Postdischarge outcomes of patients hospitalized for heart failure






Marco METRA, MD
Valentina CARUBELLI, MD
Isotta CASTRINI, MD
Alice RAVERA, MD
Edoardo SCIATTI, MD
Carlo LOMBARDI, MD
Division of Cardiology
Department of Medical and Surgical Specialties
Radiological Sciences and Public Health
University and Civil Hospital of Brescia
Brescia, ITALY

Postdischarge outcomes of patients hospitalized for heart failure


by M. Metra, V. Carubelli, I. Castrini, A. Ravera, E. Sciatti, and C. Lombardi, Italy



Hospitalization of patients for heart failure is a landmark event in the clinical course of the disease. It reflects the prevalence of mechanisms causing fluid overload and/or lung congestion with symptoms of severe dyspnea and/or fatigue and need of urgent treatment and hospitalization. Despite relatively rapid relief of symptoms, hospitalizations for heart failure are followed by an increased risk of death and rehospitalizations. The mechanisms of these poor postdischarge outcomes are still incompletely understood and, to date, no treatment has improved such outcomes. Comorbidities, persistent congestion, and end-organ damage likely play a major role.

Medicographia. 2015;37:139-143 (see French abstract on page 143)



The prognosis of ambulatory patients with chronic heart failure and reduced ejection fraction (HFREF) has substantially improved in recent years with a decrease in hospitalizations and a slightly lower, though still significant, reduction in mortality.1-5 Annual mortality rates average 7%-8% for these patients.4,5 However, heart failure (HF) remains a progressive disease and the rate of episodes of worsening HF is high, up to 20%-30% each year, in outpatients with chronic HF,4,5 with an increased risk even in patients showing ejection fraction (EF) recovery.6

Outcome rates after HF hospitalization

HF is the most important cause of hospitalization for subjects aged over 65 years and HF hospitalizations are a landmark event in the clinical course of the disease. Patients hospitalized for HF have an unacceptably high event rate, with up to 50% possibly having further events with a 10%-15% mortality rate and a 30%-40% rehospitalization rate within the first 6 months after discharge.3,7,8 Unlike for acute coronary syndromes and chronic HFREF, there is as yet no evidence of efficacy for any new specific treatment for patients hospitalized for HF, thus no change in treatment and prognosis has occurred in recent decades.

In the recent ESC-HF pilot survey (European Society of Cardiology Heart Failure pilot) of the EURObservational Research Program, there were 2 patient groups: (i) ambulatory outpatients with chronic stable HF and (ii) patients hospitalized for acute HF. Patients with chronic HF had an annual all-cause mortality of 7.2% with an annual hospitalization rate of 31.9%. These rates increased to 17.4% and 43.9%, respectively, in the patients hospitalized for acute HF.5 Similarly, the annual mortality rates of patients in the IN-HF survey (Italian Network on Heart Failure) were 5.9% in chronic outpatients with HF, and 19.2% and 27.7% in the patients hospitalized for either new-onset or chronic decompensated acute HF, respectively.4 Longitudinal prospective clinical trials have shown similar results. Compared with patients who remain in stable clinical condition, patients hospitalized for HF show a dramatic increase in their risk of dying and this is independent from baseline EF, with no difference between patients with HFREF and those with preserved EF (HFPEF).9,10 This risk of death decreases exponentially in the months following discharge, but remains three- to fourfold higher even 12-18 months after the initial hospitalization.9,11,12 HF hospitalizations are therefore associated with an increased risk of long-term death, and this effect on patient prognosis is similar to that described for acute coronary syndromes.11

Thus, improving postdischarge outcome in HF patients remains a major unmet need of current clinical practice. A better understanding of the mechanisms underlying the poor prognosis of patients hospitalized for HF may help provide better care and improve postdischarge readmission and mortality.

Deaths and hospitalizations: is there a relation?

Rehospitalization and mortality are the most important outcomes in acute HF trials. However, they are not necessarily related. Early rehospitalizations 30 days after discharge are an important performance measurement for US hospitals.13 However, early rehospitalizations are poorly related to postdischarge mortality8,14 and an inverse relationship between 30- day rehospitalizations and mortality has even been shown.13,15 In the RELAX-AHF trial (RELAXin for the treatment of acute HF), serelaxin was associated with a lower numerical incidence of 60-day mortality and a higher 60-day rehospitalization rate.16 Whereas hospitalizations in patients with chronic HF are an index of HF severity and precede deaths,9-12 early postdischarge rehospitalizations may have a different meaning, as shown by their poor relation to mortality. Social support, patient adherence to treatment, and relief from congestion at the time of discharge may have a major role.17,18 Other factors influencing the early postdischarge rehospitalization rate are the length of the initial hospitalization—with an inverse relation in some,13,19 but not all,9 studies—and the volume of HF patients in the emergency department.20 An increase in body weight after discharge, a marker of congestion, has been associated with an increased risk of rehospitalization, but not of mortality.18




Major influences on postdischarge outcomes in HF

Three major causes seem to affect postdischarge outcomes in HF patients: comorbidities, congestion, and end-organ damage, with the 2 latter causes likely related.

Comorbidities
Comorbidities, cardiovascular and noncardiovascular, have a major role in the postdischarge event rates of patients with HF. As they are, or seem, less likely to be influenced by HF treatment, they tend to be overlooked. Cardiovascular comorbidities that may precipitate rehospitalizations include myocardial ischemia, arrhythmias—namely atrial fibrillation—and uncontrolled hypertension. They are all tightly related to the clinical course of HF and may be potentially treated by targeted therapy at the time of first hospitalization.

The role of noncardiovascular comorbidities is extremely important, especially for rehospitalizations. In an analysis of the causes of rehospitalizations in US hospitals, the proportion of patients readmitted for the same condition was 35.2% after a first HF hospitalization.21 Thus, the majority of readmissions after a first HF hospitalization may not be due to HF itself.

In the EVEREST trial (Efficacy of Vasopressin antagonism in hEart failuRE: outcome Study with Tolvaptan), among the 4133 randomized patients, there were 5239 rehospitalizations and 1080 deaths during a median of 9.9 months. Of all the rehospitalizations, 39.2% were noncardiovascular, 46.3% were due to HF, and a minority due to stroke, myocardial infarction (MI), arrhythmia, or other cardiovascular causes. Of all deaths, 13.2% were due to noncardiovascular causes, 41.0% to HF, 26.0% to sudden cardiac death (SCD), and the rest to MI or stroke.22 Similar data were more recently obtained in the RELAX-AHF trial, with 19 of the 107 deaths (18%) due to noncardiovascular causes, 37 (35%) due to HF, 25 (23%) due to SCD, 15 (14%) due to other cardiovascular causes, and 11 (10%) classified as unknown.23

Patients enrolled in controlled trials generally have a lower prevalence of comorbidities compared with those in the “real world.” The impact of noncardiovascular causes of hospitalizations and death is therefore larger in observational studies. In the ESC-HF pilot survey, diabetes, chronic kidney disease, and anemia were independently associated with a higher risk of mortality and/or HF hospitalization.24 Other noncardiovascular comorbidities that may cause rehospitalizations include infections, chronic kidney dysfunction, and chronic pulmonary disease.8,17,25 Elevated blood glucose levels on admission and iron deficiency have also been shown to be independent prognostic factors in patients hospitalized for HF.26-29 In an analysis from the Cardiovascular Health Study of the risk factors for all-cause hospitalizations among elderly patients with a new diagnosis of HF, the only 2 cardiovascular variables related to outcomes were left ventricular EF and New York Heart Association (NYHA) class, whereas many noncardiovascular factors, namely diabetes mellitus, chronic kidney disease, weak grip strength, slow gait speed, and depression had prognostic value.30 As previously pointed out, many other noncardiovascular factors related to patient characteristics may affect early rehospitalizations. These include lack of adherence to treatment, dietary indiscretion, drug and alcohol abuse, family and social support, and access to care.8

Congestion
Congestion is the main cause of HF hospitalizations.7,8,31 Most HF hospitalizations are heralded by a gain in body weight18,32 and, when this does not occur because of prevailing fluid redistribution,33 other markers of congestion, such as pulmonary artery pressure or B-type natriuretic peptide (BNP) plasma levels are increased.34,35 Congestion also has a major role as a cause of postdischarge deaths and rehospitalizations.

Lack of, or slower, resolution of signs and symptoms of congestion during the first days of hospitalization for HF is associated with more adverse outcomes.31,36 In its most extreme form, lack of decongestion manifests as in-hospital worsening HF, and this event is an independent predictor of increased mortality.36-40 Clinical signs are poor surrogates of the hemodynamic status, and measurement of BNP levels may identify persistent congestion even in the presence of a seeming resolution of clinical signs.31 Lack of decrease in BNP levels during hospitalization is associated with poor prognosis.41 In the RELAX-AHF study, both worsening HF during the hospital stay and a lack of decrease in N-terminal proBNP (NTproBNP) levels during hospitalization were associated with increased 180-day all-cause mortality.35

Assessment of signs of congestion, such as pulmonary rales, jugular venous pressure, peripheral edema, and weight gain, is also important at the time of discharge or early after discharge.18,42 During hospitalization, better prognostic assessment can be obtained by other measurements, such as pulmonary artery pressure monitoring or, more simply, by BNP or NT-proBNP levels.31,35,43-46


Figure 1
Figure 1. Mechanisms of the increase in the risk of death and rehospitalizations in
patients hospitalized for heart failure decompensation.



Organ damage
There are reasons to hypothesize that congestion is not the only determinant of the increase in cardiovascular events after discharge (Figure 1). Firstly, studies have shown that measurements related to congestion, such as weight gain, or poor diuretic response, are associated with rehospitalizations and short-term outcomes, but not with long-term mortality.18,47 Secondly, risk of death after a HF hospitalization remains increased in the long-term, up to at least 12-18 months after the event.9,11,29 This is consistent with persistent organ damage associated with the hospitalization, similar to what occurs after acute MI, rather than a mechanism more likely to cause symptoms, eg, congestion. Thirdly, in addition to BNP levels, other markers related to organ damage and/or function are independently related to outcomes, namely mortality, after a HF hospitalization.

The RELAX-AHF trial was particularly important with this respect, as biomarker measurements were repeated at baseline and during hospitalization and, differently from other cases,48 the study drug was not associated with untoward effects on outcomes. Changes in markers of myocardial damage (serum troponins), renal function (cystatin C), and liver function (transaminases) were shown to have an independent relation to 180-day mortality, which persisted after adjustment for their baseline values.40

Multiple mechanisms may cause myocardial damage during acute HF.49 Consistently, an increase in plasma troponin levels is very common in patients hospitalized for HF and serum troponin levels are independent predictors of subsequent outcomes. In addition to baseline values and a rise in serum troponin levels during hospitalization, an index of an event-related myocardial necrosis, is a powerfulpredictorofoutcomes.50,51 The relationship between chronic renal dysfunction and/or worsening renal function and poor outcomes in patients with HF is well established.52,53 However, there are important exceptions, as an increase in serum creatinine may have a neutral, or even favorable, significance when it occurs after intensive diuretic treatment or after the initiation of renin angiotensin inhibitors.53-56 Acute HF may cause kidney dysfunction through multiple mechanisms.53 More recently, the role of hepatic dysfunction has been shown. The increase in inferior vena cava pressure, caused by congestion, is transmitted backward causing cholestasis and death of the hepatocytes, shown by an increase in serum transaminases, and this has independent prognostic value.40,57

Conclusions

Hospitalization is a landmark event in the clinical history of HF patients. It is caused by severe symptoms and their emergence is due to prevalence of the mechanisms causing fluid retention and congestion. Such an event is attended by other mechanisms, which in addition to the untoward effects of the hospitalization itself and to the effect of persistent congestion, cause organ damage with further deterioration of patient prognosis and increased mortality. This is the vicious cycle that new treatments for HF decompensation must try to interrupt.

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Keywords: heart failure; outcomes; postdischarge; prognosis