end using the latter instrument.  Median follow-up was 29.6 (interquartile range 23.6-34.6) months. The authors concluded that CRT improves long-term QoL and survival in patients with moderate to severe heart failure.  The effects appear sustained, and therefore, the gain in quality of life with CRT should be even greater during longer term follow-up (Cleland, 2009).

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

Delnoy and colleagues (2007) reported on a prospective observational study enrolling 263 patients undergoing CRT; 96 of these patients (37%) had coexisting AF and 167 (67%) were in normal sinus rhythm.  Clinical outcomes, hospitalization rates and left ventricular function were evaluated at 3 and 12 months.  All outcomes improved similarly in both groups.  The authors concluded that chronic AF should not be considered a contraindication for CRT. 

Upadhyay and colleagues (2008) conducted a meta-analysis of prospective cohort studies of CRT in patients with AF and sinus rhythm.  A total of 5 studies enrolling 1,164 patients met the study selection criteria.  The authors concluded that both groups benefited from CRT.  The NYHA classification improved similarly in both groups.  While the patients in sinus rhythm reported greater improvement in the 6 minute walk test, compared to those with AF, the AF group had greater improvement in the left ventricular ejection fraction.

In 2008, the American College of Cardiology, American Heart Association and the Heart Rhythm Society (ACC/AHA/HRS) published updated guideline recommendations for Device-Based Therapy of Cardiac Rhythm Abnormalities (Epstein, et al., 2008).  These guidelines noted that clinical trials of CRT have almost exclusively focused on patients in sinus rhythm, but that "limited prospective experience" suggests that patients with AF can also benefit from CRT.  These guidelines state that CRT is "indicated" for patients in sinus rhythm with chronic heart failure, (i.e., NYHA functional Class III or ambulatory Class IV symptoms) and dyssynchrony (Class I recommendation), while CRT is considered "reasonable" for the same patients with AF (Class IIa recommendation).  This Class IIa recommendation for AF was based on a single randomized controlled trial studying the effects of CRT in heart failure patients with chronic AF, within which a 42% drop-out rate was observed, and an intention-to-treat analysis showed no significant difference between those receiving right ventricular and biventricular pacing. The authors caution that, "Further studies are required and that this treatment should not yet be recommended for this group of patients" (Leclercq, 2002).  The ACC/AHA/HRS guideline adds, "…Limited prospective experience among patients with permanent AF suggests that benefit may result from biventricular pacing when the QRS is prolonged, although it may be most evident in those patients in whom AV nodal ablation has been performed, such that right ventricular (RV) pacing is obligate" (Epstein, 2008).

The ACC/AHA/HRS guidelines also note that there is insufficient evidence regarding CRT in other patients, including those with right bundle-branch block or other conduction abnormalities.  Despite these encouraging reports, the data regarding CRT in patients with atrial fibrillation remains preliminary.  Only a small number of patients have been enrolled in controlled trials.  Additional updated specialty society guidelines concur with the ACC/AHA/HRS recommendations described above (Jessup, 2009; Hunt, 2009).

Ongoing studies are examining the hypothesis that early use of CRT before the development of Class III symptoms may prevent or reverse remodeling, caused by prolonged ventricular conduction, thus preventing the progression of heart failure.  The REVERSE trial (REsynchronization reVErse Remodeling in Systolic left vEntricular dysfunction) enrolled 610 patients with NYHA class I or II heart failure and a QRS interval greater than or equal to 120 ms and an LVEF  of less than 40% (Linde, 2008).  All patients received a CRT device with or without an ICD.  Patients were then randomized to active CRT (device-on) or control CRT (device-off) for 12 months.  The primary endpoint was a heart failure clinical composite score consisting of any incidence of death, hospitalization due to worsening heart failure or worsening symptoms.  Patients were classified as "worsened" if any of the above criteria were met.  Patients were classified as "improved" if there was an improvement in the NYHA class score or an improvement in symptoms.  The remaining patients were classified as "unchanged."  This composite outcome was chosen because the mildly symptomatic nature of the patients made it likely that the event rate of any individual parameter would be low, thus requiring a more sensitive composite outcome to detect a treatment effect. 

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

Although the anticipated completion date for the REVERSE trial is November 2011, others have published information regarding the long-term effects of CRT in the European cohort of patients enrolled in the REVERSE study.  A total of 262 recipients (with QRS > or = 120 ms and LV ejection fraction < or = 40%) were randomly assigned to either CRT or CRT-ICD and were designated either to the active arm (CRT ON; n = 180) or the control arm (CRT OFF; n = 82) for 24 months.  Mean baseline LVEF was 28.0%.  All 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 left ventricular end-systolic volume index (LVESVi).  In the active treatment group, 19% of patients were worsened versus 34% in the control group (p = 0.01).  The LVESVi decreased by a mean of 27.5 +/- 31.8 ml/m(2) in the active treatment group versus 2.7 +/- 25.8 ml/m(2) in the control group (p < 0.0001).  Time to first hospital stay (for heart failure) 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 observations suggest that CRT prevents the progression of disease in patients with asymptomatic or mildly symptomatic LV dysfunction (Daubert, 2009).

Other ongoing trials are also addressing this issue, and are powered to measure morbidity and mortality rates.  The RAFT trial (Resynchronization/Defibrillation for Ambulatory Heart Failure Trial) is a randomized controlled trial designed to determine if the addition of CRT to optimal pharmacological therapy and ICD is effective in reducing mortality and morbidity in patients with mild to moderate heart failure symptoms.  The target accrual is 1800 patients who will be followed for a minimum of 18 months (NLM Identifier: NCT00251251; 2008).  The RAFT trial has an anticipated completion date of September 2010.  The MADIT-CRT is a randomized controlled trial of patients with NYHA class I and II symptoms that is similarly designed to determine if CRT combined with an ICD will reduce the risk of mortality and heart failure (HF) events.  A total of 1820 patients have been enrolled (NLM Identifier: NCT00180271; 2008).  Results of the MADIT-CRT were reported in 2009 as follows:  during an average follow-up of 2.4 years, the primary end point occurred in 187 of 1089 patients in the CRT-ICD group (17.2%) and 185 of 731 patients in the ICD-only group (25.3%) (hazard ratio in the CRT-ICD group, 0.66; 95% confidence interval [CI], 0.52 to 0.84; P=0.001). The benefit did not differ significantly between patients with ischemic cardiomyopathy and those with nonischemic cardiomyopathy.  The superiority of CRT was driven by a 41% reduction in the risk of heart-failure events, a finding that was evident primarily in a prespecified subgroup of patients with a QRS duration of 150 msec or more.  CRT was associated with a significant reduction in left ventricular volumes and improvement in the ejection fraction.  There was no significant difference between the two groups in the overall risk of death, with a 3% annual mortality rate in each treatment group.  Serious adverse events were infrequent in the two groups.  The authors concluded that CRT combined with ICD decreased the risk of heart-failure events in relatively asymptomatic patients with a low ejection fraction and wide QRS complex (Moss, 2009).   

In May of 2002, the FDA approved the first hybrid device that combines CRT with an implantable cardioverter defibrillator (ICD), the CONTAK CD^® (Guidant Corp., St. Paul, MN).  The device is indicated for patients at high-risk of sudden death due to ventricular arrhythmias and who have moderate to severe heart failure (NYHA Class III/IV), including left ventricular dysfunction (LVEF less than or equal to 35%) and QRS duration greater than or equal to 120 milliseconds, and who remain symptomatic despite stable, optimal heart failure drug therapy.  In July of 2002, the FDA approved a second device, the InSync^® ICD/CRT (Medtronic) with similar criteria including a QRS duration equal to or greater than 130 milliseconds.  In June of 2004, the FDA approved additional devices, the Epic^™ HF and Atlas^® + HF Dual Chamber Implantable Cardioverter Defibrillator Systems with cardiac resynchronization therapy (St Jude Medical^® Inc., Sunnyvale, CA) for ventricular antitachycardia pacing and ventricular defibrillation for automated treatment of life-threatening ventricular arrhythmias.  This device has similar criteria to the others, including a QRS duration equal to or greater than 150 milliseconds.

In September of 2004, the FDA expanded the indications for the CONTAK^® RENEWAL^™ combined CRT/ICD devices to include ischemic and nonischemic heart failure patients with LVEF ≤ 35% and a QRS duration ≥ 120 milliseconds, who meet standards for New York Heart Association Class III/IV functional status and remain symptomatic despite optimal medical management.  The FDA decision (Sept. 2004) to expand the indications and usage labeling was based on data from the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial. 

The COMPANION trial was a multicenter, randomized, controlled trial to investigate whether prophylactic cardiac-resynchronization therapy with a biventricular pacemaker (CRT) or a pacemaker-defibrillator (CRT/ICD) would reduce the risk of death and hospitalization among patients with advanced chronic heart failure and intra-ventricular conduction delays (Bristow, 2004).  A total of 1,520 patients who had advanced heart failure (NYHA class III or IV), due to ischemic or non-ischemic cardiomyopathies and a QRS interval of at least 120 msec, were randomly assigned in a 1:2:2 ratio to receive optimal pharmacologic therapy, (e.g., diuretics, angiotensin-converting enzyme inhibitors, beta-blockers and spironolactone) alone or in combination with CRT or CRT/ICD.  The primary composite endpoint was the time-to-death from, or hospitalization for, any cause.  The results showed that compared to optimal pharmacological therapy alone, CRT with a pacemaker decreased the risk of the primary endpoint (hazard ratio, 0.81; p=0.014), as did CRT/ICD (hazard ratio, 0.80; p=0.01).  The risk of the combined endpoint of death from, or hospitalization for, heart failure was reduced by 34% in the pacemaker group (p<0.002) and by 40% in the pacemaker-defibrillator group (p<0.001 for the comparison with the pharmacological therapy group).  CRT therapy reduced the risk of the secondary endpoint of death from any cause by 24% (p=0.059), and CRT/ICD therapy reduced the risk by 36% (p=0.003).  The researchers concluded that in patients with advanced heart failure and a prolonged QRS interval, CRT decreases the combined risk of death from any cause or of first hospitalization and, when combined with an implantable defibrillator, significantly reduces mortality.

Description of Relevant Disease

Approximately 5 million Americans are currently diagnosed with congestive heart failure, and more than 500,000 new cases are diagnosed each year. Patients with CHF often have intra-ventricular conduction delays, evidenced by a wide QRS interval on electrocardiogram (EKG), which can worsen left ventricular systolic dysfunction through asynchronous ventricular contraction. There is inadequate filling of the left ventricle, as well as a backflow of blood into the left atrium, both resulting in decreased cardiac output and increased symptoms for the patient. Medical therapy for CHF includes a combination of diuretics, digoxin, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), beta-blockers and aldosterone antagonists. Some patients may remain symptomatic, despite medical therapy. Current recommendations advise the optimization of pharmacological therapy before considering cardiac resynchronization therapy.

A biventricular pacemaker is designed to resynchronize the pumping action of the left ventricle. This type of pacing is called cardiac resynchronization therapy (CRT). Standard pacemakers pace the right side of the heart. In contrast, biventricular pacemakers pace both the right and left sides of the heart enabling the left ventricle to pump blood more efficiently. Biventricular pacemakers use three leads (one in the right atrium, one in each ventricle) and have been investigated as a technique to coordinate the contraction of the ventricles, thus, improving the hemodynamic status of the patient.

Biventricular pacemakers are manufactured as "stand alone" devices (CRT) or with a built-in implantable cardioverter defibrillator (CRT/ICD). The combination devices provide treatment of ventricular dyssynchrony and ventricular tachyarrhythmias associated with sudden cardiac death, (e.g., ventricular tachycardia and ventricular fibrillation).

Arrhythmia: irregular heartbeat; can be either atrial or ventricular arrhythmias depending on which part of the heart they originate from

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

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

Left Ventricular Ejection Fraction (LVEF): the measurement of the heart's ability to pump blood through the body; normal LVEF readings would be in the 58-70% range

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

New York Heart Association (NYHA) definitions:

The NYHA classification of heart failure is a 4-tier system that categorizes patients based on subjective impression of the degree of functional compromise; the four NYHA functional classes are as follows:

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

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

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

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

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

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

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

When services may be Medically Necessary when criteria are met:

When services are Investigational and Not Medically Necessary:
For the procedure codes listed above, when the criteria are not met, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Peer Reviewed Publications:

1. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure: The Multicenter InSync Randomized Clinical Evaluation (MIRACLE). N Engl J Med. 2002; 346(24):1845-1853.
2. Abraham WT, Young JB, Leon AR, et al. Effects of cardiac resynchronization on disease progression in patients with left ventricular systolic dysfunction and indication for an implantable cardioverter-defibrillator and mildly symptomatic heart failure.  Circ. 2004; 110:2864-2868.
3. Anand IS, Carson P, Galle E, et al. Cardiac resynchronization therapy reduces the risk of hospitalizations in patients with advanced heart failure: results from the Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) trial. Circulation. 2009; 119(7):969-977.
4. Auricchio A, Metra M, Gasparini M, et al. Multicenter Longitudinal Observational Study (MILOS) Group. Long-term survival of patients with heart failure and ventricular conduction delay treated with cardiac resynchronization therapy. Am J Cardiol. 2007; 99(2):232-238.
5. Beshai JF, Grimm RA, Nagueh SF, et al. Cardiac resynchronization therapy in heart failure with narrow QRS complexes.  N Engl J Med. 2007; 357(24):2461-2471.
6. Bleeker GB, Schalij MJ, Boersma E, 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. Am J Cardiol. 2007; 99(1):68-74.
7. Bleeker GB, Holman ER, Steendijk P, et al. Cardiac resynchronization therapy in patients with a narrow QRS complex. J Am Coll Cardiol. 2006; 48(11):2243-2250.
8. Bradley DJ, Bradley EA, Baughman KL, et al. Cardiac resynchronization and death from progressive heart failure: a meta-analysis of randomized controlled trials. JAMA. 2003; 289(6):730-740.
9. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004; 350(21):2140-2150.
10. Cazeau S, Leclercq C, Lavergne T et a.  Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay.  N Engl J Med 2001; 344:873-880.
11. Cleland JGF, Daubert JC, Erdmann E, et al. for the Cardiac Resynchronization – Heart Failure (CARE-HF) Study Investigators. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005; 352(15):1539-1549.
12. Cleland J, Freemantle N, Ghio S, et al.  Predicting the long-term effects of cardiac resynchronization therapy on mortality from baseline variables and the early response: a report from the CARE-HF (Cardiac  Resynchronization in Heart Failure) Trial.  J Am Coll Cardiol. 2008; 52(6):438-445.
13. Cleland JG, Calvert MJ, Verboven Y, Freemantle N. Effects of cardiac resynchronization therapy on long-term quality of life: an analysis from the Cardiac Resynchronization-Heart Failure (CARE-HF) study. Am Heart J. 2009; 157(3):457-466.
14. Daubert C, Gold MR, Abraham WT, et al. Prevention of disease progression by cardiac resynchronization therapy in patients with asymptomatic or mildly symptomatic left ventricular dysfunction: insights from the European cohort of the REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) trial. J Am Coll Cardiol. 2009; 54(20):1837-1846.
15. David Investigators. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the dual chamber and VVI implantable defibrillator (DAVID) trial. JAMA. 2002; 288(24):3115.
16. Delnoy PP, Ottervanger JP, Luttikhuis HO, et al. Comparison of usefulness of cardiac resynchronization therapy in patients with atrial fibrillation and heart failure versus patients with sinus rhythm and heart failure. Am J Cardiol. 2007; 99(9):1252-1257.
17. Doshi RN, Daoud EG, Fellows C, PAVE Study Group, et al. Left ventricular-based cardiac stimulation post AV nodal ablation evaluation (the PAVE study). J Cardiovasc Electrophysiol. 2005; 16(11):1160-1165.
18. Garrigue S, Bordachar P, Reuter S. et al. Comparison of permanent left ventricular and biventricular pacing in patients with heart failure and chronic atrial fibrillation: prospective haemodynamic study. Heart. 2002; 87(6):529-534.
19. Gasparini M, Auricchio A, Regoli F, 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. J Am Coll Cardiol. 2006; 48(4):734-743.
20. Kadish A, Dyer A, Daubert JP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med. 2004; 350(21):2151-2158.
21. Landolina M, Lunati M, Gasparini 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 ICD Italian Registry). Am J Cardiol. 2007; 100(6):1007-1012.
22. Leclercq C, Walker S, Linde C, et al. Comparative effects of permanent biventricular and right-univentricular pacing in heart failure patients with chronic atrial fibrillation. Eur Heart J. 2002; 23:1780-1787.
23. Leon AR, Greenberg JM, Kanuru N, et al. Cardiac resynchronization in patients with congestive heart failure and chronic atrial fibrillation: effect of upgrading to biventricular pacing after chronic right ventricular pacing.  J Am Coll Cardiol. 2002; 39:1258-1263.
24. Linde C, Abraham WT, Gold MR et al.  Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms.  J Am Coll Cardiol. 2008; 52:1834-1843.
25. Linde C, Braunschweig F, Gadler F, et al. Long-term improvements in quality of life by biventricular pacing in patients with chronic heart failure; results from the Multisite Stimulation in cardiomyopathy (MUSTIC) study (MUSTIC). Am J Cardiol. 2003; 91(9):1090-1095.
26. Lindenfeld J, Feldman AM, Saxon L, et al. Effects of cardiac resynchronization therapy with or without a defibrillator on survival and hospitalizations in patients with New York Heart Association class IV heart failure. Circulation. 2007; 115(2):204-212.
27. McAlister FA, Ezekowitz JA, Wiebe N, et al. Systematic review:  Cardiac resynchronization in patients with symptomatic heart failure.  Ann Intern Med. 2004; 141:381-390.
28. Molhoek SG, Bax JJ, Bleeker GB, et al. Long-term follow-up of cardiac resynchronization therapy in patients with end-stage heart failure. J Cardiovasc Electrophysiol. 2005; 16(7):701-707.
29. Molhoek SG, Bax JJ, Bleeker GB, et al. Comparison of response to cardiac resynchronization therapy in patients with sinus rhythm versus chronic atrial fibrillation. Am J Cardiol. 2004; 94(12):1506-1509.
30. Moss AJ, Hall WJ, Cannom DS, et al. Cardiac resynchronization therapy for the prevention of heart failure events. N Engl J Med. 2009; 361(14):1329-1338. 
31. Saxon LA, Boehmer JP, Hummel J, et al. The VIGOR CHF and VENTAK CHF investigators. Biventricular pacing in patients with congestive heart failure; two prospective randomized trials. Am J Cardiol. 1999; 83(5B):120D-123D.
32. St. John Sutton MG, Plappert T, Abraham WT, et al. Effect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure.  Circ. 2003; 107:1985-1900.
33. Sutton MG, Plappert T, Hilpisch KE, et al. Sustained reverse left ventricular structural remodeling with cardiac resynchronization at one year is a function of etiology: quantitative Doppler echocardiographic evidence from the Multicenter InSync Randomized Clinical Evaluation (MIRACLE). Circulation. 2006; 113(2):266-272.
34. Sweeney MO, Ellenbogen KA, Casavant D, et al. Multicenter prospective randomized safety and efficacy study of a new atrial-based managed ventricular pacing mode (MVP) in dual chamber ICDs. J Cardiovasc Electrophysiol. 2005; 16(8):811-817.
35. Upadhyay GA, Choudhry NK, Auricchio A et al.  Cardiac resynchronization in patients with atrial fibrillation: a meta-analysis of prospective cohort studies.  J Am Coll Cardiol. 2008; 52:1239-1246.
36. Wikstrom G, Blomström-Lundqvist C, Andren B, et al. The effects of etiology on outcome in patients treated with cardiac resynchronization therapy in the CARE-HF trial. Eur Heart J. 2009; 30(7):782-788.
37. Yancy CW, Fonarow GC, Albert NM, et al. Influence of patient age and sex on delivery of guideline-recommended heart failure care in the outpatient cardiology practice setting: findings from IMPROVE HF. Am Heart J. 2009; 157(4):754-762.
38. Young JB, Abraham WT, Smith AL, et al. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. JAMA. 2003; 289(20):2685-2694.
39. Yu CM, Abraham WT, Bax J, et al. Predictors of response to cardiac resynchronization therapy (PROSPECT)--study design. Am Heart J. 2005; 149(4):600-605.

Government Agency, Medical Society, and other Authoritative Publications:

1. Blue Cross Blue Shield Association. Cardiac Resynchronization Therapy for Mild Congestive Heart Failure. TEC Assessment, October 1, 2009.
2. Boston Scientific Corporation, University of Rochester. MADIT-CRT Automatic defibrillator implantation with cardiac resynchronization therapy. NLM Identifier: NCT00180271. Last updated on June 23, 2009. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00180271?term=MADIT+CRT&rank=1.  Accessed on December 18, 2009.
3. Centers for Medicare and Medicaid Services. National Coverage Determination for Cardiac Pacemakers. NCD#20.8. Effective April 30, 2004. Available at: https://www.cms.hhs.gov/mcd/viewncd.asp?ncd_id=20.8&ncd_version=2&basket=ncd%3A20%2E8%3A2%3ACardiac+Pacemakers.  Accessed on December 18, 2009.
4. Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices) Developed in Collaboration With the American Association for Thoracic Surgery and Society of Thoracic Surgeons. J Am Coll Cardiol. 2008; 51:1-62.  Available at: http://content.onlinejacc.org/cgi/reprint/51/21/e1.pdf.  Accessed on December 18, 2009.
5. Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, et al. American College of Cardiology; American Heart Association Task Force; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association; Heart Rhythm Society. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 guidelines for the management of patients with atrial fibrillation) developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Europace. 2006; 8(9):651-745.  Available at: http://circ.ahajournals.org/cgi/reprint/114/7/e257.  Accessed on December 18, 2009.
6. Gorcsan J 3rd, Abraham T, Agler DA, et al. American Society of Echocardiography Dyssynchrony Writing Group. Echocardiography for cardiac resynchronization therapy: recommendations for performance and reporting--a report from the American Society of Echocardiography Dyssynchrony Writing Group endorsed by the Heart Rhythm Society. J Am Soc Echocardiogr. 2008; 21(3):191-213.
7. Hunt SA, Abraham WT, Chin MH, et al. 2009 focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2009; 53:e1–90.  Available at:  http://content.onlinejacc.org/cgi/reprint/53/15/e1.pdf.  Accessed on December 18, 2009.
8. Jessup M, Abraham WT, Casey DE, et al. writing on behalf of the 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult Writing Committee. 2009 focused update: ACCF/AHA guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2009; 53:1343– 1382. Available at:  http://content.onlinejacc.org/cgi/reprint/53/15/1343.pdf.  Accessed on December 18, 2009.
9. McAlister FA, Ezekowitz J, Dryden DM, Hooton N, Vandermeer B, Friesen C, Spooner C, Rowe BH. Cardiac Resynchronization Therapy and Implantable Cardiac Defibrillators in Left Ventricular Systolic Dysfunction. Evidence Report/Technology Assessment No. 152 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No. 290-02-0023). AHRQ Publication No. 07-E009. Rockville, MD: Agency for Healthcare Research and Quality. June 2007. Available at:  http://www.ahrq.gov/downloads/pub/evidence/pdf/defib/defib.pdf.  Accessed on December 18, 2009.
10. McAlister F, Ezekowitz J, Wiebe N, Rowe B, Spooner C, Crumley E, Hartling L, Kaul P, Nichol G, Klassen T. Cardiac Resynchronization Therapy for Congestive Heart Failure. Evidence Report/Technology Assessment No. 106. (Prepared by the University of Alberta Evidence-based Practice Center under Contract No. 290-02-0023.) AHRQ Publication No. 05-E001-2. Rockville MD: Agency for Healthcare Research and Quality. November 2004.  Available at:  http://www.ahrq.gov/downloads/pub/evidence/pdf/resynchf/resynchf.pdf.  Accessed on December 18, 2009.
11. Medtronic Cardiac Rhythm Disease Management.  Medtronic, Inc.  REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction (REVERSE).  NLM Identifier: NCT00271154.  Last updated on March 26, 2009.  Available at: http://clinicaltrials.gov/ct2/show/NCT00271154?term=NCT00271154&rank=1.  Accessed on December 20, 2009.
12. National Institute for Health and Clinical Excellence (NICE). Technology appraisal guidance TA120. Cardiac resynchronization therapy for the treatment of heart failure. May 23, 2007. Available at: http://www.nice.org.uk/nicemedia/pdf/TA120guidance.pdf.  Accessed on December 18, 2009.
13. Strickberger SA, Conti J, Daoud EG, et al. Council on Clinical Cardiology Subcommittee on Electrocardiography and Arrhythmias and the Quality of Care and Outcomes Research Interdisciplinary Working Group; Heart Rhythm Society. 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):2146-2150.
14. University of Ottowa Heart Institute, Canadian Institutes of Health Research (CIHR), Medtronic, Inc. Resynchronization/Defibrillation for Ambulatory Heart Failure Trial (RAFT).  NLM Identifier: NCT00251251. Last updated on April 27, 2009  Available at: http://www.clinicaltrials.gov/ct2/show/NCT00251251?term=Resynchronization%2Fdefibrillation&rank=1  Accessed on December 18, 2009.
15. U.S. Food and Drug Administration (FDA). Center for Devices and Radiological Health. Summary of Safety and Effectiveness for Medtronic InSync^® Biventricular Pacing System. P010015. Original PMA date: August 30, 2001. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm?id=6458.  Accessed on December 18, 2009.
16. U.S. Food and Drug Administration (FDA). Center for Devices and Radiological Health. Premarket Approval (PMA) Database. St. Jude Medical^® Frontier and Frontier II biventricular pacing systems. PMA number P030035. Original PMA date:  May 26, 2004.  Available at URL address: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm?id=11694.  Accessed on December 18, 2009.
17. U.S. Food and Drug Administration (FDA). Center for Devices and Radiological Health. Update of FDA Preliminary Public Health Notification: Guidant VENTAK PRIZM^® 2 DR and CONTAK RENEWAL^® Implantable Cardioverter Defibrillators.  October 13, 2005.  Available at: http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/PublicHealthNotifications/ucm062113.htm. Accessed on December 18, 2009.
18. U.S. Food and Drug Administration (FDA). Center for Devices and Radiological Health. St. Jude Medical^® Epic^™ HF dual chamber implantable cardioverter defibrillator systems with cardiac resynchronization therapy. P030054. July 16, 2004. Available at:   http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm?id=9423.  Accessed on December 18, 2009.
19. U.S. Food and Drug Administration (FDA).  Center for Devices and Radiological Health.  Premarket Approval (PMA) Database.  Ela Medical, Inc., (Plymouth, MN) Ovatio CRT-D System.  PMA number P060027.  July 28, 2008.  Available at:  http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm?id=11566.     Accessed on December 18, 2009.
20. Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to develop guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death). Circulation. 2006; 114(10):1088-1132. Available at: http://circ.ahajournals.org/cgi/reprint/114/10/e385. Accessed on December 18, 2009.

1. Consumer information from the U.S. Food and Drug Administration (FDA).  Available at: http://www.fda.gov/hearthealth.  Accessed on December 18, 2009.
2. Heart failure. Available at: http://www.heartfailure.org/.  Accessed on December 18, 2009.
3. Heart Rhythm Society- Cardiac Resychronization Therapy.  Available at: http://www.hrspatients.org/patients/treatments/resync.asp.  Accessed on December 18, 2009.
4. National Heart, Lung and Blood Institute available at:  Available at: http://www.nhlbi.nih.gov/health/dci/Diseases/Hf/HF_WhatIs.html.  Accessed on December 18, 2009.

Atlas^® + HF
Biventricular Pacemaker
CONTAK^®RENEWAL^™
Epic^™ HF
InSync^® Biventricular Pacing System
InSync^® ICD Dual Chamber ICD with CRT 

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