Biventricular Resynchronization Pacing

Large observational studies performed in patients with advanced HF have demonstrated that right ventricular (RV) pacing results in worsening symptoms and long-term outcome.33 This is most likely because of the development of RV pacing-induced left bundle branch block, resulting in intra- and interventricular dyssynchrony with resultant worsening of left and RV systolic and diastolic function. An analogous phenomenon is seen in patients with advanced HF and bundle branch block. Indeed, the majority of patients with HF have interventricular conduction delay, and up to 30% to 50% have manifest bundle branch block caused by direct pathologic involvement of specialized conduction or by scarring of the myocardium.34 In those with conduction delay, pacing from the LV or simultaneously from the basal-lateral LV and RV can reduce the delay between septal and posterolateral contraction, to "resynchronize ventricular contraction." Cardiac resynchronization therapy (CRT) seeks to normalize depolarization to improve the efficiency of ventricular contraction and ventricular septal motion, decrease atrioventricular (AV) valve regurgitation, and increase diastolic filling time.35

Isolated Biventricular Pacing. The early promise of biventricular pacing34,35 was tested in the Multicenter InSync Clinical Study (MIRACLE),36 which randomized 453 patients to activation or nonactivation of cardiac resynchronization, using a double-blind study design. Inclusion criteria were NYHA III/IV, QRS >130 ms, LVEF <35%, and LV end-diastolic dimension >55 mm, as determined by echocardiography. Patients were required to be on optimal medical therapy, defined as ACE inhibitors and beta blockers, for 1 to 3 months before inclusion. Resynchronization improved symptoms, quality of life, and exercise capacity, while reducing LV dimension and improving LVEF at 6 months. Hospitalization or intravenous medications for HF treatment were both reduced by approximately 50%. There was no difference in cardiac or all-cause mortality. This study was not subjected to an intention-to-treat analysis, because randomization occurred only after successful device implantation. The Cardiac Resynchronization-Heart Failure (CARE-HF) study enrolled 813 patients with NYHA class III-IV HF resulting from LV systolic dysfunction and cardiac dyssynchrony with an LVEF <=35% and a QRS duration >=120 ms despite standard medical therapy.37 After a follow up of just under 30 months, the CRT-treated patients showed a significant benefit in terms of the primary end point of all-cause mortality and unplanned hospitalization (HR 0.63, P<.001) and the secondary end point of all-cause mortality (HR 0.64, P<.002). Those in the CRT group also showed improved LVEF, NYHA class, end-systolic volume, mitral valve function, blood pressure, and quality-of-life indices. It should be noted that for those patients with a QRS lengthening of 120-149 ms, echocardiographic confirmation of mechanical dyssynchrony was required. This subselection criterion could have favorably influenced the outcomes by preferential enrollment of those more likely to respond to CRT. It is not known how many patients were excluded by this criterion.

Virtually all randomized trials of CRT have required subjects to be in sinus rhythm at the time of randomization. Thus few data are available to determine the benefits of CRT in patents with atrial fibrillation. Retrospective studies and a meta-analysis suggest that patients with chronic atrial fibrillation may benefit from CRT though the benefits may be less than in patients with sinus rhythm.38 Patients with previous AV nodal ablation and RV pacing may be most likely to benefit from CRT.39 Prior to considering CRT in a patient with atrial fibrillation, it is important to determine if rate control is adequate to allow biventricular pacing.40

Biventricular Pacing With ICD. Initial studies of biventricular pacing with an ICD41 led to the COMPANION trial,17 which enrolled patients with HF and NYHA Class III or IV symptoms despite maximized medical therapy. Inclusion criteria included a QRS duration >=120 ms and a PR interval >150 ms. The trial had 3 treatment arms: optimal pharmacologic therapy (OPT), optimal pharmacologic therapy plus biventricular pacing (CRT), and biventricular pacing plus backup ICD therapy (CRTD). In contrast to all others, this study was powered to evaluate a primary endpoint of combined all cause mortality and hospitalization. Data were analyzed using an "intention to treat" statistical approach. Of the 1580 patients randomized, 1080 were implanted with a CRT pacer or defibrillator (CRTD). As compared with patients treated with medical therapy only, there was a statistically significant event rate reduction in the primary combined endpoint of total hospitalization and total mortality at 1 year in the CRT and CRTD groups, as well as in the combined endpoint of death and hospitalization for HF. There was a trend toward reduced mortality in the CRT-alone group, although this finding did not reach statistical significance.

Asymptomatic or Mild HF symptoms. MADIT-CRT enrolled and followed 1820 patients with ischemic or nonischemic cardiomyopathy, a LVEF of 30% or less, a QRS duration of 130 msec or more, and NYHA class I or II symptoms.42 Patients were randomly assigned to receive CRT plus an ICD or an ICD alone. The primary end point was death from any cause or a nonfatal heart-failure event (whichever came first). The primary end point occurred in 17.2% of the CRT-ICD group and 25.3% of the ICD only group (hazard ratio in the CRT-ICD group, 0.66; 95% confidence interval [CI], 0.52 to 0.84; P=0.001). The superiority of CRT was present in patients with both ischemic and non-ischemic cardiomyopathy and resulted from 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 LV volumes and improvement in the LVEF. 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.42

Biventricular Pacing when Conventional Pacing is Indicated. There are few data concerning the use of CRT in either patients with reduced LVEF HF and a QRS >=120 msec who have an additional indication for ventricular pacing or for those who would likely have a significant burden of RV pacing following ICD implantation. However, substantial data exist to suggest that CRT rather than conventional RV pacing may be considered in these patients. The Homburg Biventricular Pacing Evaluation (HOBIPACE) prospectively randomized 30 subjects with standard indications for pacing and reduced LV function as determined by an LVEF <=40% or an LV end diastolic diameter >=60 mm to RV or biventricular pacing.43 Peak oxygen consumption, BNP levels, and LVEF were improved in the CRT group compared to the RV pacing group. In another study, patients with chronic atrial fibrillation who had AV junction ablation were randomized to either RV or biventricular pacing. At 6 months post-ablation, patients treated with cardiac resynchronization had a significant improvement in 6-minute walk distance, (31%) above baseline (82.9 +/- 94.7 m), compared to patients receiving RV pacing, (24%) above baseline (61.2 +/- 90.0 m) (P=0.04). There were no significant differences in the quality-of-life parameters. At 6 months post-ablation, the LVEF in the biventricular group (0.46 +/- 0.13) was significantly greater in comparison to patients receiving RV pacing (0.41 +/- 0.13, P=0.03). Patients with a LVEF <=45% or with NYHA Class II/III symptoms appeared to have the most benefit.44 Other studies have demonstrated an improvement in symptoms and LVEF in patients with reduced LVEF and chronic RV pacing with an upgrade to CRT.45-47

Unresolved Issues With Biventricular Pacing

The evidence supporting CRT in severe HF is compelling. However, device placement exerts a substantial "placebo" response of improved functional capacity and quality of life parameters in those randomized to the control group, and it is hampered by a significant nonresponder rate.48,49 Most trials of CRT have excluded patients with atrial fibrillation. Thus the benefit of biventricular pacing in these patients remains unknown.

Should resynchronization be done in isolation or must it be accompanied by an ICD device? The findings in SCD-HeFT and COMPANION suggest that CRT therapy ideally should be accompanied by ICD placement in patients with NYHA III symptoms. When considering resynchronization in patients with more severe HF, the appropriateness of ICD implantation is uncertain. A recent analysis of ambulatory NYHA class IV patients in the COMPANION trial demonstrated a benefit of CRT and CRTD, but one year mortality remained high.50

Patients With a QRS Duration 120-150 ms. A substantial number of potential candidates for CRTs will have a QRS duration between 120 and 150 ms. Although such patients were entered in the clinical trials assessing efficacy of CRT, the average QRS duration was in the range of 160-170 ms and there are concerns that patients with moderate prolongation of the QRS interval may not derive the same benefit as those with more marked prolongation. Although CRT reduced the primary endpoint of time to death or all cause hospitalization compared to patients randomized to optimal medical treatment by 19% (P=.014) in the COMPANION Trial, a significant risk reduction was seen only in patients whose QRS was >168 ms.17 Patients whose QRS was <=147 ms demonstrated essentially no benefit of treatment, whereas CRT had an intermediate effect in the patients whose QRS duration fell in between these groups. In CARE-HF, there was a benefit of CRT in subjects with a QRS duration of 120-149 msec, but to be enrolled in the study these patients had to have two of three criteria for dyssynchrony (an aortic pre-ejection delay of more than 140 msec, an interventricular mechanical delay of more than 40 msec, or delayed activation of the posterolateral LV wall).37

There is no universally accepted method for measuring dyssynchrony, the methods may be operator or equipment dependent, and the strategy of using echocardiographic methods has not been tested against the well-studied strategy of using QRS duration. Therefore, caution should be applied when attempting to interpret echocardiographic measures of dyssynchrony in patients who meet standard criteria for CRT; in particular, caution should be applied when considering patients who do not meet criteria shown to benefit in randomized clinical trials (e.g. narrow QRS duration). Ongoing investigations will likely clarify use of imaging strategies for assessing dyssynchrony in the future.