Association of systolic blood pressure with mortality in patients with heart failure with reduced ejection fraction: a complex relationship

Abstract

Background: In ambulatory patients with heart failure with reduced ejection fraction (HFrEF), high systolic blood pressure (SBP) is associated with better outcomes. However, it is not known whether there is a ceiling beyond which high SBP has a detrimental effect. Thus, our aim was to assess the linearity of association between SBP and mortality.

Methods: We used the External Peer Review Program (EPRP) and Digitalis Investigation Group (DIG) trial databases of HFrEF patients. Linearity of association of SBP with mortality was assessed by plotting Martingale residuals against SBP. To assess the patterns of relationship of SBP with mortality, we used restricted cubic spline analysis with Cox proportional hazards model.

Results: In patients with mild-to-moderate left ventricular systolic dysfunction (LVSD) (30% ≤ LVEF < 50%), SBP had a nonlinear association with mortality in both EPRP (n = 3,693) and DIG (n = 3,263) databases. In these patients, SBP had a significant U-shaped association with mortality in EPRP and a trend toward U-shaped relationship in DIG database. In patients with severe LVSD (LVEF <30%), SBP had a linear association with mortality in both EPRP (n = 2,906) and DIG (n = 3,537) databases, with lower SBP being associated with increased mortality.

Conclusions: Systolic blood pressure has a complex nonlinear association with mortality in patients with heart failure. Whereas it has a U-shaped association in patients with mild-to-moderate LVSD, it has a linear association with mortality in patients with severe LVSD. Recognition of this pattern of association of blood pressure profile may help clinicians in providing better care for their patients and help improve existing prediction models.

Figure 1

Restricted cubic spline analysis for Cox proportional hazards model, in patients with heart failure with mild-to-moderate left ventricular systolic dysfunction (LVSD), showing A. significantly increased all-cause mortality for systolic blood pressure (SBP) below 120 mm Hg and above 150 mm Hg in External Peer Review Program (EPRP) database and B. significantly increased mortality for SBP below 110 mmHg and a non-significant increase above 150 mmHg in Digitalis Investigation Group (DIG) trial. Solid line represents the estimated logarithmic hazard ratio of all cause mortality with 95% pointwise confidence band represented by broken lines.

Figure 2

Restricted cubic spline analysis for Cox proportional hazards model, in patients with heart failure with severe left ventricular systolic dysfunction (LVSD), showing a relatively linear association of systolic blood pressure with all cause mortality in A. External Peer Review Program (EPRP) database and B. Digitalis Investigation Group (DIG) trial. Solid line represents the estimated logarithmic hazard ratio of all cause mortality with 95% pointwise confidence band represented by broken lines.