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Therapeutic options for chronic HFrEF are well delineated and are founded in strong clinical trial evidence. In contrast, therapy for AHF has been met with largely negative or neutral clinical trials and less established treatment protocols. As new treatment options for AHF emerge, there is a critical need to identify patients appropriate for various therapies. Careful consideration should be paid to the need for inpatient management.50 A general approach to the treatment of AHF is addressed in the American College of Cardiology (ACC)/American Heart Association (AHA)51 guidelines, which include recommendations for the following: immediate determination of volume and perfusion status; addressing precipitating factors and comorbidities; recognition of acuity versus chronicity of the disease process; interpretation of contributing biomarker data; initiation or cautious uptitration of loop diuretic therapy without time delay; and initiation of intravenous inotropic or vasopressor drugs in those patients with systemic hypotension as indicated by acute kidney injury or change in mental status and severe elevation in cardiac filling pressures. Treatment of AHF centers on maintenance or restoration of systemic perfusion and preservation of end-organ performance and relieving congestion, while consideration of more definitive or advanced therapies takes place. In most patients admitted with AHF and HFrEF, chronic oral maintenance therapies, such as β-blocker (BB), ACE inhibitor (ACEI), or angiotensin receptor blocker (ARB), can be continued without interruption, assuming relative hemodynamic stability. In patients with HFrEF who are not already on neurohormonal antagonist medications, these agents should be initiated once hemodynamic stability and euvolemia have been achieved, because these therapies are known to improve outcomes51 (Table 71–2). Hospitalization provides an opportunity for timely and comprehensive assessment.52
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There is significant variability in patients who present with AHF, making appropriate classification paramount to appropriate triage and therapeutic targets. Although the majority of patients present with congestion, there is a significant variability in underlying cardiac and noncardiac comorbidities and variation in clinical presentation in AHF. There are many published classification systems for AHF (Table 71–3). The European Society of Cardiology (ESC) guidelines propose six clinical profiles, including: (1) worsening or decompensated chronic HF, (2) pulmonary edema, (3) hypertensive HF, (4) cardiogenic shock, (5) isolated right HF, and (6) acute coronary syndrome and HF.53 The ACC/AHA describes three groups, including: (1) patients with volume overload (generally with pulmonary and/or systemic congestion and often hypertension), (2) those with hypotension and severe reduction in CO, and (3) those with combination cardiogenic shock and congestion.54
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Pang et al55 describe a classification framework combining both ACC/AHA and ESC guidelines, highlighting the need for optimization of management of known targets and the importance of recognizing “responders” to therapy.55 Gheorghiade and Braunwald56 propose a six-axis model in which severity informs immediate versus deferred therapy and inpatient management, using readily available intake parameters. This model takes into account de novo versus worsening chronic HF, blood pressure (low, normal, or high), heart rate and rhythm, severity of dyspnea, comorbidities, and precipitants.56 Felker et al57B highlighted a need for classification with respect to clinical trial design, proposing a clinically useful classification framework in this context. The authors recommend separation into clinical profiles of AHF based on patients with AHF and hypertension, hypotension, volume overload, and other precipitating factors.57B
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Signs, Symptoms, Physical Examination, and Hemodynamic Profiling
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Dyspnea, or breathlessness, is the most common symptom reported by patients with AHF regardless of severity, followed by fatigue. In Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF),58 64% of enrolled patients had rales on exam, likely reflecting increased pulmonary capillary wedge pressure (PCWP). Dyspnea can be assessed by the provocative dyspnea assessment, which uses varying positions and maneuvers to assess level of dyspnea under stress, with and without oxygen.59 Pang et al60 proposed a dyspnea severity score, based on provocative dyspnea assessment performance using a 5-point Likert scale to standardize degree of dyspnea in clinical trials. Signs and symptoms in AHF vary based on clinical phenotype and inform treatment decisions.57 For example, patients in AHF who present with hypertension may present with primarily pulmonary congestion with or without systemic congestion, with acute pulmonary edema in the most severe cases. AHF patients with worsening chronic HF and volume overload are likely to present with peripheral edema and less likely pulmonary or radiographic congestion. Patients with AHF and hypotension suggestive of a low CO state may have symptoms of poor end-organ perfusion, such as confusion, lethargy, and abdominal discomfort. A small subset of these patients present in cardiogenic shock.57 Those with isolated right HF are likely to present with absence of pulmonary congestion with signs of low LV filling pressures with or without hepatomegaly.53
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The physical exam in AHF must focus on vital signs (tachycardia, hyper- vs hypotension, narrow pulse pressure), heart and lung exam, neck veins, and assessment of volume overload in general.51 The presence of jugular venous distention suggests elevated right-sided filling pressures, which in 80% of cases suggests elevated left-sided filling pressures.61 In AHF, proportional pulse pressure ([systolic – diastolic blood pressure]/systolic blood pressure) < 25% is associated with low cardiac index (< 2.2 L/min/m2) with high sensitivity and specificity, and can therefore be an easy clinical marker.62 Cardiac exam may reveal a third heart sound, suggestive of LV dilatation, or fourth heart sound, which may indicate poor LV compliance. The Valsalva maneuver may be used to indicate the presence of altered arterial pressures, suggesting LV systolic dysfunction,63 but may be more challenging to perform in the acute setting. New or worsened murmur may indicate worsened ventricular dilatation or new valvular disease. Lung exam can reveal rales or wheezing. Abdominal exam may reveal hepatomegaly signifying passive congestion, or ascites. The presence of a hepatojugular reflux can indicate right ventricular dysfunction. Extremity exam can provide insight on both congestion (presence of lower extremity and dependent edema) and perfusion (poor capillary refill, cool temperature) (Table 71–4).59
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Hemodynamic Profiling
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The conventional approach to therapy in AHF begins with bedside determination of the hemodynamic profile. Nohria et al64 described four patient profiles based on volume and perfusion status (Fig. 71–7). This simple classification has proven to be very useful in clinical practice.
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Profile A: Patients without evidence of congestion with adequate perfusion (“dry-warm”)
Profile B: Patients with congestion but adequate perfusion (“wet-warm”)
Profile C: Patients with congestion and hypoperfusion (“wet-cold”)
Profile L: Patients without congestion, with hypoperfusion (“dry-cold”)64
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Survival analysis revealed that clinical profiles predicted outcomes in HF, with profiles B and C portending increased risk of death or urgent transplantation, adding prognostic value even when limited to patients with New York Heart Association (NYHA) class III and IV symptoms. The presence of congestion was determined by orthopnea and/or physical exam evidence of jugular venous distention, pulmonary rales, hepatojugular reflux, ascites, peripheral edema, leftward radiation of the pulmonic heart sound, or a square wave blood pressure response to the Valsalva maneuver. Perfusion status was determined by the presence of narrow pulse pressure ([systolic – diastolic]/systolic blood pressure < 25%), pulsus alternans, symptomatic hypotension, cool extremities, and/or impairment in mentation.64
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Patients with profile A (“dry-warm”) are compensated from a cardiac perspective, and presence of dyspnea in these patients should prompt evaluation for alternative causes of dyspnea. These patients, if not already taking a BB and ACEI/ARB should have these medications initiated and uptitrated as tolerated. Patients with profile B (“wet-warm”) generally require diuresis with or without vasodilation. Importantly, profile B patients generally do not require lowering or discontinuation of their background HF medications. Profile C (“wet-cold”) patients, in contrast, are generally a sicker group who may require inotropic support in order to achieve adequate diuresis and may require alteration in background HF medications such as holding or lowering BB and ACEI/ARB secondary to hypotension and/or WRF. This group may also require invasive hemodynamic monitoring, particularly if conventional therapy does not result in clinical improvement. Lastly, patients with profile L (“dry-cold”) are not common but include those with severe limitation in cardiovascular reserve.64 Along with symptom relief, careful consideration to more definitive therapies for HF or advanced planning should be considered for these patients.
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Several diagnostic tests are essential as part of a workup for AHF. All patient should have an electrocardiogram in the emergency department.51 Specific attention should be paid to signs of acute coronary syndromes and ischemia, QRS prolongation potentially indicating ischemia or ventricular dyssynchrony or dilatation, atrial and ventricular arrhythmias, and heart block. Chest radiography should be performed to assess for pulmonary congestion, cardiomegaly, pleural and pericardial effusions, and the other pulmonary processes that may be contributing factors, such as infection or pulmonary disease.59 Initial laboratory testing should include complete blood count, serum electrolytes, renal indices, liver function testing, and urinalysis. Specific attention should be paid to the presence of hyponatremia, anemia, and renal function. Evidence of hepatic abnormalities may signify passive congestion and right ventricular dysfunction. Measurement of natriuretic peptides is recommended for patients in whom the diagnosis of AHF is undetermined or for additional prognostic information.51
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Other noninvasive testing includes echocardiogram and, in appropriate cases, assessment for the presence of ischemia and myocardial viability. Echocardiography can be useful for determining severity of valvular abnormalities, assessment of diastolic dysfunction, quantification of pulmonary hypertension by estimation of pulmonary artery systolic pressures, and other hemodynamic parameters noninvasively.65 Most importantly, echocardiogram is often useful in providing estimated right atrial pressure using the inferior vena cava size and collapse index. Transesophageal echocardiography may be performed in AHF patients who have inadequate quality of transthoracic images, in cases of severe valvular disease for additional quantification, in suspected endocarditis, in patients with suspected source of cardiac thrombus, and in congenital disease.66 Although the role of handheld echocardiography is still evolving, this imaging modality may aid in estimation of LV filling pressures as well.67 There are several modalities that can be used for noninvasive assessment of myocardial ischemia and/or viability in suitable patients. These include stress echocardiography, nuclear imaging (single-photon emission computed tomography and positron emission tomography), as well as cardiac magnetic resonance imaging.51
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Pulmonary Artery (Swan-Ganz) Catheterization: Use and Indications
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Pulmonary artery catheters (PACs) have historically been used as part of a “tailored therapy” approach in AHF. More recently, routine use of PAC-guided management has been discouraged.68 The Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization and Effectiveness (ESCAPE) trial evaluated the use of PACs in patients hospitalized with HF in whom the use of a PAC was deemed to be of potential benefit but not essential.69 The use of PACs was compared to clinical assessment alone in 433 patients with comparable baseline characteristics, including severe elevation in PCWP, diminished LV ejection fraction, and cardiac index 1.9 ± 0.6 L/min/m2. The ESCAPE trial reported no differences between groups in the primary end point of days alive out of the hospital. Subgroup analysis showed a trend toward improved outcomes in the PAC group in the highest enrollment centers and a trend toward favor of PAC group for functional assessment (6-minute walk, Minnesota Living With Heart Failure testing), but also a trend toward higher adverse events.
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It is important to note that the ESCAPE trial excluded patients whom physicians felt clearly required PAC for optimal management and involved physician investigators who were highly experienced in the evaluation and treatment of HF. With the bedside availability of astute physical exam skills, serum biomarkers and laboratory results, and point-of-care and advanced imaging techniques, PACs should be reserved for selective situations.70 The ACC/AHA guidelines state that invasive hemodynamic monitoring should not be routinely used, but can play a role in carefully selected patients for whom hemodynamics are unclear or AHF symptoms are persistent.51
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There may be a role for use of PACs, when performed by skilled operators knowledgeable in hemodynamic assessment, in identifying high-risk HF patients with persistent hemodynamic abnormalities, as well as in the trials for development of novel agents; however, improvement in education and guidelines are necessary to establish appropriate contemporary use of PACs.71
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Predicting individual risk in patients with AHF is challenging because of tremendous diversity in clinical presentation and underlying pathophysiology. The use of biomarkers can be additive in predicting risk after an AHF hospitalization72 and inform decision making regarding treatment.73 Different biomarkers for use in AHF relate to the varied underlying pathophysiologic targets (Fig. 71–8).73 Biomarkers reflecting myocardial stretch, the natriuretic peptides, are the most widely studied and used in AHF patients, and are powerful predictors of outcome.74 Both atrial natriuretic peptide and B-type natriuretic peptide (BNP) have vasodilatory, natriuretic, and diuretic properties.75 N-terminal pro–B-type natriuretic peptide (NT-proBNP) is a part of the precursor peptide BNP and has a longer half-life.76 BNP and NT-proBNP are similar for diagnosis of AHF,77 but NT-proBNP is superior in predicting clinical outcome.78 Serial measurement may add to prognostic prediction. The Pro-BNP Outpatient Tailored Chronic Heart Failure Therapy (PROTECT) study showed that a 50% reduction in NT-proBNP correlated with a nearly 50% reduction in event rate.79 Discharge value may be more predictive than admission value.80,81
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Several biomarkers may be reflective of the underlying neurohormonal imbalance of AHF, including activation of SNS, RAAS, and ADH release. Adrenomedullin (ADM), a peptide hormone secreted by myocardial tissue and endothelial cells, may be reflective of neurohormonal activation. ADM, because of a short half-life, is difficult to measure. Midregional pro-adrenomedullin (MRproADM) is more stable and thus more useful in the clinical setting.82,83,84 Elevated levels of MRproADM are associated with adverse outcome in AHF patient.85 High levels of vasopressin reflect severity of HF, but are difficult to measure as a result of instability and rapid clearance.86 Copeptin is the C-terminal portion of the vasopressin prohormone and can be more easily measured. Copeptin is a marker for HF disease progression.87 In patients with AHF, high levels of copeptin were predictive of mortality at 12 and 24 months.88,89 Chromogranin A, a prohormone, is produced by adrenergic and neuroendocrine cells90 and ultimately leads to vasoconstriction and catecholamine release.91 Chromogranin A is found in higher levels in patients with HF. Similar to copeptin, higher levels are associated with HF severity and can be predictive of mortality.92
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Another group of biomarkers is used to reflect the underlying pathophysiologic cardiac remodeling seen in HF, including myocardial hypertrophy, fibrosis, apoptosis, and necrosis. Soluble ST2, in response to volume overload and myocardial strain, is found in higher levels in patients with HF and is associated with poor prognosis.93,94 ST2 levels can also add prognostic value to NT-proBNP and high-sensitivity troponin T.95 Elevations in ST2 can aid in the identification of patients with decompensation and cardiac remodeling.96 Galectin-3 is released by activated macrophages in response to cardiac stress and stimulates production of collagen, which leads to fibrosis and worsening ventricular dysfunction.97,98,99 Galactin-3 has been shown to be an independent predictor of mortality100 and rehospitalization101 in patients with AHF.
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Downstream myocyte necrosis and apoptosis may be a result of increased myocardial wall stress, elevated LVEDP, and decreased myocardial perfusion.84 Biomarkers of myocyte injury, such as troponins T and I, have been shown to add to prognosis in patients with AHF,102 although certain patient factors, such as renal failure, sex, age, and the presence of LV hypertrophy, can influence levels.103 Patients with elevated troponin levels are generally sicker, with lower systolic blood pressure, lower ejection fractions, and higher inpatient mortality.102
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WRF and acute kidney injury are correlated with worsened mortality104 and are prevalent in patients with AHF. There has been growing interest in biomarkers reflecting renal injury, such as cystatin C and neutrophil gelatinase-associated lipocalin, to predict prognosis. Cystatin C is a cysteine protease inhibitor released from all kidney cells and filtered by the glomerulus.105,106 High levels of cystatin C are associated with AHF outcome.107 Neutrophil gelatinase-associated lipocalin is secreted by kidney cells in response to acute kidney injury, preceding creatinine elevation,108 and predicts 30-day mortality after AHF hospitalization.108
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AHF reflects a proinflammatory state. Levels of high-sensitivity CRP are elevated in AHF and associated with mortality.109,110 Reliability of CRP levels may be diminished in patients with infections.111
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Biomarker utilization may add to risk prediction, although which combination and in what capacity remain largely undefined. In the Multinational Observational Cohort on Acute Heart Failure (MOCA) trial, a multinational cohort of AHF patients that studied the value of adding biomarkers to a clinical prediction model, MRproADM had the highest 30-day mortality, and the combination of elevated CRP and ST2 had the highest 1-year mortality in risk prediction. The Biomarkers in Acute Heart Failure (BACH) trial, a prospective multicenter study of patients presenting with dyspnea, showed MRproADM to be the best predictor of mortality compared with BNP and NT-proBNP, but showed that BNP was still a superior predictor of rehospitalization.112 In AHF, BNP was superior to troponin I and high-sensitivity CRP for mortality prediction, but the combination improved statistical significance.109
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Identification and Management of Precipitating Factors
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Patients requiring hospitalization for HF exacerbation can often be characterized as having a precipitating event (Table 71–5). Data from OPTIMIZE-HF represent the most comprehensive identification of precipitants leading to hospitalization for AHF,113 reporting that of the almost 50,000 patients included, roughly 60% had one or more identified precipitating factors. These precipitants independently predicted clinical outcomes, making early identification and targeted therapy critical. In the OPTIMIZE-HF registry, there were a number of factors found to precipitate hospital admission for AHF including ischemia or acute coronary syndromes, arrhythmia, uncontrolled hypertension, pneumonia, WRF, and noncompliance with diet or medications.113
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Prompt identification and early medical management of precipitating factors in AHF are essential to improve outcomes of these patients.