In this clinical investigation we were able to demonstrate that heart rate at discharge is a predictor of mortality in patients with HFrEF and HFmrEF discharged to ambulatory care after an episode with ADHF. A heart rate ≥77 bpm was associated with a nearly two-fold increased mortality in this patient population. We could not detect differences for the role of this parameter in regard to the existing cardiac rhythm at discharge. In addition, this parameter was not predictive for rehospitalization.
The prognostic impact of heart rate in ADHF is still a matter of debate. In contrast to the predictive role of this biomarker in chronic systolic heart failure the role of heart rate in ADHF is much more controversial. This is partly due to differences in the time point when heart rate was measured during an acute decompensation period and focusing on different end points like in-hospital mortality and readmission in various studies16-22.
Risk of in-hospital mortality and particularly mortality and rehospitalization for patients hospitalized with ADHF remains high25. It is increased in patients with impaired metabolic status, neurohormonal activation and reduced cardiac performance, gauged by BUN, serum albumin and cholesterol levels, systolic blood pressure, heart rate, and respiratory rate26. Particularly, admission heart rate has been shown to be an independent risk factor for mortality during the acute phase as well as in the long term. A higher heart rate on admission was independently associated in a J-shape relationship with higher in-hospital mortality in ADHF patients with the lowest mortality seen at heart rates of 70-75 bpm16. Furthermore, a higher heart rate at presentation in the emergency department with ADHF was associated with an increased 7-day mortality27. On the other hand, higher admission heart rate can also predict survival advantage in acute HF and improve left ventricular reverse remodeling19, 28. However, lower heart rate is also a marker for increased in hospital mortality in ADHF, suggesting the existence of an ideal heart rate window in these patients18.
Some studies have correlated the difference between admission and discharge heart rate to hard cardiovascular end points20. Patients presenting with tachycardia and discharged with a controlled heart rate were shown to have a better outcome than those admitted non-tachycardic or discharged with a non-controlled heart rate19. These observations are explained by the hypothesis that elevated heart rate in the initial period of ADHF may be an indicator of preserved cardiac reserve and chronotropic competence, as the ability of the cardiovascular system to respond to this extraordinary stress situation with an adrenergic burst is preserved. Hence, heart rate recovery indicates a functioning vagal arm of the autonomous nervous system resulting in a better prognosis in patients with systolic heart failure. Nevertheless, both admission heart rate as well as heart rate difference (admission – discharge heart rate) are complicated to introduce into routine clinic algorithms for risk prediction in ADHF.
A variety of short and long-term mortality predictors have been analyzed in patients with ADHF. Nevertheless, application of a sophisticated risk-prediction algorithm to identify patients at high risk for mortality who might benefit from aggressive monitoring and intervention using various variables suggested in the Organized Program to Initiate Lifesaving Treatment In Hospitalized Patients With Heart Failure (OPTIMIZE-HF) trial are even more cumbersome to perform in routine clinical practice17, 25, 26.
Only few studies like ours have concentrated on heart rate at discharge for risk prediction. This parameter has several advantages: it is easy and reliably to determine, routinely available and reflects the most stable condition the patient is able to achieve and therefore may be much more relevant for the future course. Indeed, an elevated discharge heart rate is independently associated with a poor prognosis in patients revascularized with percutaneous coronary intervention for stable angina or acute coronary syndromes as well as after acute myocardial infarction21, 29.
Our results are in line with a big retrospective cohort study of registry data showing that a higher discharge heart rate after treatment for ADHF in unselected heart failure patients is associated with an increased risk of death and rehospitalization with an even higher risk in the first 30 days after discharge30.
The strength of our study is a high percentage of patients with guideline-based medical and device therapy and the unique long term follow up period with a mean duration of more than three years. Besides that, compared to previous studies we focused on patients with primarily systolic heart failure with an ejection fraction <50%. The population analyzed ended up with a sicker cohort of HFrEF and HFmrEF patients with a more severely reduced mean EF. Probably due to the nearly optimal guideline directed medical therapy and the younger mean age of our study cohort, the mortality rates were noticeably lower compared to previously published studies. However, observed survival rates similar to predicted survival rates calculated with the SHFM were confirmative to exclude selection bias.
Particular differences in the study cohort might account for the differences observed in the mortality rates. In contrast to our study the population investigated by Laskey et al. included patients who were nearly a decade older (median age 80 years) with systolic and diastolic heart failure. They had a more preserved LVEF (median 45%). In addition, this cohort included fewer ICD patients, more women and less patients with heart failure due to ischemic origin. Lastly, the follow-up period in this analysis was only 12 months. Overall, both studies underscore the positive association between discharge heart rate and mortality in patients with heart failure.
While this association is true for patients in sinus rhythm, the data in regard to Afib patients is less clear. Atrial fibrillation is not only independently associated with adverse prognosis in chronic but also in acute heart failure at least up to one year post discharge31. Only few studies have analyzed the relationship between heart rate and mortality in ADHF patients with atrial fibrillation thereby obtaining divergent results22, 30 In our study, we could not detect a difference in the association of heart rate at discharge and mortality between patients presenting in SR versus those with Afib, although there was tendency that Afib was more prevalent in patients who died (p=0,107; Table 2). A recent meta-analysis of randomized controlled trials suggests that in regard to mortality a lower heart rate in stable HFrEF patients is associated with a better prognosis only when patients were in sinus rhythm, while this association was not seen in Afib patients32.
The optimum heart rate at discharge in respect to mortality risk for heart failure patients is not clear. We performed an exploratory analysis of the heart rate – mortality association to determine a cut-off heart rate with incremental hazard. From previous and our investigation there seems to be an upper cut-off window of 75-76 bpm. When the resting heart rate is above this rate mortality seems to increase disproportionately. This upper cut-off window might be higher in Afib patients, although we were not able to detect significant differences in our study due to the small sample size and supposedly higher heart rate variability during Afib.
Lastly, in regard to the observed significantly higher mortality in patients taking xanthine oxidase inhibitors, indeed, in a recent systematic review and meta-analysis of uric acid-lowering agents on cardiovascular outcome in patients with heart failure treatments, allopurinol treatment was associated with a significant increase in the risk for all-cause and cardiovascular mortality33. Whether the observed effect of an increased mortality in patients treated with a xanthine oxidase inhibitor in our study is due to a treatment effect or elevated uric acid levels leading to medical treatment characterizes a sicker heart failure population cannot be answered with the data presented. Xanthine oxidase inhibition with allopurinol has not been demonstrated to show additional benefit nor harm in high-risk HFrEF patients with elevated uric acid levels34.