Systolic Blood Pressure and Outcome in Patients Admitted With Acute Heart Failure: An Analysis of Individual Patient Data From 4 Randomized Clinical Trials

Abstract

BACKGROUND In acute heart failure (AHF), systolic blood pressure (SBP) is an important clinical variable. This study assessed the association between SBP and short-term and long-term outcomes in a large cohort of patients with AHF. METHODS AND RESULTS This is an analysis of 4 randomized controlled trials investigating serelaxin versus placebo in patients admitted with AHF and SBPs from 125 to 180 mm Hg. Outcomes were 180-day all-cause mortality and a composite end point of all-cause mortality, worsening heart failure, or hospital readmission for heart failure the first 14 days. Left ventricular ejection fraction (LVEF) was examined as LVEF<40% and LVEF≥40%. Multivariable Cox regression models were adjusted for known confounders of outcomes in AHF. A total of 10 533 patients with a mean age of 73 (±12) years and a mean SBP of 145 (±7) mm Hg were included. LVEF was assessed in 9863 patients (93%); 4737 patients (45%) had LVEF<40%. Increasing SBP was inversely associated with 180-day mortality (adjusted hazard ratio [HRadjusted], 0.93; 95% CI, 0.89-0.98; P=0.008 per 10 mm Hg increase) and with the composite end point (HRadjusted, 0.90; 95% CI, 0.85-0.94; P<0.001 per 10 mm Hg increase). A significant interaction with LVEF was observed, revealing that SBP was not associated with mortality in patients with LVEF≥40% (HRadjusted, 0.98; 95% CI, 0.91-1.04; per 10 mm Hg increase), but was strongly associated with increased mortality in LVEF<40% (HRadjusted, 0.84; 95% CI, 0.77-0.92; per 10 mm Hg increase). CONCLUSIONS Elevated SBP is associated with favorable short-term and long-term outcomes in patients with AHF. In our predefined subgroup analysis, we found that baseline SBP was not associated with mortality in LVEF≥40%, but was strongly associated with mortality in patients with LVEF<40%.

Trial registration: ClinicalTrials.gov NCT01870778 NCT00520806 NCT02064868 NCT02007720.

Keywords: acute heart failure; blood pressure; left ventricular ejection fraction; mortality; worsening heart failure.

Conflict of interest statement

Dr Maggioni received personal fees for the participation in committees of studies sponsored by Novartis, Fresenius, and Bayer. Dr Nielsen received personal fees for the participation in committees of studies sponsored by Novartis and advisory boards sponsored by Astra‐Zeneca and Novo Nordisk. Dr López‐Sendón received personal fees and institutional grants for the participation in committees of studies sponsored by Novartis, Bayer, Sanofi, Merck, and Pfizer. Dr Ertl received personal fees for the participation in committees of studies sponsored by Novartis and Bayer. Dr Metra received personal fees from Actelion, Amgen, Astra‐Zeneca, Abbott Vascular, Bayer, Servier, Edwards Therapeutics, Livanova, Vifor Pharma, WindTree Therapeutics, and as a member of trials’ committees or for speeches at sponsored meetings. Dr Holbro is an employee and shareholder of Novartis Pharma AG. Dr Teerlink reports research support from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol‐Myers Squibb, Cytokinetics, Medtronic, Novartis, and Windtree Therapeutics and personal fees for consulting from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol‐Myers Squibb, Cytokinetics, Medtronic, Merck, Novartis, Servier, and Windtree Therapeutics. Dr Gimpelewicz is a Novartis employee.

Figures

Figure 1. Flowchart of study population.

SBP indicates systolic blood pressure. Relax‐AHF‐1, effects of serelaxin in patients with acute heart failure; RELAX‐AHF‐2, serelaxin, recombinant human relaxin‐2, for treatment of acute heart failure: a randomised, placebo‐controlled trial; RELAX‐AHF‐ASIA, the efficacy, safety, and tolerability of additional serelaxin administration to standard therapy in Asian patients with acute heart failure; RELAX‐AHF‐EU, efficacy and safety of serelaxin when added to standard of care in patients with acute heart failure: results from a PROBE study.

Figure 2. Risk of 180‐day all‐cause mortality (left) and short‐term composite end point (right; worsening heart failure, hospital readmission for heart failure, or all‐cause mortality through day 14) and as a function of systolic blood pressure at baseline as illustrated by a Cox regression model with cubic smoothing splines.

The mountain plot on top of the x axis shows the density of the population along the spline variable. Multivariable Cox models are adjusted for age, sex, baseline body mass index, left ventricular ejection fraction, serum estimated glomerular filtration rate, allocated treatment (placebo/serelaxin), diabetes, ischemic heart disease, and atrial fibrillation/flutter. The blue line shows the hazard ratios with their 2‐sided 95% CIs (light blue area).

Figure 3. Kaplan–Meier survival curves for specified subgroups showing the cumulated mortality rate through day 180 for the 2 blood pressure groups.

Left, Kaplan–Meier survival curve illustrates the subgroup with LVEF<40%. Middle, Kaplan–Meier survival curve illustrates the subgroup with LVEF 40% to 49%. Right, Kaplan–Meier survival curve shows the subgroup with LVEF≥50%. LVEF indicates left ventricular ejection fraction.

Figure 4. Risk of 180‐day mortality (left) and risk of a short‐term composite end point (right; worsening heart failure, hospital readmission for heart failure, or all‐cause mortality through day 14) as a function of systolic blood pressure at baseline illustrated by a multivariable Cox regression model with cubic smoothing splines.

The mountain plot on top of the x axis shows the density of the population along the spline variable. Multivariable Cox models are adjusted for age, sex, baseline body mass index, LVEF, serum estimated glomerular filtration rate, allocated treatment (placebo/serelaxin), diabetes, ischemic heart disease, and atrial fibrillation/flutter. The blue line shows the hazard ratios with their 2‐sided 95% CIs (light blue area). LVEF indicates left ventricular ejection fraction.

Figure 5. Subgroup analyses of a short‐term composite end point (left; worsening heart failure, hospital readmission for heart failure, or all‐cause mortality through day 14) and 180‐day mortality (right).

Hazard ratios with 95% CIs are from multivariable Cox regression models with the following prespecified covariates: age, sex, baseline body mass index, left ventricular ejection fraction, serum estimated glomerular filtration rate, allocated treatment (placebo/serelaxin), diabetes, ischemic heart disease, and atrial fibrillation/flutter. BP indicates blood pressure; and SBP, systolic blood pressure.