Cardiac resynchronization therapy (CRT) is beneficial in patients with New York Heart Association (NYHA) functional class III and IV heart failure and wide QRS duration, especially due to left bundle branch block (LBBB) or nonspecific intraventricular conduction defect. Since right ventricular (RV) apical pacing creates an LBBB morphology on surface electrocardiogram, it can also cause left ventricular (LV) dyssynchrony similar to that of intrinsic LBBB.
Using subset data from the InSync III trial, the aim of the current analysis was to assess the clinical impact of CRT in patients with and without previously implanted bradycardia pacemakers.
InSync III: Overview of Study Design and Results
InSync III trial was a multicenter safety and efficacy study of CRT performed on 189 patients in class II-IV heart failure with QRS ≥ 130 ms (unpaced) and LVEF ≤ 35%, including patients with underlying paced rhythm. The patients were mostly male with an average age of 66 ± 11 years and average LVEF of 24 ± 7%. About half of them had ischemic cardiomyopathy with average QRS width 176 ± 27 ms. Medical treatment was suboptimal, with only 50% receiving beta-blocker therapy.
Table 1. Total InSync III Population: Baseline Characteristics
| Characteristic | Patients (n = 189) |
|---|---|
| Male (%) | 72 |
| Age (yrs) | 66 ± 11 |
| CAD (%) | 42 |
| LVEF (%) | 24 ± 7 |
| LVEDD (mm) | 69 ± 9 |
| NYHA class (%) | |
| II | 17 |
| III | 69 |
| IV | 14 |
| QRS width (ms) | 176 ± 27 |
| ACE inhibitor (%) | 81 |
| Antiarrhythmic drug (%) | 25 |
| Beta-blocker (%) | 50 |
In the overall patient population, CRT was associated with significant improvements in NYHA functional class and 6-minute hall walk distance from baseline to 1- and 3-month follow-up (Table 2).
Table 2. Overall InSync III: Functional Class and 6-min Walk Distance Improvement
| N = 189 | NYHA |
P Value (vs baseline) |
6-min Walk Distance (meters) |
P Value (vs baseline) |
|---|---|---|---|---|
| Baseline | 2.97 ± 0.6 | -- | 329 ± 115 | -- |
| 1 month | 2.04 ± 0.7 | < .001 | 395 ± 144 | < .001 |
| 3 months | 1.87 ± 0.7 | < .001 | 402 ± 137 | < .001 |
Investigators of the current study stratified the overall InSync III patient population on the basis of whether or not they had a bradycardia pacemaker at time of enrollment. An additional analysis was performed to determine whether there were any clinical differences in outcome associated with CRT depending upon original pacing indication.
The primary hypotheses of the subset analysis were that:
CRT is an effective treatment for patients with a previous pacemaker.
Clinical impact may differ between patients with and without previous pacemakers.
CRT may be the treatment of choice in patients with classic pacing indications and cardiac disease.
Eighty-eight patients with complete baseline and 3-month follow-up data were included in the current subanalysis, of which 20% (n = 18) had a pacing indication, including third-degree AV block (9%), sinus node dysfunction (7%), or first/second AV block (4%). Baseline characteristics were well balanced between the paced and unpaced groups, with the exception of QRS width, which, as expected, was longer in the pacemaker group than in the nonpacemaker group (201 ± 30 ms vs 171 ± 28, respectively; P = .006), and there was a slight trend indicating the nonpaced group had larger LV dimensions (Table 3).
Table 3. InSync III Subset Analysis: Baseline Characteristics -- Pacing vs No Pacing
| Baseline | All (n = 88) |
No Pacemaker (n = 70) | Pacemaker (n = 18) |
|---|---|---|---|
| Male (%) | 76.1 | 75.7 | 77.8 |
| Age (yrs) | 67 ± 9.6 | 67 ± 9.9 | 67 ± 8.3 |
| CAD (%) | 47 | 49 | 39 |
| LVEF (%) | 24 ± 6.7 | 24 ± 6.7 | 22 ± 6.8 |
| LVEDD (mm) | 69.0 ± 8.4 | 69.8 ± 8.4 | 66 ± 8.0 |
| QRS (ms) | 177 ± 28 | 171 ± 23 | 201 ± 30* |
| NYHA class | 2.9 ± 0.6 | 29 ± 0.6 | 3.0 ± 0.4 |
| 6 min walk (m) | 334 ± 105 | 334 ± 108 | 335 ± 95 |
| Activity (min/day) | 168 ± 114 | 162 ± 113 | 192 ± 118 |
CAD = coronary artery disease; LVEF = left ventricular ejection fraction; LVEDD = left ventricular end diastolic dimension; NYHA = New York Heart Association
Compared with baseline, at 3 months, the pacemaker group experienced a significantly higher increase in 6-minute walk distance than the nonpaced group (152.2 ± 99 vs 67.2 ± 92, respectively; P = .02); there were similar improvements observed in NYHA class and duration of daily activity (Table 4). In addition, in the pacemaker group, patients with third-degree AV block benefitted the most with respect to 6-minute hall walk distance from baseline to follow-up (201.0 ± 58 vs 67.2 ± 92, respectively; P =.003) compared with other indications for pacing.
Table 4. Substudy Results: Changes From Baseline to 3-month Follow-up
| Previous Pacemaker | Change in NYHA Class | P Value | Change 6-min walk | P Value |
|---|---|---|---|---|
| None | 1.08 ± 0.73 | NS | 67.2 ± 92 | .02 |
| Yes | 1.18 ± 0.73 | 152.2 ± 99 |
Patients with a previously implanted pacemaker seemed to improve functionally as much as those with wide QRS secondary to intrinsic conduction defect. Those with a pacemaker had a wider QRS than those without and seemed to have longer 6-minute walking distance. There was no significant difference in NYHA class between the groups. Of the varying indications for pacemaker, third-degree heart block derived the most benefit.
As noted by the presenter, there were some limitations associated with the subanalysis; namely that it was retrospective and that the previous pacing mode, as well as the duration and extent of previous pacing, were unknown.
Comments
RV pacing causes worsening cardiac systolic function due to ventricular dyssynchrony similar to that caused by intrinsic LBBB. RV pacing has been compared to biventricular (BiV) pacing in the Multisite Stimulation in Cardiomyopathies - Atrial Fibrillation (MUSTIC-AF) and Left Ventricular-based Cardiac Stimulation Post AV Nodal Ablation Evaluation (PAVE) trials, which enrolled patients undergoing AV nodal ablation for atrial fibrillation. In these trials, BiV pacing was associated with improvements in exercise capacity and maintenance of LVEF.
In this subset analysis of InSync III, paced and nonpaced patients demonstrated similar benefits of CRT, which emphasizes the deleterious effects RV pacing has on LV synchrony. Perhaps if the current study had used more objective endpoints, such as VO2max, LVEF, and LV end diastolic dimensions, the results may have shown benefits of CRT on long-term follow-up. We await the results of future studies to establish more clearly the role that CRT plays in previously paced patients.
The results of this study found that patients with underlying third-degree AV block (a very small percentage of the overall patient group), appeared to gain the most benefit from CRT with respect to 6-minute hall walk distance compared with patients who had other indications for pacing. This finding may potentially be explained by the fact that these patients were likely paced more often than other pacemaker patients. The percentage of RV pacing has not been presented for comparison.
Overall, this study confirms that the dyssynchrony caused by RV pacing can be improved by CRT.
References
Gras D, Mortensen PT, Reiser W, et al. Is the clinical response to cardiac resynchronisation therapy in heart failure patients equal in patients with and without a previous pacemaker? Heart Rhythm. 2004;1:S16. Abstract 48.
Wilkoff BL, Cook JR, Epstein AE, et al; Dual Chamber and VVI Implantable Defibrillator Trial 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;288:3115-3123.
Leclercq C, Walker S, Linde C, et al; MUSTIC Investigators. Comparative effects of permanent biventricular and right- univentricular pacing in heart failure patients with chronic atrial fibrillation. Eur Heart J. 2002;23:1780-1787.