Visit-to-visit changes in heart rate in heart failure: a pooled participant-level analysis of the PARADIGM-HF and PARAGON-HF trials

Abstract Background Resting heart rate (HR) is a strong established marker of risk in patients with heart failure (HF), but the clinical implications of changes in HR over time are less well established. We aimed to explore the association between visit-to-visit changes in HR and cardiovascular (CV) outcomes in a pooled participant-level dataset of 2 large cohorts of patients with HF across the full range of left ventricular ejection fraction (LVEF). Methods PARADIGM-HF and PARAGON-HF were global, multicenter, randomized clinical trials testing sacubitril/valsartan against an active control (enalapril or valsartan, respectively) in patients with HF and LVEF ≤40% (in PARADIGM-HF) or LVEF ≥45% (in PARAGON-HF). Change in HR was defined as the difference in HR between a visit at any time and the preceding visit. The association between the change in HR and subsequent risk of first HF hospitalization (HFH) or CV death was assessed using Cox proportional hazards models, after adjusting for HR at the preceding visit and potential confounders. HR at any time was also assessed using repeated measures regression models with restricted cubic splines, and was plotted relative to time defined as the number of months prior to or immediately following a HFH event or end of follow-up. Patients who experienced HFH during the study period were compared to a control population who remained free of all-cause hospitalization and all-cause death during the follow-up period. Results A total of 13,194 patients (mean age 67±11 years, 67% men, mean LVEF 40±15%) were included. Heart rates were available in 16 visits in both PARADIGM-HF and PARAGON-HF. Over a median follow-up of 2.4 years, 3,114 patients underwent a first HFH or CV death (10.4 events per 100 patient-years). Any increase in HR from the preceding visit, compared with no change, was associated with a significantly higher risk of first HFH or CV death (Figure 1, adjusted hazard ratio 1.10, 95% confidence interval, CI: 1.08–1.13, P<0.001, per 5 bpm increase in HR). Conversely, a drop in HR was associated with significantly lower risk. This prognostic association between temporal changes of HR and risk of first HFH or CV death was consistent across the range of LVEF (Pinteraction=0.34) and seen irrespective of background use of β-blockers (Pinteraction=0.91). Relative increases in HR were especially prognostic in patients without a history of atrial fibrillation/flutter (Pinteraction=0.01). HR at any time appeared to increase during the 8 months prior to a HFH event, and remained elevated after hospitalization, in comparison to a relatively stable HR observed in the control group (Figure 2). Conclusions Across a broad spectrum of patients with chronic HF, relative increases in HR from a preceding visit strongly and independently predicted both CV and non-CV outcomes. Our findings suggest that detection of notable increases in HR between outpatient visits may help identify patients at heightened risk of adverse events.