Editor's Note: This Article of the Month is based on Curtis AB, Worley S. Adamson PB, et al. Biventricular Pacing for Atrioventricular Block and Systolic Dysfunction. NEJM 2013;368:1585-1593.

Summary

Patients with symptomatic atrioventricular (AV) block typically receive a single or dual chamber pacemaker that delivers right ventricular (RV) pacing. However, RV pacing has been associated with an increase in heart failure (HF) hospitalization and atrial fibrillation (AF)¹ and a composite of HF admissions plus mortality.² Compared to RV pacing, biventricular (BiV) pacing has been shown to preserve systolic function in patients with complete AV block and an LVEF of ≤ 45%.³ A large body of evidence exists for the treatment of symptomatic HF with BiV pacing^4-8, and cardiac resynchronization therapy (CRT) reduces mortality⁹ and the development of HF^9,10 in patients with significant systolic dysfunction. However, the evidence for prevention of HF attributable to RV pacing in patients with limited HF symptoms or mild systolic dysfunction is less robust.The current study, BLOCK-HF, compared BiV and RV pacing for patients with a need for "significant ventricular pacing" and NYHA class I-III HF utilizing a composite endpoint of death, urgent HF care and Left Ventricular End Systolic Volume Index (LVESVI).

Methods

In this study, 918 patients with a class I or IIa ventricular pacing indication, NYHA class I, II or III HF and an LVEF of ≤ 50% were deemed eligible for implantation with a CRT pacemaker (CRT-P) or defibrillator (CRT-D) as dictated by their clinical indication. Exactly 691 were implanted and randomized to either RV or BiV pacing and followed for a mean of 37 months. Patients were excluded if they had any prior cardiac implantable electrical device (CIED), an indication for CRT, valvular disease with an indication for repair or replacement, unstable angina, or an acute MI or coronary revascularization in the prior 30 days.

The pre-specified composite primary endpoint included time to death from any cause, HF care requiring IV therapy or a ≥ 15% increase in LVESVI (a measure of adverse cardiac remodeling).

Results

Compared to the RV pacing cohort, BiV pacing patients experienced statistically significantly fewer primary outcome events (first occurrence of death, urgent HF care requiring IV therapy or a ≥ 15% increase in LVESVI) with a hazard ratio (HR) of 0.74 and a 95% credible interval (CI) of 0.60 – 0.90. This benefit was similar for both pacemaker (n = 484, HR = 0.73, CI 0.58 – 0.91) and ICD patients (n = 207, HR = 0.75, CI 0.57 – 1.02) despite the LVEF for these groups being markedly different (mean LVEF for PM = 43.0%, ICD = 33.0%). Death, as an independent secondary outcome measure, was less frequent for the BiV pacing group but did not achieve a statistically significant reduction (HR = 0.83, CI 0.61-1.14). Hospitalization for heart failure was significantly reduced for the BiV pacing group (HR = 0.70, CI 0.52 – 0.93). However, an isolated secondary outcome result for LVESVI was not reported; a total of 154 patients' data was censored as a result of missing echocardiography data.

About 97 patients crossed over (13 BiV to RV, 84 RV to BiV), but the majority did so after a primary endpoint event (BiV 3 of 13, RV 50 of 84).

Of the 918 patients enrolled, 95 were deemed ineligible for device placement, typically as a result of AV nodal function testing. About 14 patients withdrew after initial enrollment but prior to device implantation. Of the 809 patients in whom CRT device placement was attempted, 51 (6.3%) were unsuccessful. Of the 758 receiving a CRT device, 4.9% suffered a device related adverse event in the six months following implant. Such events included implant site infection, lead dislodgement, pacing failure or inappropriate tissue stimulation.

Conclusions

In patients with a need for ventricular pacing, mild-to-moderate heart failure and some degree of systolic dysfunction, BiV pacing, as compared to RV pacing, resulted in a significant reduction in the composite primary outcome of death, urgent HF care and adverse LV remodeling. A secondary endpoint, HF hospitalization, was significantly reduced for the BiV pacing cohort. While not statistically significant, death was less frequent for the BiV paced patients.

Perspective

Previous studies including the Mode Selection Trial in Sinus-Node Dysfunction (MOST)¹ and the Dual Chamber and VVI Implantable Defibrillator (DAVID)² trial have demonstrated an association between RV pacing and heart failure. For every 10% increase in RV pacing, MOST patients suffered a 20% increase in HF hospitalization risk. In patients with ≥ 40% RV pacing, HF hospitalization risk was 2.5 fold higher than for patients with < 40% RV pacing. Based on results such as these, it is now standard practice to program non-CRT CIEDs to minimize RV pacing. For patients with abnormal AV nodal function, or for those who require beta blocker or other medical therapy, however, ventricular pacing is sometimes difficult or impossible to avoid. If frequent RV pacing is known to be detrimental, what is the best strategy for patients that require ventricular pacing?

The Post AV Nodal Ablation Evaluation (PAVE) study reported that patients with a LVEF of ≤ 45% and permanent AF who underwent AV nodal ablation preserved their LVEF and improved their 6 minute walk time when provided BiV instead of RV pacing. Patients in PAVE had complete heart block, but BLOCK-HF now expands the population shown to benefit from BiV pacing by enrolling patients with a "significant need for ventricular pacing", including some patients with prolonged first degree AV block. BLOCK-HF also allowed enrollment of patients with LVEFs as high as 50%. BLOCK HF adds further evidence that patients who require ventricular pacing are better served with a BiV pacing system rather than traditional RV pacing. BLOCK-HF's benefit of BiV pacing was similar for both CRT-P and CRT-D patients despite their disparate LVEFs (43% versus 33%) suggesting that that the degree of RV pacing, not the degree of systolic dysfunction, is the more important component in predicting a patient's need for BiV pacing. If a clinical trial were performed that enrolled patients with a need for ventricular pacing but without consideration of their LVEF, could benefits similar to that of BLOCK-HF be demonstrated for patients with normal LVEFs?

The high number of crossovers might give some readers pause. However, as the authors point out, the majority of crossover events occurred after a primary endpoint was observed. In addition, most crossover events were from the RV to the BiV pacing arm, and given the study's intention-to-treat design, such crossover would likely have diluted the impact of BiV pacing, suggesting the benefit may be even greater. It is thus likely that BLOCK-HF's stated conclusions are valid.

From a practical perspective, the incomplete echocardiographic data is perhaps the greater missed opportunity. Many implanting physicians are vigilant for signs of heart failure and LVEF declines in their patients receiving RV pacing. Detection of these downstream events typically results not only in a device upgrade, but also initiation of multi-drug HF medical therapy. The ability to perhaps intervene prior to the development of HF symptoms or LVEF declines would be worthwhile. If LVESVI or some other echocardiographic measure had demonstrated value as an early signal for adverse cardiac remodeling attributable to RV pacing, clinicians might have had a noninvasive tool for earlier detection of such changes.

BLOCK-HF is a significant step forward in our understanding of the detriments of RV pacing and the ability to reduce these detriments with BiV pacing. Patients who require significant ventricular pacing, even if their LVEF is as high as 50% or their HF is merely NYHA class I, should be considered for a CRT device instead of RV pacing.

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References

1. Sweeney MO, Hellkamp AS, Ellenbogen KA, et al. Adverse Effect of Ventricular Pacing on Heart Failure and Atrial Fibrillation Among Patients with Normal Baseline QRS Duration in a Clinical Trial of Pacemaker Therapy for Sinus Node Dysfunction (MOST). Circulation 2003;107: 2932-2937.
2. Wilkoff BL, Cook JR, Epstein AE, et al. Dual-Chamber Pacing or Ventricular Backup Pacing in Patients with an Implantable Defibrillator (DAVID). JAMA 2002; 288:3115-3123.
3. Doshi RN, Daoud EG, Fellows C, et al. Left Ventricular-based Cardiac Stimulation post AV Nodal Ablation Evaluation (PAVE). J Cardiovasc Electrophysiol 2005; 16:1160-1165.
4. Cazeau S, Leclercq C, Lavergne T, et al. Effects of Multisite Biventricular Pacing in Patients with Heart Failure and Intraventricular Conduction Delay (MUSTIC). N Engl J Med 2001; 344:873-880.
5. Auricchio A, Stellbrink C, Sack S, et al. Long-term Clinical Effect of Hemodynamically Optimized Cardiac Resynchronization in Patients with Heart Failure and Ventricular Conduction Delay (PATH-CHF). J Am Coll Cardiol 2002; 39:2026-2033.
6. Abraham WT, Fisher WG, Smith AL, et al. Cardiac Resynchronization in Chronic Heart Failure (MIRACLE). N Engl J Med 2002; 346:1845-53.
7. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac Resynchronization Therapy with or without an Implantable Defibrillator in Advanced Chronic Heart Failure (COMPANION). N Engl J Med 2004; 350:2140-2150.
8. Cleland JG, Daubert JC, Erdmann E, et al. The Effect of Cardiac Resynchronization on Morbidity and Mortality in Heart Failure (CARE-HF). N Engl J Med 2005; 352:1539-1549.
9. Moss AJ, Hall WJ, Cannom DS, et al. Cardiac-Resynchronization Therapy for the Prevention of Heart-Failure Events (MADIT-CRT). N Engl J Med 2009; 361:1-10.
10. 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 (REVERSE). J Am Coll Cardiol 2008; 52:1834-1843.

Keywords: Atrial Fibrillation, Atrioventricular Block, Heart Failure, Heart Ventricles

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