Recommended for all HF patients
Exacerbating factors addressed
Near optimal volume status observed
Transition from intravenous to oral diuretic successfully completed
Patient and family education completed, including clear discharge instructions
LVEF documented
Smoking cessation counseling initiated
Near optimal pharmacologic therapy achieved, including ACE inhibitor and beta blocker (for patients with reduced LVEF), or intolerance documented (Sections 7 and 11)
Follow-up clinic visit scheduled, usually for 7–10 days
Should be considered for patients with advanced HF or recurrent admissions for HF
Oral medication regimen stable for 24 h
No intravenous vasodilator or inotropic agent for 24 h
Ambulation before discharge to assess functional capacity after therapy
Plans for post-discharge management (scale present in home, visiting nurse or telephone follow up generally no longer than 3 days after discharge)
Referral for disease management, if available
The transition from the inpatient to the outpatient setting is a vulnerable time for patients who have been hospitalized for ADHF. Hospitalization for heart failure may reflect an important change in cardiac function and pathophysiology and may indicate that the trajectory of the patient’s underlying disease has changed. Patients are frequently discharged on a medical regimen that is different from and more complex than their regimen on admission. Patients are also discharged at a time when vital signs, volume status, renal function, appetite, salt and water intake, and the absorption, metabolism and effect of medications are changing. In addition, the majority of patients with heart failure have multiple comorbidities that are associated with an increased risk of mortality and preventable hospitalization and that are frequently not addressed during the ADHF hospitalization [35].
Patient Education
The education of patients, family members and care-providers is an essential component of discharge planning. Patients should be educated about:
- 1.
the dose, frequency and potential side effects of each medication; patients should be able to identify their medications and understand the reason for taking each medication; patients should receive explicit instructions about medication adjustment.
- 2.
warning signs and symptoms of worsening heart failure
- 3.
self-management skills including monitoring daily weights, controlling sodium intake, and monitoring blood pressure
- 4.
recommended level of activity
- 5.
clear guidelines for reporting signs and symptoms of heart failure, change in weight, and abnormal blood pressure to the appropriate care provider
- 6.
factors that may aggravate heart failure
- 7.
follow up in anticoagulation clinic in patients taking warfarin
In a randomized controlled trial of 223 patients hospitalized with ADHF, the addition of a 60 minute one-on-one teaching session with a nurse educator to the standard discharge process resulted in fewer days hospitalized or death within the first 180 days after discharge, a lower risk of rehospitalization or death, fewer heart failure hospitalizations, increased self-care measures and a reduced cost of care [37]. In a smaller study, patients hospitalized for ADHF were randomized to an in-hospital educational program conducted by a multidisciplinary team (nurse or educator and a pharmacist) or standard care. Patients randomized to the educational program showed higher knowledge scores at discharge, an improvement in quality of life measured by the MLWHF Questionnaire and trends toward better compliance with ACEI and β-blocker therapy [38].
Discharge on GDMT
Insuring that patients are discharged on appropriate heart failure medications reduces mortality and rehospitalization. An analysis from the National Heart Care Project (an initiative by the Centers for Medicare & Medicaid Services designed to improve the quality of care for Medicare beneficiaries hospitalized with heart failure) looked at 17,456 patients age ≥ 65 years who had systolic dysfunction and no contraindication to ACEI or ARB who survived hospitalization for heart failure. ACEI were prescribed to only 68 % of this ideal cohort. 78 % of patients were prescribed either an ACEI or ARB. ACEI prescription was associated with a lower risk-adjusted 1-year mortality rate (HR 0.86) [39].
The relationship between the five ACC/AHA performance measures for patients hospitalized with heart failure (discharge instructions, evaluation of left ventricular systolic function, ACEI or ARB for LV systolic dysfunction, adult smoking cessation counseling and anticoagulation at discharge for atrial fibrillation) and sixty- to ninety-day mortality and combined mortality/rehospitalization rates were evaluated in 5791 patients in the Follow-up Cohort in the OPTIMIZE-HF registry [40]. None of the 5 measures was significantly associated with risk-adjusted 60–90 day post-discharge mortality using multivariable and propensity-adjusted analysis. ACEI or ARB use at discharge was associated with a significant decrease in risk-adjusted 60–90 day mortality or rehospitalization (HR 0.51). Beta-blocker use at discharge, which was also evaluated, was associated with a significant reduction in 60–90 day mortality [HR 0.48] and combined mortality or rehospitalization (HR 0.73).
A hospital based discharge medication program was initiated by Intermountain Health Care, a non-profit integrated health system including 20 hospitals that serves ~60 % of the population of Utah and southern Idaho. The intent of this program was to insure that appropriate medications for secondary prevention were prescribed at discharge to all patients hospitalized for acute myocardial infarction, coronary heart disease, heart failure or atrial fibrillation. The measure for patients with HF was the prescription for an ACEI (or ARB if intolerant) at discharge. The proportion of HF patients who received a prescription for ACEI or ARB increased from ~64 % before the initiation of the program to > 90 % after. This was associated with statistically significant reductions in 30 day and 1 year mortality (HR of 0.76 and 0.77, respectively) and 30 day and 1 year readmission (HR of 0.84 and 0.91, respectively) [41].
Comorbidities
Addressing the long-term management of common comorbid conditions should be part of transitional care planning [35, 36]. Community acquired pneumonia, influenza and other respiratory infections are among the most common precipitants of hospitalization for ADHF [42, 43]. Influenza and pneumococcal vaccination remain significantly underutilized in heart failure patients. The prevalence of vaccination varies widely by region and country from 22 % – 37 % for influenza vaccine and 1 % to 22 % for pneumococcal vaccine [44–46]. Patients hospitalized for ADHF should have their immunization status for influenza and pneumococcal disease reviewed and updated [47–49].
Patient Safety
Systems of care that insure patient safety should be adopted by all hospitals. This includes the adoption of “Safe Practices” endorsed by the National Quality Forum [50]. This document emphasizes the importance of accurate and timely communication of clinical information among patient caregivers, medication reconciliation, and the important components of safe discharge practices.
Written Discharge Instructions and Discharge Summary
All patients should be provided with written discharge instructions that address: discharge medications, activity level, diet, weight monitoring, follow-up appointments and what to do if symptoms worsen. In addition, clear and specific care information should be transmitted in a timely manner from the cardiologist to all of the patient’s current health care providers and should address new medication initiation and dose up-titration, adverse effects of new medications, need for laboratory monitoring, and follow up plan [36, 51].
Post-discharge Follow Up
There is significant variation among institutions with respect to time from discharge to physician follow up [52]. The ACCF/AHA guidelines recommend scheduling an early follow-up visit within 7–14 days and an early telephone follow-up within 3 days of hospital discharge [33] The HFSA practice guidelines recommend a follow-up clinic visit in 7–10 days after hospital discharge [34].
Before discharge, at the first post-discharge visit and at all subsequent visits, the following should be addressed: the initiation, titration and optimization of GDMT; assessment of vital signs, volume status and systemic perfusion; assessment of electrolytes and renal function; screening for common causes of worsening heart failure; and reinforcement of HF education including medication adherence and self-monitoring [53].
Multidisciplinary Disease Management Programs
The ACCF/AHA, HFSA, Canadian Cardiovascular Society and ESC guidelines endorse the use of multidisciplinary heart failure disease management programs (DMP) for patients discharged after hospitalization for ADHF, especially those at high risk for hospital readmission [33, 34, 36, 54]. These programs generally include comprehensive discharge planning plus post-discharge support. The ESC Guidelines recommend that the key characteristics of a heart failure DMP include [54]:
- 1.
using a team approach
- 2.
providing inpatient and outpatient services
- 3.
discharge planning, education and counseling strategies which promote self-care
- 4.
ongoing optimization of medical therapy
- 5.
prescription of a flexible diuretic regimen
- 6.
close attention to clinical deterioration
- 7.
vigilant follow-up and enhanced access to care.
Multiple meta-analyses of DMPs have confirmed that these programs reduce all-cause mortality at 12 months, reduce HF-related readmissions at 12 months and improve quality of life [55–58]. Yu and colleagues compared randomized controlled clinical trials of DMPs that were and were not effective in improving discharge outcomes in an effort to identify the essential characteristics of DMPs that resulted in improved outcomes [57]. They concluded that to be effective, DMPs should be multifaceted and should include: an in-hospital phase of care; intensive patient education; self-care supportive strategies; optimization of GDMT; and ongoing surveillance for and management of clinical deterioration. Another meta-analysis suggested that DMPs that employ case management interventions where patients are intensively monitored by telephone calls and home visits (usually by a specialist nurse), were especially effective in improving outcomes [58]. Strategies that employ follow-up by a specialized multidisciplinary team are also especially effective [55].
There has been increasing interest in structured telephone support (STS) and especially in home telemonitoring (TM). STS is monitoring and/or self-care management delivered using simple telephone technology. Home telemonitoring is a form of non-invasive, remote patient monitoring that involves the use of electronic devices and telecommunication technologies (e.g., monitoring devices, hand-held or wearable technologies, and intelligent sensors) for the digital transmission of physiologic and other disease-related data from the patient’s home to a health care center providing care and clinical feedback. Several meta-analyses have demonstrated that STS reduces HF-related hospitalizations and probably all-cause mortality while TM reduces HF-related hospitalizations and all-cause mortality [59–61]. Both interventions improve quality of life, functional class, patient-knowledge and self-care [59].
A comprehensive systematic review and meta- analysis of transitional care interventions to prevent readmissions for people hospitalized with heart failure contracted by the Agency for Healthcare Research and Quality was recently published [62]. This analysis found that a high-intensity home-visiting program reduced all-cause readmission and the composite of all-cause readmission or death at 30 days and 3–6 months and decreased HF-specific readmission over 3–6 months. Multi-disciplinary HF (MDS-HF) clinic interventions reduced all-cause readmission. STS interventions reduced HF-specific readmission but not all cause readmission. Home-visiting programs, MDS-HF clinics, and STS interventions reduced mortality. Neither telemonitoring nor nurse-led clinic interventions reduced readmission or mortality.
Palliative Care
The ACCF/AHA and Canadian Cardiovascular Society (CCS) endorse early involvement of palliative care, especially in patients with advanced heart failure [33, 63, 64]. Palliative care needs to be distinguished from hospice. Palliative care is specialized multidisciplinary care that focuses on improving the quality of life for people of any age who are living with any serious illness. Hospice is a system of interdisciplinary care that is focused on improving quality of life and relieving suffering in the dying patient in the last months of life [65]. Palliative care should be considered in all patients with advanced heart failure to help identify and manage physical, psychological, and spiritual issues, to assist with decisions concerning advanced heart failure therapies, and to help with advance and end-of-life directives. Palliative care should be considered for many patients hospitalized with ADHF and should not be reserved for only patients at the end of life.
Risk for Rehospitalization
Transitional care is especially important in patients at high risk for rehospitalization. This includes patients with advanced age, previous hospitalizations for heart failure, multiple concomitant comorbidities, limited social support, frailty, cognitive and functional impairment or depression [66, 67]. A review of 26 unique readmission risk prediction models found that they performed poorly in discriminating which patients were at risk for rehospitalization [68]. Data from the EVEREST trial suggests that findings of persistent congestion identified a population at high risk for readmission [69]. Cognitive impairment measured by the Mini Cog exam in patients hospitalized for ADHF was found to be strongly associated with the composite end-point of rehospitalization or mortality (HR = 1.90) [70]. Cognitive impairment was identified as the most important predictor of post-discharge outcomes among 55 variables analyzed.
Other Issues
Treatment Based on Systolic Blood Pressure
Current practice guidelines emphasize the use of parenteral loop diuretics in the initial treatment of ADHF. Several expert panels have suggested that initial blood pressure be integrated into the initial treatment paradigm [71–73]. There is data that suggests that volume redistribution rather than volume overload causes acute decompensation in patients with ADHF who present with hypertension. In some of these patients, an acute increase in systemic vascular resistance results in an acute reduction in stroke volume and an acute elevation in PCWP with the rapid development of dyspnea with or without flash pulmonary edema. These patients generally do not have gradually progressive symptoms prior to hospitalization and have less evidence of edema and systemic venous congestion on presentation [74–76]. Mobilization of venous fluid from the splanchnic circulation may also play a role in these patients [77].
A consensus document from the Society of Academic Emergency Medicine /HFSA Acute Heart Failure Working Group has proposed that presenting systolic blood pressure be incorporated into the initial treatment paradigm by dividing patients into three groups: (1) hypertensive (SBP > 140 mmHg); (2) normotensive (SBP 100–140 mmHg); and (3) hypotensive (SBP < 100 mmHg). Patients in the hypertensive group would be treated with low dose diuretics and higher dose vasodilators. Patients in the normotensive group would be treated with diuretics and moderate dose vasodilators. Patients in the hypotensive group would be treated with diuretics and inotropes as needed [72]. There have been no prospective randomized trials that have evaluated a treatment strategy based on initial systolic blood pressure but several reports suggest that performing a randomized trial evaluating this approach is feasible [78–80].
Improving Survival After Hospitalization for ADHF
Hospitalization for ADHF is an event that identifies a patient at high risk for dying in the next year. In patients with chronic heart failure, HF hospitalization is a marker of disease progression and probably reflects a change in the trajectory of the underlying heart disease. A retrospective analysis from the Candesartan in Heart failure: Assessment of reduction in Mortality and morbidity (CHARM) trials assessed the risk after discharge from a first hospitalization for HF compared to patients who were not hospitalized for HF using time-updated Cox proportional-hazards models [81]. After adjustment for predictors of death, mortality rate was found to be increased after HF hospitalization with a HR of 3.15. Longer duration of hospitalization and repeat hospitalization increased the risk of dying. A retrospective analysis from the Digitalis Investigation Group (DIG) trial assessed the effect of incident HF hospitalization on subsequent mortality compared with no HF hospitalization in a propensity matched population [82]. Using matched Cox regression analysis, patients in the HF hospitalization group had a significantly increased risk of subsequent mortality compared with the no HF hospitalization group with a HR of 2.49. The HR for CV and HF mortality were 2.88 and 5.22, respectively. An analysis using health care utilization databases from British Columbia confirmed that the number of HF hospitalizations is a strong predictor of mortality in community HF patients with median survivals after the first, second, third and fourth hospitalizations of 2.4, 1.4, 1.0, and 0.6 years, respectively [83].
A number of clinical trials of newer medications that have attempted to show an impact on post-discharge outcomes have largely been negative. Agents that have been studied and shown to be ineffective include milrinone [84], nesiritide [85], the selective vasopressin (V2) receptor antagonist tolvaptan [86, 87], levosimendan [88], the direct renin inhibitor aliskerin [89], the adenosine A1 receptor antagonist rolofylline [90], and the endothelin receptor antagonist tezosentan [91]. There is substantial data that discharge on an ACEI and a β-blocker improves survival and decreases hospitalization [39–41, 92–94].
The Prospective Comparison of ARNI [Angiotensin Receptor–Neprilysin Inhibitor] with ACEI [Angiotensin-Converting–Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) Trial randomized 8442 patients with NYHA FC II, III or IV heart failure to receive a combination of valsartan and the neprilysin inhibitor sacubitril or enalapril [95–97]. The primary end-point of the trial was the composite of cardiovascular death and heart failure hospitalization. Neprilysin is a neutral endopeptidase inhibitor that degrades several endogenous vasoactive peptides including natriuretic peptides, bradykinin and adrenomedullin. Sacubitril inhibits neprilysin (but not ACE or aminopeptidase P) and increases the levels of natriuretic peptides, bradykinin and adrenomedullin. In PARADIGM-HF, when compared with enalapril, the combination of valsartan and sacubitril reduced the primary end-point by 20 %. Death from any cause was reduced by 16 %, cardiovascular death by 20 %, and HF hospitalization by 21 %. Symptoms and physical limitations of heart failure were decreased. This combination was well tolerated with lower proportions of hyperkalemia, renal impairment and cough compared with enalapril.
This study was not conducted with patients hospitalized for ADHF. The combination has been approved by the FDA for use in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction to reduce the risk of cardiovascular death and hospitalization for heart failure in place of ACEI or ARB. The combination is marketed as Entresto. There has not been a consensus document that addresses whether patients with ADHF should be started on Entresto instead of ACEI or ARB or switched from ACEI or ARB to Entresto during HF hospitalization.
Ongoing Drug Development
A number of new drugs with novel mechanisms of action are being evaluated in ongoing clinical trials in patients with ADHF [98, 99].
Relaxin/Serelaxin
Relaxin is a naturally occurring vasoactive peptide hormone that is produced by the placenta and corpus luteum and also by the failing myocardium. It acts on a G-protein coupled receptor, RXFP1, which is abundantly expressed in the cardiovascular, renal, and reproductive systems. Activation of RXFPI increases the production of cAMP with a resulting increase in nitric oxide production. In addition, relaxin has anti-inflammatory and anti-fibrotic effects and causes upregulation of vascular matrix metallo-proteinase-2 activity all of which result in vasodilation and increased vessel compliance [98–100].
In the Preliminary study of RELAXin in Acute Heart Failure (Pre-RELAX-AHF), 234 patients with acute heart failure, evidence of congestion on CXR, elevated BNP or NT-BNP, systolic blood pressure > 125 mmHg, and mild-moderate renal insufficiency were treated with standard care and randomized to a 48-h infusion of placebo or one of four doses of relaxin [101]. When compared to placebo, treatment with relaxin was associated with dyspnea improvement at 6, 12, and 24 h by Likert scale and through day 14 by visual analogue scale. In addition, patients treated with relaxin had a shorter length of stay, greater days alive and out of the hospital, and reduced risk of cardiovascular death or HF readmission.
The RELAXin in Acute Heart Failure (RELAX-AHF) Trial randomized 1161 patients with the same clinical characteristics as Pre-RELAX-AHF to receive standard care plus a 48-h infusion of placebo or serelaxin 30 mcg/kg per day [102]. Serelaxin is recombinant human relaxin-2. Serelaxin is identical in structure to naturally occurring relaxin and is formulated as a sterile solution for infusion. The study had two primary end-points that evaluated dyspnea improvement. Serelaxin improved the change in the visual analogue scale area under the curve (VAS AUC) from baseline to day 5. Serelaxin had no significant effect on the proportion of patients with moderate or marked dyspnea improvement measured by Likert scale during the first 24 h. Serelaxin had no effect on cardiovascular death or HF readmission at 60 days or days alive and out of the hospital at 60 days. Treatment with serelaxin was associated with fewer deaths at 180 days. Several phase three trials of serelaxin are ongoing.
Ularitide
Urodilatin is a natriuretic peptide that is synthesized and secreted by distal renal tubular cells. Following intraluminal secretion, it binds to NPR-A receptors in the inner medullary collecting duct regulating renal sodium resorption and water homeostasis via cGMP-dependent signal transduction. Intravenous urodilatin increases diuresis and natriuresis and reduces pulmonary capillary wedge pressure (PCWP) and systemic vascular resistance [98, 99, 103].
Ularitide is a synthetically derived form of urodilatin. The SIRIUS II trial was a phase 2, randomized, double-blind, placebo controlled, dose-finding study in 221 patients with acute decompensation of chronic heart failure with dyspnea at rest or with minimal activity, cardiac index ≤ 2.5 L/min/m2, and pulmonary capillary wedge pressure ≥18 mmHg. Patients received standard care and were randomized to a 24-h infusion of placebo or one of three doses of ularitide. At 6 h, patients treated with ularitide demonstrated a significant decrease in PCWP, improved dyspnea score, decreased systemic vascular resistance and increased cardiac index [104].The Efficacy and Safety of Ularitide for the Treatment of Acute Decompensated Heart Failure (TRUE-AHF) is an ongoing phase 3 trial designed to assess the effect of a 48-h continuous IV infusion of ularitide (15 ng/kg/min) versus placebo on the clinical status of patients with acute decompensated heart failure [43].
Istaroxime
Istaroxime is a novel steroidal intravenous inotropic agent unrelated to cardiac glycosides. The drug has unique inotropic/lusitropic properties [42, 98, 105]. Istaroxime inhibits Na+/K+ ATPase and stimulates sarcoplasmic reticulum Ca2+adenosine triphosphatase isoform 2a. This affects cytosolic accumulation of calcium during systole resulting in an inotropic response and rapid sequestration of calcium during diastole resulting in a lusitropic response.
The Hemodynamic, Echocardiographic and Neurohormonal Effects of Istaroxime, a Novel Inotropic Agent: A Randomized Controlled Trial in Patients with Heart Failure (HORIZON-HF) trial randomized 121 patients with acute decompensated heart failure and LVEF ≤ 35 % on standard heart failure therapy to a 6-h infusion of placebo or one of three doses of istaroxime [106]. Patients underwent pulmonary artery catheterization within 48 h of admission and prior to randomization. Comprehensive 2-dimensional, Doppler, and tissue Doppler echocardiography were performed immediately before and within the last 30 minutes of study drug infusion. The primary end-point of the trial was change in PCWP from baseline compared to placebo after the 6-h infusion. Istaroxime significantly reduced PCWP, left ventricular end-diastolic pressure and heart rate and increased systolic blood pressure and cardiac index. There were no changes in neurohormones, renal function or troponin I. In addition, istaroxime improved systolic and diastolic function by echo parameters with evidence of increased contractility and decreased diastolic stiffness.
Omecamtiv Mecarbil (OM)
Omecamtiv Mecarbil is a small-molecule, cardiac-selective myosin activator. OM increases the number of myosin heads interacting with actin resulting in the generation of greater contractile force. OM improves myocardial contractility by prolonging systolic ejection time without changing myocardial oxygen consumption, myocyte calcium levels or the rate of left ventricular pressure development (LV dP/dt). In contrast, dobutamine increases LV dP/dt, decreases systolic ejection time, and increases myocardial oxygen consumption [98, 99, 106]. In healthy men, OM infusion resulted in dose-related increases in systolic ejection time, associated with increases in stroke volume, fractional shortening, and ejection fraction without changes in diastolic function [13]. In the phase II Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure (ATOMIC-AHF) study, patients admitted with acute heart failure, LVEF ≤ 40 %, dyspnea and elevated natriuretic peptides were randomized to receive a 48-h infusion of placebo or one of three doses of OM [107]. The primary end-point was dyspnea relief at 6, 24 and 48 h using a patient-reported 7-level Likert scale. OM did not improve the primary endpoint. There were plasma concentration-related increases in left ventricular systolic ejection time (p < 0.0001) and decreases in end-systolic dimension (p < 0.05).
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