Prior pacemaker implantation associated with increased CV death and HF hospitalization in HFpEF
Prior Pacemaker Implantation and Clinical Outcomes in Patients With Heart Failure and Preserved Ejection Fraction
Introduction and methods
Conventional right ventricular (RV) pacing causes dyssynchronous contraction of the left ventricle(LV) in HF patients with reduced ejection fraction (HFrEF), which may result in worsening of LV systolic function and HF . The BLOCK-HF (Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block) trial showed that cardiac resynchronization therapy (CRT) was superior to RV pacing for clinical outcomes, including all-cause death, and need for urgent HF care, in HFrEF patients with atrioventricular block and an indication for pacing . As a result, recent guidelines recommend CRT for HFrEF patients who require a pacemaker for atrioventricular block or for those who already have a conventional pacemaker and a high frequency of RV pacing [3,4].
Some studies have shown that QRS prolongation and bundle branch block in HF with preserved EF (HFpEF) patients is associated with worse clinical outcomes compared to those without QRS prolongation and bundle branch block , but the effect of RV pacing on LV dyssynchrony in HFpEF patients is not known. Interestingly, some studies have suggested that conventional RV pacing may induce HF in patients without HF .
Altogether, it is suggested that RV pacing-induced LV dyssynchrony results in poor outcomes in HFpEF patients, similar as in those with HFrEF. Therefore, this study examined the association between baseline pacemaker implantation and clinical outcomes in HFpEF patients in 3 large randomized trials, the CHARM-Preserved (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity), the I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction), and the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial) [7-9].
The CHARM-Preserved trial included 3023 HF patients with NYHA functional classes II to IV with an ejection fraction (LVEF) >40%. The I-PRESERVE study enrolled 4128 patients ≥60 years with NYHA functional classes II to IV and with an LVEF ≥45%. The TOPCAT study included 3445 patients ≥50 years with NYHA functional classes II to IV with an LVEF ≥45%. For this analysis, patients with an LVEF <45% in the CHARM-Preserved study were excluded for a similar threshold across the trials, resulting in a total of 8466 patients, of which 682 (8%) with pacemaker at baseline.
Primary outcome was a composite of CV death or HF hospitalization and other outcomes were individual components of the composite, sudden death and pump failure death, and all-cause mortality.
- In an unadjusted analysis, implantation with pacemaker was associated with higher risk of the composite outcome compared to those without pacemaker, which remained significant after adjustment for prognostic factors (adjHR: 1.17, 95%CI:1.02-1.33, P=0.026).
- HF hospitalization was higher in those with pacemaker vs. those without, also after adjustment (adjHR: 1.37, 95%CI:1.17-1.60, P<0.001). CV death and all-cause mortality were higher in those with pacemaker compared to those without, but this was no longer significant after adjustment.
- There were no differences in sudden death according to pacemaker status. Pump failure death was more common in patients with a pacemaker than in those without, but the difference was no longer significant after adjustment for prognostic variables.
- There was no interaction between LVEF and pacemaker implantation for any of the outcomes.
An analysis of pooled data from 3 large HFpEF trials (CHARM-Preserved, I-PRESERVE, and TOPCAT) demonstrated that prior pacemaker implantation resulted in increased risk of CV death and hospitalization for HF compared to those without. These data suggest that in patients with prior pacemaker implantation, RV pacing may result in LV dyssynchrony leading to poor clinical outcomes.
In their editorial comment, Kaye and Patel  write that the study by Shen et al. ‘prompts one to question whether the presence of a pacemaker is simply a metric of disease origin or severity, or whether the application of pacing promotes the progression of HFpEF, and therefore, whether alternate pacing modalities should be considered.’ First they describe some of the mechanisms that can explain atrial mechanical and electrical dysfunction observed in HFpEF, including fibrosis, and cardiac amyloidosis (present in ~10% of HFpEF patients) and the consequence of atrial electrical pathology, that is, restriction in functional capacity. Then Kaye and Patel discuss the possibility that RV pacing induces poor outcomes in HFpEF and list several explanations. First, RV pacing was associated with worse outcomes when compared with biventricular pacing in patients with reduced LVEF and normal LVEF. Second, RV pacing increases the risk of developing AF. Third, LV dyssynchrony can induce mitral regurgitation, resulting in increased left arterial pressure. Finally, RV pacing in patients with pre-existing intraventricular conduction delay can worsen contractile dysfunction.
In the end, Kaye and Patel raise 2 questions that need attention in future trials. First, what form of pacing should be used in patients with conventional indications? Alternative options might include atrial, biatril, His-bundle or biventricular pacing. Second, can pacing play a role in the treatment of HFpEF? They end by stating that ‘there are presently few effective tools in the therapeutic arsenal available to treat patients with HFpEF. Although HFpEF is commonly considered a mechanical myocardial disorder, the common coexistence of arrhythmias and conduction delays in patients with HFpEF should prompt further evaluation of phenotype-specific electrophysiological adjuncts.’