INTRODUCTION — Medical therapies, such as angiotensin converting enzyme inhibitors, beta blockers, and spironolactone, have led to marked improvements in both symptom control and overall survival in patients with heart failure (HF). (See "Overview of the therapy of heart failure due to systolic dysfunction".)

Implanted devices, such as cardioverter-defibrillators (ICDs) and pacemakers, can also be beneficial. In particular, ICDs are now recommended for primary prevention of sudden cardiac death in selected patients with ischemic and nonischemic cardiomyopathy. (See "Secondary and primary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Primary prevention of SCD'.)

In addition, some HF patients benefit from simultaneous pacing of both ventricles (biventricular or BiV pacing) or of one ventricle in patients with bundle branch block. This approach is referred to as cardiac resynchronization therapy (CRT) [1-6]. CRT can be achieved with a device designed only for pacing or can be incorporated into a combination device with an ICD (figure 1).

CRT is recommended in patients with advanced HF (usually NYHA class III or IV), severe systolic dysfunction (eg, left ventricular ejection fraction (LVEF) ≤35 percent) and intraventricular conduction delay (eg, QRS >120 msec). The rationale for CRT is that ventricular dyssynchrony can further impair the pump function of a failing ventricle. Resynchronization may improve pump performance and reverse the deleterious process of ventricular remodeling. (See "Rationale for and mechanisms of benefit of cardiac resynchronization therapy".)

The role of cardiac resynchronization therapy (CRT) in the management of patients with HF will be reviewed here. Studies evaluating standard dual-chamber pacing in HF and the possible role of CRT in patients with atrial fibrillation are discussed separately. (See "Overview of cardiac pacing in heart failure" and "Cardiac resynchronization therapy in atrial fibrillation".)

RATIONALE FOR CRT — The rationale for CRT is based upon the observation that the presence of a bundle branch block or other intraventricular conduction delay can worsen HF due to systolic dysfunction by causing ventricular dyssynchrony, thereby inducing regional loading disparities and reducing the efficiency of contraction. Consistent with the idea that ventricular dyssynchrony exacerbates left ventricular dysfunction is the observation that a variety of hemodynamic benefits follow the correction of dyssynchrony with CRT.

As will be described below, a number of randomized controlled trials have shown improved outcomes with CRT in appropriately selected patients with systolic HF who have an intraventricular conduction delay or left bundle branch block. Potential mechanisms of benefit include improved contractile function and reverse ventricular remodeling.

Both the rationale for CRT and the mechanisms of benefit in patients with HF are discussed in detail elsewhere. (See "Rationale for and mechanisms of benefit of cardiac resynchronization therapy".)

IMPLANTATION TECHNIQUE — The initial clinical trials, which led to the approval of CRT in Europe and Canada, utilized an epicardial lead for LV pacing or a transvenous lead that was not specifically designed and tested for long-term LV pacing [7,8]. Epicardial leads have a greater risk of failure to capture with chronic pacing, and placement of an epicardial LV lead requires a limited thoracotomy, which is performed under general anesthesia and associated with a greater operative risk than a completely transvenous system [9].

The development of a completely transvenous coronary sinus lead designed for long-term LV pacing has simplified the implant procedure while markedly reducing operative risk, as demonstrated in numerous clinical trials. However, implantation of a coronary sinus catheter may result in perforation or dissection and other complications, and should be performed only by experienced operators.

Complications — The most common complication with transvenous CRT implantation is inability to implant the left ventricular pacing lead successfully. Additional complications include coronary sinus or coronary vein trauma, pneumothorax, diaphragmatic/phrenic nerve pacing, and infection [10-13]. There are also specific concerns with LV lead placement such as prolonged radiation exposure due to the complexity of the transvenous implantation procedure [14], and the theoretical risk that pacing from an LV lead may be proarrhythmic due to alterations in depolarization and repolarization sequences [15].

The incidence of complications is illustrated by the following results from a review of implantation success rates and safety outcomes in 89 studies of patients undergoing CRT or CRT-ICD implantation [12]:

• In 54 studies (6123 patients) of CRT-alone devices, implantation was unsuccessful in 7 percent and 0.3 percent of patients died during implantation. During a median 6 months follow-up, 5 percent of CRT devices malfunctioned and 2 percent of patients were hospitalized for infections in the implant site. During a median follow-up of 11 months, lead problems occurred in 7 percent of CRT devices.

Despite concern about a theoretical proarrhythmic effect [15], pooling of data from 14 randomized controlled trials did not reveal any excess risk of sudden death or noncardiac death in CRT device recipients.

• In 36 studies (5199 patients) of combined CRT-ICD devices, implantation was unsuccessful in 6 percent and 0.5 percent of patients died during implantation. Over a median 12 months follow-up, 5 percent of CRT-ICD devices malfunctioned, 1 percent of patients developed site infection, and lead problems were detected in 7 percent of patients.

These complications have led some investigators to consider returning to intrathoracic procedures now that minimally invasive techniques are available. Such an approach permits more freedom of lead placement and, in an initial report of 41 patients, there were no in-hospital deaths, intraoperative complications, or failures to implant the left ventricular lead [16].

CLINICAL TRIALS — A number of randomized trials have demonstrated a benefit from CRT in selected patients with HF due to systolic dysfunction and evidence of dyssynchrony. The usual inclusion criteria include NYHA class III to IV HF (most were class III) despite appropriate medical therapy, left ventricular ejection fraction (LVEF) <35 percent, and QRS duration >120 to 140 msec (table 1).

The following discussion will focus on three sources. First, a meta-analysis of trials including 14 randomized controlled trials published before 2007 including CARE-HF [11,17], COMPANION [10,18], MIRACLE and MIRACLE ICD [19-22], MUSTIC-SR and MUSTIC-AF [23-25], PATH-CHF [26], VENTAK CHF/CONTAK CD [7], and HOBIPACE [27]. In addition, the CARE-HF and COMPANION trials will each be discussed.

Meta-analysis of CRT — The magnitude of the benefit of CRT was illustrated in a meta-analysis of 14 randomized, controlled trials of 4420 patients [12]. The following benefits of CRT were noted:

• A greater likelihood of improving at least one NYHA class (table 1) (59 versus 37 percent, relative risk [RR] 1.6, 95% CI 1.3-1.9), with improvements in six minute walk distance (mean difference 24 meters) and quality of life.
• A reduced rate of hospitalizations for HF (RR 0.63, 95% CI 0.43-0.93).
• A reduced rate of all-cause mortality (RR 0.78, 95% CI 0.67-0.91), primarily due to fewer deaths from progressive HF (RR 0.64, 95% CI 0.49-0.84).

CARE-HF trial — The CARE-HF trial randomly assigned 813 patients (mean age 67) with NYHA class III or IV HF (94 percent class III, 62 percent nonischemic), an LVEF ≤35 percent (median 25 percent), and QRS prolongation (median QRS duration 160 msec) to CRT with BiV pacing and medical therapy or medical therapy alone [11]. Patients with a QRS duration of 120 to 149 msec were required to have echocardiographic evidence of ventricular dyssynchrony. (See 'QRS duration' below.)

The primary end point was the time to death from any cause or unplanned hospitalization for a major cardiovascular event; the major secondary end point was death from any cause.

The following significant benefits were noted with CRT at a mean of 29 months:

• A reduction in the primary end point (39 versus 55 percent, hazard ratio [HR] 0.63, 95% CI 0.51-0.77). The benefit increased over time (graph 1) and did not vary with age, sex, NYHA class, baseline systolic pressure, LVEF, QRS duration, or routine therapies for HF (eg, beta blockers, spironolactone, digoxin).
• A reduction in mortality (20 versus 30 percent, HR 0.64, 95% CI 0.48-0.85). The mortality benefit increased over time (graph 2) and was largely due to a reduction in deaths due to worsening HF (8.1 versus 13.9 percent), with a lesser reduction in SCD (7.1 versus 9.4 percent). It was proposed that an ICD might further reduce the risk of sudden death, which was evaluated in the COMPANION trial described in the next section.

The mortality benefit for both HF and SCD increased slightly at extended follow-up of 38 months [17].

• An increase in LVEF relative to the control arm of 3.7 percent at three months and 6.9 percent at 18 months. This was associated with a rise in systolic pressure of about 6 mmHg compared to no CRT (median baseline 110 mmHg) and a reduction in plasma N-terminal-pro-brain natriuretic peptide (BNP) of 225 pg/mL at three months and 1122 pg/mL at 18 months (median baseline 1800 to 1900 pg/mL).
• At 90 days, improvements in quality of life and NYHA class (2.1 versus 2.7 with medical therapy alone).
• Evidence of reverse remodeling (see "Rationale for and mechanisms of benefit of cardiac resynchronization therapy".

The reductions in mortality, both due to HF and SCD, persisted and increased slightly at an extended follow-up of 38 months [17].

COMPANION trial — The COMPANION trial was a study of CRT with and without an ICD in 1520 patients (mean age 67) with NYHA class III-IV HF, a QRS duration ≥120 msec, and an LVEF ≤35 percent (median 21 percent) who had had a hospitalization for HF within the year prior to enrollment [10]. With the exception of the approximately 15 percent of patients with NYHA class IV HF, all patients also met current criteria for an ICD for primary prevention. Nearly half of patients enrolled had a nonischemic etiology of HF.

Patients were randomly assigned to optimal medical therapy, CRT alone, or CRT with an ICD. Medical therapy for HF included angiotensin converting enzyme inhibitors or angiotensin receptor blockers in 89 percent, beta blockers in 66 percent, and spironolactone in 55 percent.

During the course of the study, a significant number of patients in the medical therapy only arm of the trial withdrew to receive a device because of arrhythmia or HF (26 percent versus 6 and 7 percent in the CRT and CRT plus ICD arms, respectively). Patients who withdrew from the trial were asked in a second consent to agree to the collection of follow-up data.

At a mean follow-up of 12 months, the following findings were noted:

• There was a significant reduction in the incidence of the primary composite end point of all-cause mortality and all-cause hospitalization in the two arms receiving CRT compared to the medical therapy only arm (56 and 56 versus 68 percent, HR 0.80, 95% CI 0.68-0.95) (graph 3). There were similar differences for cardiovascular causes of death or hospitalization.

On subgroup analysis according to baseline characteristics, the primary end point benefit did not vary with age, sex, NYHA class, ischemic or nonischemic origin of the cardiomyopathy, LVEF, or other routine therapies for HF (eg, angiotensin converting enzyme inhibitors, beta blockers, spironolactone). Although a relative improvement in outcomes with CRT and CRT plus ICD was present in all subgroups, some characteristics were associated with an increased absolute rate of SCD, including male gender, renal dysfunction, NYHA class IV HF, and an LVEF ≤20 percent [18].

• The CRT plus ICD arm and the CRT only arm experienced a significant and an almost significant improvement, respectively, in the secondary end point of all-cause mortality alone (12 and 15 versus 19 percent in the medical therapy only arm, HR for CRT plus ICD versus medical therapy 0.64, 95% CI 0.48-0.86, HR for CRT only versus medical therapy 0.76, 95% CI 0.58-1.01) (graph 4) [10].
• All-cause mortality for CRT plus ICD compared to CRT alone was almost significantly lower (odds ratio 0.79, 95% CI 0.60-1.06 in an analysis not presented in the original report but calculated as part of a later meta-analysis) [28].

On subgroup analysis according to baseline characteristics, the mortality benefit of CRT plus ICD as compared to medical therapy was significant in nonischemic cardiomyopathy (HR 0.50) and less prominent and not quite significant in ischemic cardiomyopathy (HR 0.73).

• At three and six months, both CRT arms showed significant improvements in NYHA class, six minute walk distance, and systolic pressure compared to medical therapy alone [10].
• All-cause, cardiac, and HF hospitalization rates were significantly reduced in both CRT arms compared to medical therapy alone [29]. This benefit was observed within days or weeks of CRT initiation and was sustained throughout the trial.

The mortality benefit in COMPANION began immediately in the CRT plus ICD group compared to eight months with CRT alone (graph 4) [10]. A similar delayed benefit was seen with CRT alone in CARE-HF (graph 2) [11]. These observations suggest that the ICD prevents sudden death from the beginning, while the mortality benefit of CRT requires time for reverse ventricular remodeling [5].

Summary of CRT benefit — Both CARE-HF and COMPANION support the use of CRT for symptom and survival improvement [10,11]. The symptomatic benefit (eg, improvement by about one NYHA class or increased six minute walk distance) occurs early. In the MIRACLE trial, most of the improvement in symptoms and quality-of-life were seen at one month [19]; a symptomatic benefit was not assessed before three months in CARE-HF and COMPANION [10,11].

CRT plus ICD versus CRT alone — As noted above, in the COMPANION trial CRT plus ICD showed an almost significant trend toward lower all-cause mortality compared to CRT alone [28]. Many patients who are eligible for CRT also meet criteria for ICD implantation. The SCD-HeFT and DEFINITE trials in patients with NYHA class II or III HF (table 1) and an LVEF ≤35 percent demonstrated significant and near significant survival benefit when an ICD was implanted for primary prevention of sudden cardiac death. Almost all of the patients in CARE-HF and COMPANION, met these criteria. (See "Secondary and primary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Primary prevention of SCD'.)

Based upon the results of the COMPANION trial, the United States Food and Drug Administration approved the use of devices that combine an ICD and a biventricular (BiV) pacemaker in patients who meet criteria for CRT. Because most patients who receive a BiV pacemaker are also suitable candidates for ICD therapy, combination devices have been estimated to account for over 80 percent of BiV pacemaker implants.

USE IN PATIENTS WITH OTHER DEVICE INDICATIONS

Patients with pacemakers or standard pacemaker indications — It is estimated that approximately 8 to 15 percent of patients with advanced HF have pacemakers implanted for symptomatic bradycardia. Such patients have an increased risk of mortality or urgent transplantation due to progressive pump dysfunction; in one series, the risk at one year was 49 versus 15 percent in patients without a pacemaker [30]. This difference may be due in part to the dyssynchronous contraction caused by RV based pacing.

Whether such patients would derive long-term benefit from "upgrading" these devices to achieve resynchronization by the addition of an LV lead is under investigation. Initial data in patients with severe HF, prior AV junction ablation for rate control of AF, and chronic RV pacing has shown that there are significant benefits obtained from upgrading from RV to BiV pacing. (See "Cardiac resynchronization therapy in atrial fibrillation".)

In addition, it is possible that selected patients with standard indications for pacemaker placement might benefit from the prophylactic implantation of a CRT system. In particular, this approach may be helpful in patients with LV dysfunction who require a standard pacemaker, but do not at baseline meet criteria for CRT.

This strategy was evaluated in the HOBIPACE trial, a randomized crossover study of 30 patients [27]. CRT systems were implanted in all patients, and each patient had 3 months of RV pacing and CRT. Compared to baseline and to RV pacing, CRT was associated with reverse remodeling, lower NT-proBNP levels, and improvements in LVEF, oxygen consumption, and heart failure symptoms. The authors suggest that for patients with LV systolic dysfunction who require pacemakers for standard bradycardic indications, prophylactic implantation of a CRT system may be beneficial. However, there were several limitations to this trial that need to be addressed in further studies before this approach can be recommended. These limitations include:

• Many enrolled patients already appeared to meet standard indications for CRT. The average NYHA class was 3, the average QRS duration was 174 msec, and 63 percent had a LBBB.
• Standard medical therapy for HF was better after pacemaker implantation, particularly with more frequent use and increased doses of beta blockers and ACE inhibitors or ARBs.
• Some measures of reverse remodeling and HF severity improved with RV pacing compared to baseline. Although these improvements were smaller than those seen with CRT, they are contrary to what one would expect, suggesting a significant placebo effect, and/or the impact of improved medical regimens.

Guideline recommendations for CRT in patients with pacemakers are discussed below. (See 'Indications' below.)

ICD candidates — Many patients who are candidates for CRT are also candidates for ICD placement. The COMPANION trial described below showed that CRT with an ICD resulted in a near significant trend toward lower mortality than CRT alone [10,28]. (See 'COMPANION trial' above and 'CRT plus ICD versus CRT alone' above.)

Electronic pacing in the presence of a separate ICD could lead to inappropriate ICD firing. As a result, devices that combine ICD and BiV pacing functions were developed to prevent "crosstalk" between separate devices.

The issue of patient selection for ICD implantation for primary prevention of sudden cardiac death in HF is discussed separately. (See 'COMPANION trial' above and "Secondary and primary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Primary prevention of SCD'.)

TIMING OF BENEFIT — LV resynchronization occurs immediately after CRT initiation and is sustained with continued therapy [31]. Acute resynchronization is predictive of reverse remodeling at six months.

Symptomatic benefit (eg, improvement in NYHA class by one class or increased six minute walk distance) occurs early and has persisted through extended follow-up [10,11,19,32]. This pattern is illustrated by the following observations:

• In the MIRACLE trial, most of the improvement in symptoms and quality-of-life were seen at one month [33]; a symptomatic benefit was not assessed before three months in CARE-HF and COMPANION [11,34].
• In a cohort of 22 patients who underwent repeat invasive hemodynamic assessment six months after implantation, the improvements associated with CRT were maintained [32].

These findings are consistent with the adverse effects observed with late interruption of CRT. (See 'Interruption of CRT' below.)

SPECIFIC ISSUES — CRT is a rapidly evolving field. Investigation in a number of areas is ongoing, particularly with respect to the identification of appropriate candidates.

Efficacy in NYHA class I or II HF — The above CRT trials demonstrating functional and mortality benefit of CRT largely consisted of patients with NYHA class III to IV HF (table 1). Evidence from randomized trials of CRT or CRT-ICD in patients with reduced LVEF and NYHA class I or II HF indicate that CRT can provide functional improvement and decrease the risk of heart failure events, although no impact on mortality has been demonstrated [7,22,35,36].

Data from two CRT-ICD trials (VENTAK CHF/CONTAK CD and MIRACLE ICD II) in which subjects were randomly assigned to CRT on or off suggested both functional improvement and evidence of reverse ventricular remodeling in patients randomly assigned to CRT [7,22]. Although the degrees of hemodynamic improvement and reverse remodeling were similar to those seen in patients with more advanced HF, patients with baseline NYHA class II HF had less clinical improvement.

The REVERSE trial evaluated the effects of CRT with or without an ICD in 610 patients with NYHA class I (18 percent) or II (82 percent) HF, QRS ≥120 msec, LVEF ≤40 percent, and LV end-diastolic diameter ≥55 mm [35]. The patients with NYHA class I HF had been previously symptomatic and were currently asymptomatic. Following CRT implantation, patients were randomly assigned to CRT on or off for 12 months. Use of CRT did not reduce the proportion of patients who clinically worsened, although it reduced the rate of HF hospitalization and improved LV remodeling.

The MADIT-CRT trial demonstrated a beneficial impact of cardiac resynchronization therapy on heart failure events and remodeling in patients with mild or no HF symptoms [36]. The study population consisted of 1820 patients with an LVEF ≤30 percent, QRS ≥130 msec, and NYHA class I or II HF who were randomly assigned to CRT-ICD or ICD alone. The primary endpoint was death from any cause or a nonfatal HF event. CRT-ICD produced a decrease in the primary endpoint as compared to ICD alone, the benefit driven by a 41% reduction in HF events. Evidence of CRT induced reverse remodeling was also demonstrated by echocardiographic measures. The benefit was observed primarily in patients with a QRS duration > 150 msec. The results of this trial await further confirmation.

Efficacy in NYHA class IV HF — Although patients with NYHA class IV HF were included in the above clinical trials, the majority of enrolled patients were NYHA class III (table 1). It has been suggested that NYHA class IV patients may not benefit from CRT or CRT-D, since the implantation procedure may destabilize their HF and their life expectancy may preclude them from achieving longer-term benefits.

This question was addressed in a retrospective analysis of the COMPANION trial [37]. Among the 1520 patients enrolled in COMPANION, 217 patients were classified as NYHA class IV. However, patients were excluded from the trial if they were expected to undergo cardiac transplantation within six months or had been hospitalized for HF within 30 days of entry. Thus, the 217 included patients represent a relatively stable, ambulatory class IV cohort. In an analysis limited to these class IV patients, the following findings were noted:

• Both CRT and CRT-D significantly reduced the primary endpoint of time to death or hospitalization.
• There were trends towards reduced all cause mortality in both arms (HR 0.67 CI 0.41 to 1.10 and HR O.63 CI 0.39 to 1.03 for CRT and CRT-D, respectively).

Further support for the efficacy of CRT in selected NYHA class IV HF patients comes from a series of 10 patients with inotrope-dependent HF and either ECG or echocardiographic evidence of dyssynchrony [38]. Patients had been on inpatient or outpatient inotropic therapy for a median of 146 days. At a median follow-up of three years, the following findings were noted:

• All patients were alive.
• Three patients had undergone cardiac transplantation.
• Nine patients had inotropic therapy discontinued.
• HF symptoms improved to NYHA class III and II in five and four patients, respectively.

Age — Randomized trials have not specifically addressed the benefit of CRT in elderly patients. However, in two major CRT trials (CARE-HF and COMPANION), the mean age was about 65 years and the benefit from CRT was similar in patients above and below the mean age [39,40]. Equivalent benefits were also noted in an observational study of patients ≥70 years of age (mean age 76) compared to patients <70 years of age (mean age 59) [41].

Right bundle branch block — The efficacy of CRT in patients with right bundle branch block (RBBB) is not established. Most patients in the controlled CRT trials had LBBB; RBBB was present in 5 to 13 percent of patients [7,10,21]. Recommendations for CRT in the 2008 ACC/AHA/HRS guidelines do not specify QRS morphology. The guidelines note that there is not yet sufficient evidence to provide specific recommendations for patients with right bundle branch block.

A possible explanation for why some patients with RBBB might benefit from CRT [42] was provided in a study in which detailed activation mapping was performed in patients with advanced HF and a bundle branch block [43]. The six patients with RBBB had evidence of left-sided activation delay.

Cost-effectiveness — Although CRT devices are expensive, the costs may be offset in part by savings from reduced hospitalizations for HF. Cost-effectiveness analyses from both the CARE-HF and COMPANION trials suggested acceptable cost-effectiveness ratios for CRT [44,45].

• Data from the COMPANION trial were extrapolated to develop a cost-effectiveness estimate for CRT-P (biventricular pacing alone), and CRT-D (biventricular pacing with an ICD). The cost-effectiveness ratio projected over seven years was estimated to be $19,600 per quality-adjusted life-year (QALY) for CRT-P, and $43,000 per QALY for CRT-D [44].
• An analysis of CARE-HF patients found that over a median follow-up of 29 months, the cost-effectiveness ratio was 19,319 euros per QALY [46].

These numbers compare favorably to the target of $50,000 per QALY that is commonly considered acceptable in the United States, and also to a European target of 29,400 euros per QALY. (See "A short primer on cost-effectiveness analysis".)

However, using a different set of assumptions, the cost-effectiveness ratio of CRT has also been estimated at $107,000 per QALY [47]. Furthermore, it has been suggested that cost-effectiveness calculations for CRT-D should be based upon comparison to CRT-P and not medical therapy. Since long-term outcomes were similar in COMPANION among patients assigned to CRT-P and CRT-D (graph 3 and graph 4), the cost-effectiveness of CRT-D compared to CRT-P is less favorable [48].

These analyses are based upon extrapolated results and the results vary substantially according to changes in input variables (eg, magnitude of reduction in HF admissions, cost of device implantation, and frequency of device complications).

Efficacy in AF — The use of CRT in patients with atrial fibrillation is discussed in detail separately. (See "Cardiac resynchronization therapy in atrial fibrillation".)

MAJOR SOCIETY GUIDELINES — The recommended indications for CRT have evolved. There is general agreement that CRT is appropriate in patients with advanced HF due to systolic dysfunction and ventricular dyssynchrony. It is not yet clear how best to assess patients for dyssynchrony (eg, QRS width and/or morphology, tissue Doppler echocardiography, or advanced cardiac imaging). In addition, the degree of dyssynchrony necessary before benefit from CRT can be expected is uncertain, and prior guidelines have used slightly different cutoffs for QRS duration [49,50].

Indications — We agree with the recommendations regarding CRT in the 2008 American College of Cardiology/American Heart Association/Heart Rhythm Society (ACC/AHA/HRS) guidelines for device-based therapy of cardiac rhythm abnormalities [51].

• CRT is recommended for patients with LVEF ≤35 percent, a QRS duration ≥120 msec, and NYHA functional class III or ambulatory class IV symptoms with optimal medical therapy [51,52].

Most patients who satisfy these criteria are also candidates for an ICD and receive a combined device. The main exclusions are those with advanced noncardiac disease who are not expected to survive for longer than six months to one year and those who do not desire an ICD. (See "Secondary and primary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Primary prevention of SCD'.)

• CRT is reasonable for patients with LVEF ≤35 percent with NYHA functional class III or ambulatory class IV symptoms who are receiving optimal recommended medical therapy and who have frequent dependence on ventricular pacing [51].
• CRT may be considered for patients with LVEF ≤35 percent with NYHA functional class I or II symptoms who are receiving optimal recommended medical therapy and who are undergoing implantation of a permanent pacemaker and/or ICD with anticipated frequent ventricular pacing [51].
• CRT is NOT indicated for asymptomatic patients with reduced LVEF in the absence of other indications for pacing [51]. CRT is NOT indicated for patients whose functional status and life expectancy are limited predominantly by chronic noncardiac conditions.

Approximately 20 to 30 percent of patients with symptomatic HF have an IVCD [1,2], and it has been estimated that about 10 percent of an unselected group of patients with HF would be appropriate candidates for CRT [53]. The most common cause of an IVCD in patients with HF is delayed LV activation due to LBBB, which was present in 70 percent of cases in the COMPANION trial [10].

Echocardiography — We agree with the ASE consensus statement that patients who meet accepted criteria for CRT should NOT have therapy withheld because of results of an echocardiographic Doppler dyssynchrony study [54]. In addition, the consensus statement advises that dyssynchrony reports should NOT include a recommendation as to whether a patient should undergo CRT, as this should be a case-by-case clinical decision [54]. (See 'Significance of dyssynchrony measures' below.)

Class I or II HF — As discussed above, evidence from randomized trials in patients with class I or II HF indicate that CRT can provide functional improvement, improve remodeling and decrease the risk of HF events, although no impact on mortality has been demonstrated. In the MADIT-CRT trial, reduction in HF events was seen primarily in patients with QRS ≥150 msec [36]. (See 'Efficacy in NYHA class I or II HF' above.)

In the United States, the Centers for Medicare and Medicaid Services, which determines governmental reimbursement, approved CRT only for appropriate patients who have NYHA class III and IV HF (table 1) [46]. The 2008 American College of Cardiology/American Heart Association/Heart Rhythm Society (ACC/AHA/HRS) guidelines for device-based therapy indicate that CRT may be considered for patients with LVEF ≤35 percent with NYHA functional class I or II symptoms who are receiving optimal recommended medical therapy and who are undergoing implantation of a permanent pacemaker and/or ICD with anticipated frequent ventricular pacing [51]. Major societies have not yet had an opportunity to comment on the results of the MADIT-CRT trial.

Combination with an ICD — The data from clinical trials evaluating the efficacy of adding an ICD to CRT compared to CRT alone are described above. (See 'CRT plus ICD versus CRT alone' above.)

Most patients who satisfy criteria for requiring CRT are also candidates for an ICD and receive a combined device.

• As noted in the 2005 ACC/AHA heart failure guidelines, use of an ICD in combination with CRT should be based upon the indications for ICD therapy [52].
• The 2008 ACC/AHA/HRS guidelines for device-based therapy of cardiac rhythm abnormalities included recommendations for both CRT devices and ICD implantation [51]. The guidelines did not include specific recommendations regarding when a device with both capabilities should be used.
• The 2006 Heart Failure Society of America (HFSA) practice guidelines recommend that concomitant ICD placement be considered in NYHA class III or IV patients undergoing implantation of a biventricular pacing device according to HFSA criteria [55].

The issue of patient selection for ICD implantation for primary prevention of sudden cardiac death in HF is discussed separately. (See 'COMPANION trial' above and "Secondary and primary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Primary prevention of SCD'.)

OTHER CONSIDERATIONS

AV delay — With CRT devices, as with standard dual chamber pacemakers, the delay between atrial and ventricular stimulation (the AV delay) can be adjusted. In standard pacemakers, the AV delay is often programmed to approximate a physiologic AV interval (eg, 160 to 180 msec) or longer to allow native AV conduction.

Because ventricular pacing is desired in CRT, a short AV delay is often used to prevent native AV conduction (eg, 110 msec). Further adjustments in the AV delay may improve cardiac output and reduce pre-systolic mitral regurgitation in selected patients. The clinical benefit of AV optimization is not fully defined, and the best method for optimizing AV delay is not known. A small study suggested that the optimal AV delay could be defined by Doppler echocardiography; the end of the A wave (indicating the end of atrial contraction) should coincide with the onset of systolic mitral regurgitant flow (indicating the onset of ventricular contraction) [56]. (See "Echocardiographic evaluation of the mitral valve".)

Left ventricular pacing — The above trials of CRT utilized BiV pacing to restore ventricular synchrony. However, among patients with a bundle branch block (most often LBBB), single ventricle pacing on the side of the bundle branch block is another method to restore ventricular synchrony [40]. The two approaches to CRT were compared directly in two randomized trials, PATH-CHF and DECREASE-HF.

In PATH-CHF, 42 patients with class III to IV HF were randomly assigned to four weeks of BiV pacing or four weeks of univentricular pacing [26]. The initial four-week pacing period was followed by four weeks of no pacing, and then four more weeks using the opposite pacing strategy. The benefits of CRT (increases in oxygen uptake at anaerobic threshold and peak exercise as well as six-minute walk distance) were comparable with BiV pacing and univentricular pacing.

The DECREASE-HF trial enrolled 306 patients with NYHA class III or IV HF, an LVEF ≤35 percent and a QRS ≥150 msec [57]. The patients were randomly assigned to simultaneous BiV pacing, sequential BiV pacing (ie, LV activation preceding RV activation by 20 to 80 msec) or LV pacing. The outcomes evaluated were changes in echocardiographic parameters (eg, LVEF and LV volumes). At six months, all groups had a significant improvement in these measures. The standard BiV pacing group had the greatest improvement in end-systolic dimensions, but there were no other differences in echocardiographic parameters among the three groups.

A randomized trial comparing long-term clinical outcomes with LV and BiV pacing has not been performed. At present, BiV pacing is the preferred approach.

Lead positioning — The optimal position for the LV lead is not fully defined. Because the posterolateral wall is often the latest segment to contract in a dyssynchronous LV, it is the preferred location.

The value of placing the LV pacing lead at or near the area of maximal mechanical delay, identified by tissue Doppler imaging, was assessed in a series of 54 patients [58]. Reverse remodeling, defined as a reduction in end-systolic volume, was significantly greater among patients in whom the LV pacing lead was placed at the site of maximal delay. Determining the clinical benefit from tissue Doppler guided lead positioning requires further study.

Scar burden — The following observations suggest that the presence, location and/or extent of left ventricular scar may impact response to CRT:

• In a series of 40 patients with indications for CRT who underwent cardiac magnetic resonance imaging, 14 had a transmural posterolateral scar [59]. These patients had a lower response rate to CRT (14 versus 81 percent of patients without posterolateral scar).
• In a series of 50 patients with indications for CRT who underwent SPECT imaging, global scar burden, number of severely scarred segments and scar burden near the LV lead were all inversely correlated with increase in LVEF after CRT [60].

Right atrial pacing — Dual-chamber pacing (right atrium and right ventricle) in patients with HF has adverse effects on outcome and is not recommended. (See "Overview of cardiac pacing in heart failure".)

Right atrial pacing also has adverse effects in patients treated with CRT as illustrated in a crossover study of 17 patients who paced in the DDD and VDD modes [61]. Avoidance of right atrial pacing was associated with significantly greater improvements in ventricular dyssynchrony and in myocardial performance. With VDD pacing, both atria are activated via the intrinsic conduction system. In contrast, pacing of the right atrial appendage in the DDD mode leads to delayed activation of the left atrium, which may impair left ventricular preload due a reduction in the left atrial contribution. If pace compensation is used to account for this problem, there is some loss of ventricular synchrony.

Interruption of CRT — CRT may be interrupted for a variety of reasons during long term follow-up after device implantation. In a review of 443 patients with a successfully implanted device from the VENTAK CHF/CONTAK CD trial, CRT was interrupted in 161 (36 percent) during 2.5 years of follow-up [41]. The most common reasons for interruption of therapy were atrial tachyarrhythmias (81 patients) and loss of left ventricular capture (44 patients). In 95 percent of cases, it was possible to reinitiate CRT after appropriate intervention (eg, amiodarone therapy, device reprogramming, lead repositioning).

Malfunction or cessation of BiV pacemakers typically results in recurrence or exacerbation of HF. The magnitude and rapidity of the hemodynamic deterioration was illustrated in a report of 20 patients with advanced HF and functional mitral regurgitation who had received CRT for a median of 427 days [62]. At 72 hours after elective temporary cessation of biventricular pacing, there was a marked decline in the maximal rate of rise of left ventricular systolic pressure (711 to 442 mmHg/sec). This was associated with approximately two-fold increases in mitral effective regurgitant orifice area, regurgitant volume, and regurgitant fraction. (See "Functional mitral regurgitation", section on 'Cardiac resynchronization therapy'.)

The evaluation and management of BiV pacemaker malfunction is discussed separately. (See "Dual chamber pacing system malfunction: Evaluation and management", section on 'Biventricular pacemakers'.)

QRS duration — Approximately 20 to 30 percent of patients treated with CRT do not appear to benefit [63-65]. In addition, the benefits that do occur cannot be consistently predicted from either the baseline QRS duration or the extent of QRS narrowing after therapy. As a result, some have suggested that the duration of the QRS complex may not be the optimal criterion for defining dyssynchrony and selecting patients for CRT [66].

Findings in two major trials addressed the predictive value of QRS duration via subgroup analysis. In the COMPANION trial, there was a suggestion that QRS duration was important. The reduction in the primary end point was significant in patients with a QRS duration >168 msec and almost significant between 148 and 168 msec; there was virtually no effect at a QRS duration between 120 and 147 msec [10]. Similar findings were noted in the much smaller PATH-CHF II trial of 86 patients, which found no benefit in patients with a QRS duration of 120 to 150 msec [67].

In the CARE-HF trial, subgroup analysis revealed similar benefits in patients with QRS durations ≥160 and 120 to 160 msec. [11]. However, for entry into the trial, patients with a QRS duration of 120 to 149 msec had to have evidence of mechanical dyssynchrony on at least two of three directly measured criteria: an aortic preejection delay of >140 msec; an interventricular mechanical delay of more than 40 msec; or delayed activation of the posterolateral LV wall.

Dyssynchrony and a normal QRS — Mechanical dyssynchrony has been reported in 20 to 40 percent or more of patients with HF, LV systolic dysfunction and a QRS duration ≤120 msec [68-71]. In HF patients with QRS duration ≤120 msec, dyssynchrony was found to be a predictor of mortality [72]. Although a few series suggested that these patients may experience clinical improvement and reverse remodeling with CRT [73-75], a randomized trial found no benefit from CRT in this population [76].

In the randomized trial,172 patients with QRS duration <130 msec and mechanical dyssynchrony received a CRT-defibrillator device; patients were then randomly assigned to be programmed for CRT or no CRT (control group) [76]. All patients had NYHA Class III HF and an LVEF <35 percent. At 6 months, there was no difference between control and CRT groups in the proportion of patients with the primary endpoint (increase in peak oxygen consumption of at least 1 ml/kg/min). Peak oxygen consumption increased in a prespecified subgroup with QRS interval ≥120 msec but was unchanged in a subgroup with QRS interval <120 msec.

Delta QRS duration — It has been suggested that the delta QRS duration is a better predictor of benefit from CRT than the baseline QRS duration [39,77]. In a retrospective study of 139 consecutive patients, for example, 73 percent were considered responders at six months as defined by being alive, not being rehospitalized for HF, and a decrease in NYHA class by one class and/or an increase in six-minute walk distance or peak VO2 by more than 10 percent [77]. The absolute amount of QRS shortening was significantly greater in responders (37 versus 11 msec) and was the only independent predictor of a response to CRT.

A virtually identical response rate (74 percent) and difference in absolute amount of QRS shortening (29 versus 11 msec) was noted in another retrospective report of 61 patients [39]. An optimal amount of QRS shortening could not be defined. More than a 50 msec shortening was highly specific (88 percent) but not sensitive (18 percent) for predicting the response to CRT.

Other measures of dyssynchrony — Although direct measures of mechanical or electrical dyssynchrony have been investigated as a means of identifying responders to CRT [73-75,78,79], the clinical utility of such assessment has not been established. (See 'Significance of dyssynchrony measures' below.)

A number of imaging modalities and electrocardiographic parameters have been evaluated as tools for quantifying LV dyssynchrony. Echocardiography including tissue Doppler imaging (TDI) has been the most widely studied and is currently the most widely used method to assess mechanical dyssynchrony in clinical practice [65,68,72,80-84].

Recommendations for performance and reporting of echocardiography for CRT were provided in the 2008 American Society of Echocardiography (ASE) consensus statement [54]. The ASE statement advises that dyssynchrony reports should NOT include a recommendation for whether a patient should undergo CRT, as this should be a case-by-case clinical decision.

Additional methods for assessing dyssynchrony that have been investigated include cardiac magnetic resonance imaging (CMR) [59,85,86], myocardial strain imaging [87,88] and electrical activation patterns assessed by electrophysiologic mapping [89]. (See "Noninvasive methods for measurement of left ventricular systolic function".)

Tissue Doppler imaging — TDI is currently the most widely studied method for direct measurement of dyssynchrony [54,65,72,74,75,80-84]. Doppler echocardiography measures velocity of movement at a defined point within the heart. By measuring the velocities of myocardial movement (tissue Doppler), one can assess the timing of contraction in various segments of the left ventricle. (See "Tissue Doppler echocardiography".)

Comparing the timing of contraction in different ventricular segments permits calculation of ventricular dyssynchrony. A variety of measures have been proposed, including the absolute differences in time to peak contraction and the standard deviation of the time to contraction in multiple segments (Yu index).

Significance of dyssynchrony measures — Numerous single-center studies of response to CRT in patients with HF and prolonged QRS duration found that reverse remodeling was more likely and cardiac events were less likely in patients with mechanical dyssynchrony on baseline imaging studies [65,80,81,84,90-92]. Furthermore, among 100 patients with TDI evidence of dyssynchrony at baseline, reverse remodeling with CRT only occurred in those whose TDI dyssynchrony assessment improved by at least 20 percent [31].

However, the multicenter, prospective, nonrandomized PROSPECT study of 498 patients with standard CRT indications found that 12 echocardiographic dyssynchrony measures (including seven TDI parameters) offered only modest sensitivity (9 to 77 percent) and specificity (31 to 93 percent) to predict clinical composite score response [93]. For all the parameters, the area under the receiver-operator characteristics curve for clinical or volume response to CRT was ≤0.62. In addition, there was large variability in the analysis of the dyssynchrony parameters. Therefore, no single echocardiographic measure of dyssynchrony can be recommended to improve patient selection for CRT.

As many as 30 to 40 percent of patients with advanced HF who have a prolonged QRS duration do not have mechanical dyssynchrony [69]. As noted in the 2008 American Society of Echocardiography consensus statement, there is at present insufficient evidence to exclude such patients from consideration of CRT therapy if they are otherwise eligible [54].

SUMMARY AND RECOMMENDATIONS

• CRT is an effective therapy in patients with HF and IVCD. CRT can improve exercise tolerance and NYHA functional class and reduce both mortality and the need for hospitalization in patients in sinus rhythm (see 'Clinical trials' above.
• For patients who are in sinus rhythm, with an LVEF ≤35 percent, and as QRS >120 msec, who have moderate to severe symptoms (NYHA class III or IV HF) despite optimal medical therapy, we recommend CRT (Grade 1A).

Most patients who satisfy these criteria are also candidates for an ICD and should receive a combined device. (See "Secondary and primary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Primary prevention of SCD'.)

• For patients who are in sinus rhythm, with an LVEF ≤35 percent, and a QRS >150 msec, who have mild symptoms (NYHA class II HF) despite optimal medical therapy, we suggest CRT at the time of ICD implantation (Grade 2B).
• For patients with LVEF ≤35 percent with NYHA functional class III or ambulatory class IV symptoms who are receiving optimal recommended medical therapy and who have frequent dependence on ventricular pacing, we suggest CRT (Grade 2B).
• For patients whose functional status and life expectancy are limited predominantly by chronic noncardiac conditions, CRT is NOT indicated.

The role of CRT in patients with atrial fibrillation is discussed separately. (See "Cardiac resynchronization therapy in atrial fibrillation".)