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Authors and Disclosures James C. Coons, Pharm.D., BCPS, Molly McGraw, Pharm.D. and Srinivas Murali, M.D., FACC, FACP James C. Coons, Pharm.D., BCPS (AQ Cardiology), is Clinical Specialist, Cardiology; and Molly Mcgraw, Pharm.D., is Postgraduate Year 2 Critical Care Pharmacy Resident, Allegheny General Hospital, Pittsburgh, PA. Srinivas Murali, M.D., FACC, FACP, is Professor of Medicine, College of Medicine, Drexel University, Philadelphia, PA, and Medical Director, Gerald McGinnis Cardiovascular Institute, Allegheny General Hospital Address correspondence to Dr. Coons at the Department of Pharmacy, Allegheny General Hospital, 320 East North Avenue, Pittsburgh, PA 15212 ([email protected]). From American Journal of Health-System Pharmacy w GGhGoGmGz James C. Coons, Pharm.D., BCPS; Molly McGraw, Pharm.D.; Srinivas Murali, M.D., FACC, FACP Posted: 01/11/2011; American Journal of Health-System Pharmacy. 2011;68(1):21-35. © 2011 American Society of HealthSystem Pharmacists, Inc. Abstract and Introduction Abstract Purpose. Drug therapies for patients with acute heart failure syndromes (AHFS) are reviewed, including clinical practice guideline recommendations for the treatment of hospitalized patients with heart failure (HF). Summary. AHFS may be defined as new-onset, gradual, or rapidly worsening HF signs and symptoms that require urgent therapy. Clinical practice guidelines from the American College of Cardiology Foundation–American Heart Association, Heart Failure Society of America, and European Society of Cardiology offer recommendations for the management of AHFS, addressing the role of diuretics, vasodilators, and inotropes. The guidelines emphasize the utility of vasodilators for patients with signs and symptoms of pulmonary congestion, including pulmonary edema or severe hypertension or both, who have not responded to diuretics. The early initiation of vasoactive medications, including diuretics and vasodilators, has been linked to improved outcomes in some reports. Conversely, the use of inotropes is deemphasized, particularly as part of the routine management of these patients. Newer agents, including vasopressin antagonists, have also been approved recently but are not addressed by the clinical practice guidelines. The guidelines address the importance of initiating and optimizing evidence-based oral medications for long-term use, including angiotensin-converting-enzyme (ACE) inhibitors, angiotensin-receptor blockers, -blockers, and aldosterone antagonists, during the patient's hospital stay in an effort to address long-term outcomes. Conclusion. Drug therapy of AHFS may include diuretics, vasodilators, morphine, ACE inhibitors, digoxin, inotropes, and vasopressin antagonists. Clinical practice guidelines for patients with AHFS provide a useful mechanism to incorporate available evidence and standards of practice into patient care. Introduction At least 5 million people in the United States have heart failure (HF) and another 550,000 are diagnosed with HF each year. The number of hospitalizations associated with HF as a primary diagnosis grew from 810,000 in 1990 to over 1 million in 1999 and from 2.4 million to 3.6 million for patients with a primary or secondary diagnosis of HF over the same time period.[1] A retrospective cohort study of Medicare beneficiaries hospitalized with HF demonstrated that short- and long-term outcomes from 2001 to 2005 continued to be poor and changed very little.[2] In fact, more than 1 in 10 patients died and more than 1 in 5 were readmitted within 30 days of hospitalization for HF. During a one-year follow-up period, more than 1 in 3 patients died, and approximately two thirds were readmitted to the hospital. Even more alarming is that 40% of patients were readmitted at least twice. The economic burden continues to be staggering, with an estimated total cost of managing HF as a primary diagnosis in the United States of $39 billion in 2010.[3] While these trends have occurred in the context of an aging population and better management of patients with acute myocardial infarction (MI), it is clear that the management of HF continues to be a major public health challenge. Several factors contribute to the difficulties in improving outcomes for patients hospitalized with HF, including the heterogeneity of the patient population, high rate of co-morbid conditions, lack of a universally accepted definition for acute HF, incomplete understanding of HF's pathophysiology, and general lack of evidence-based data for most HF treatment regimens.[4] Clinical practice guidelines have recently been published to provide a better construct for management of this patient population.[1,5,6] This review highlights guideline recommendations for the treatment of hospitalized patients with HF and reviews the medical options for managing these patients. Acute Heart Failure Syndromes Acute heart failure syndromes (AHFS) may be defined as new-onset, gradual, or rapidly worsening HF signs and symptoms that require urgent therapy.[7] Patients with AHFS can be further classified as having new-onset or worsening chronic HF. Approximately 80% of patients with AHFS have chronic HF, whereas the remainder have newonset HF and may or may not have evidence of structural abnormalities (e.g., reduced ejection fraction).[4] Patients with HF and a preserved left ventricular ejection fraction (LVEF) are just as likely to be hospitalized as those with a reduced LVEF. Patients with advanced HF have low blood pressure (BP), renal impairment, and signs or symptoms refractory to standard medical therapy and represent up to 10% of hospitalized patients with AHFS.[4] The concept of AHFS as a patho-physiologic syndrome has been compared to acute coronary syndromes in that patients have a spectrum of clinical profiles. Unlike acute coronary syndromes, in which the underlying pathophysiology can be attributed to a unique precipitating event (e.g., plaque rupture with thrombosis), a common process leading to AHFS has yet to be identified.[8] It is well established that there may be single or multiple underlying etiologies of AHFS, including ischemia, hypertension, dysrhythmias, valvular abnormalities, renal insufficiency, and iatrogenic effects. All of these factors may result in derangements in neurohormonal systems (e.g., renin–angiotensin– aldosterone, sympathetic nervous system) and hemodynamics that ultimately affect the structure and function of the myocardium.[7,8] Regardless of the underlying etiology, the most common presentation usually includes pulmonary and systemic congestion without a reduction in cardiac output. Pulmonary congestion is defined by an increase in the left ventricular filling pressure or preload and is reflected hemodynamically by an increase in the pulmonary capillary wedge pressure (PCWP). A typical clinical manifestation is pulmonary edema with severe dyspnea, tachypnea, tachycardia, and hypoxemia. Pulmonary congestion can be the result of an abrupt increase in BP, reflected as an increase in vascular resistance or afterload and recorded hemodynamically as systemic vascular resistance (SVR). Systemic congestion can result in jugular venous distention, peripheral edema, and increases in body weight. While impaired cardiac output (CO) is less commonly seen in AHFS, it is characterized by tissue hypoperfusion with cool extremities and the potential for end-organ damage (e.g., renal insufficiency).[4] At least six clinical profiles that describe the hospitalized patient with HF have been proposed (Table 1).[4,6,7,9] This classification addresses both clinical and etiologic factors, whereas another outlines clinical profiles based on the degree of congestion and perfusion (Figure 1).[9,10] In fact, the latter has been shown to correlate with invasive hemodynamics and provide prognostic information,[10] both of which are used to help guide therapeutic management. Table 1. Clinical Classification of Acute Heart Failure Syndromes (AHFS)a Clinical Profile Comments Therapeutic Interventions Acute decompensation of History of progressive worsening chronic HF, evidence of systemic and pulmonary Loop diuretics, vasodilators chronic HF congestion Acute HF with hypertension or hypertensive crisis Systolic blood pressure of >160 mm Hg, pulmonary congestion predominant, systolic function generally preserved Acute HF with pulmonary edema Abrupt onset with severe respiratory distress, could be a result of acute decompensation of chronic HF or of acute Loop diuretics, vasodilators, morphine HF with hypertension or hypertensive crisis Acute coronary 15–25% of patients with ACS have HF syndromes (ACS) and signs and symptoms AHFS Loop diuretics, vasodilators Reperfusion (e.g., percutaneous coronary intervention, thrombolytics), antiplatelet agents, anticoagulants, antiischemics Cardiogenic shock Often due to acute MI, organ hypoperfusion despite adequate correction of preload, oliguria or anuria common Inotropes, diuretics with or without vasodilators, mechanical support (e.g., intraaortic balloon counterpulsation) Isolated acute right HF May be due to pulmonary hypertension, right ventricular infarct, pulmonary embolus, valvular abnormalities; evidence of systemic congestion with clear lungs Nitrates, prostacyclins, endothelin antagonists, or phosphodiesterase inhibitors or any combination for select patients; reperfusion for right ventricular MI aAdapted from references 4, 6, 7, and 9. HF = heart failure, MI = myocardial infarction. Figure 1. Classification scheme for assigning clinical profiles in patients with advanced heart failure.9,10 Patients may be classified as "warm" (indicating adequate perfusion) or "cold" (indicating compromised perfusion) by, among other signs or symptoms, the hotness or coolness of their extremities. They may also be classified as "wet" (indicating pulmonary congestion) or "dry" (indicating a lack of pulmonary congestion) by, among other signs or symptoms, the presence of edema or rales. The profile labels (A, B, C, and L) are arbitrary. Management Approximately 80% of patients with AHFS receive initial care at the emergency department.[11] It is important in this setting to define the clinical profile in order to evaluate the best approach to management. Another important first step in evaluating patients hospitalized with HF is to identify the precipitating factor (Table 2). The recognition that approximately 50% of readmissions after an index HF hospitalization are not related to HF underscores the heterogeneity of AHFS and the need to promptly evaluate for potential etiologies.[4] Initial treatment goals for patients are to improve symptoms, especially those that relate to pulmonary congestion or low cardiac output. Because hospitalization for AHFS is one of the most important predictors of postdischarge mortality and readmission in patients with chronic HF, goals to improve these outcomes should remain a top priority.[12,13] Other prognostic factors are associated with greater postdischarge mortality and may help identify higher-risk patients and guide therapeutic decision-making in AHFS. These factors include low systolic BP, coronary heart disease, troponin release, high blood urea nitrogen (BUN), high serum creatinine (SCr) concentration, high BUN:SCr ratio, hyponatremia, increased levels of natriuretic peptides, reduced PCWP during hospitalization, reduced functional capacity, and several other factors (e.g., nonuse of neurohormonal antagonists).[7] Table 2. Precipitants of Hospital Admission for Heart Failurea Precipitant Examples Indiscretion Nonadherence with medications, restriction of sodium or fluids or both Alcohol or illicit drug use Iatrogenic factors Negative inotrope use (e.g., verapamil, diltiazem, nifedipine, -blockers), class Ia and Ic antiarrhythmics (e.g., procainamide, flecainide, propafenone) Agents that promote retention of sodium or water or both (e.g., NSAIDs, corticosteroids, thiazolidinediones, pregabalin) Sympathomimetic use (e.g., pseudoephedrine, ephedra, amphetamines) Cardiotoxins (e.g., anthracyclines, trastuzumab, alcohol, cocaine) Dysrhythmias Atrial fibrillation, atrial flutter Hypertension Uncorrected high blood pressure Ischemia Acute coronary syndromes Valvular disorders Mitral regurgitation Endocrine disorders Diabetes mellitus, hyperthyroidism, hypothyroidism Hematologic disorders Anemia (e.g., bleeding, bone marrow suppression) Infection Pneumonia, viral illness Pulmonary disorders Pulmonary embolus, chronic obstructive pulmonary disease Renal disorders Renal failure, cardiorenal syndromes aAdapted from references 1 and 5. NSAIDs = nonsteroidal antiinflammatory drugs. Overview of Guidelines Clinical practice guidelines for the management of AHFS have only recently been addressed.[1,5,6] Guidelines addressing this patient population have been promulgated by the Heart Failure Society of America (HFSA), the American College of Cardiology Foundation/American Heart Association (ACCF/AHA), and the European Society of Cardiology (ESC). The lack of evidence-based guidelines to this point is largely reflective of the relative paucity of robust data.[1] In fact, the first randomized trial of therapies for AHFS was published in 2002.[14] Further, no placebocontrolled trial of pharmacotherapy for AHFS has shown an improvement in short-term survival or hospital readmissions.[7] Published studies to date have generally focused on symptomatic relief and hemodynamic improvement. Nonetheless, guidelines provide a useful construct for bridging the gap between evolving evidence and current practices. Guideline recommendations from professional organizations are based on randomized trials, large registries, and expert opinion. Pharmacotherapeutic recommendations are generally congruent, with each group addressing the role of diuretics, vasodilators, and inotropes. A consistent theme is the increased emphasis on the utility of vasodilators for patients with signs and symptoms of pulmonary congestion, including pulmonary edema or severe hypertension or both, that have not responded appropriately to diuretics. Conversely, the use of inotropes is deemphasized, particularly as part of the routine management of these patients. Inotropes are best reserved to ameliorate symptoms and improve end-organ function in the setting of advanced HF (e.g., systolic BP of <90 mm Hg despite adequate left ventricular filling pressures, not responsive to other therapies).[1,5,6] A comparison of the guidelines is presented in the appendix. Pharmacotherapeutic Options While the clinical practice guidelines are integral to developing a uniform approach to the pharmacologic management of AHFS, observational data from large registries also serve a practical purpose to understanding and analyzing current treatment patterns. The Acute Decompensated Heart Failure National Registry (ADHERE) database is one such observational database that collected data across the spectrum of the patient's hospital course with HF.[15] Data from this registry have been extensively analyzed and provide a perspective on real-world treatment and inhospital clinical outcomes. For example, it has been estimated that 88% of patients with HF received i.v. loop diuretics during their hospitalization.[11] Only about 18% of patients received i.v. vasodilators, including nitroglycerin and nesiritide, during their hospitalization. Interestingly, sodium nitroprusside represented <1% of all vasodilators used.[16] These are notable findings, given that up to two thirds of patients with AHFS have a clinical picture consistent with hypertensive crisis with an increase in SVR.[17] This scenario leads to a worsening of diastolic or systolic function or both through increased myocardial wall stress and a resultant reduction in CO along with volume overload. Consequently, diuretics and vasodilators are the mainstays of treatment for addressing this clinical picture and are the focus of the clinical practice guidelines. Diuretics All three of the clinical practice guidelines advocate i.v. loop diuretics as the preferred first-line therapy for patients with evidence of volume overload. ACCF/AHA guidelines advise the initiation of these drugs in either the emergency department or clinic setting.[1] The early initiation of vasoactive medications, including diuretics, has been linked to improved outcomes in recent reports.[17–19] Diuretics have gained widespread acceptance in the management of HF, despite limited formal evaluation in randomized clinical trials.[20] Diuretics are known to improve symptoms of pulmonary congestion and decrease body weight; however, these short-term clinical benefits have not shown improvements in rehospitalization or mortality.[4,21] Furosemide, bumetanide, and torsemide are the most commonly used diuretics and demonstrate some important pharma-cokinetic differences. Furosemide is primarily eliminated renally, whereas bumetanide and torsemide are hepatically metabolized. Consequently, longer half-lives may be observed with different agents in the setting of renal or hepatic disease. The oral bio-availability of furosemide is erratic and less predictable compared with the relatively complete absorption of bumetanide and torsemide.[22] Other potential differences in neurohormonal activity have been described in animal models, with torsemide, as opposed to furosemide, having an inhibitory effect on aldosterone activity.[23] Nonetheless, all three of the commonly prescribed loop diuretics are a mainstay in the management of AHFS. Despite the well-established, short-term benefits of loop diuretics, several observational studies have shown an association among these medications and the risk for rehospitalization or death from worsening HF, increased length of stay, and higher resource utilization.[21,24,25] Reasons for this are not completely clear but may relate to augmentation of neurohormonal pathways, including the renin–angiotensin–aldosterone system due to reductions in intravascular volume and sodium depletion. In accordance with these findings is the observation that diuretics are known to adversely affect renal function, which is an independent predictor of mortality in patients with HF.[1,16,26] The dose–response relationship with i.v. diuretics has also been long debated, and recommendations have largely been empirical. The ACCF/AHA guidelines recommend an initial i.v. dose that equals or exceeds the patient's long-term oral daily dose. Dosage should be adjusted to attain symptom relief while avoiding a rapid reduction in intravascular volume. Recent studies have provided some clarity to the dose–response debate. An analysis of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheter Effectiveness (ESCAPE) trial database showed a dosedependent relationship with mortality risk, especially with a furosemide dosage exceeding 300 mg/day.[27] A singlecenter study also demonstrated a dose-dependent mortality effect with diuretics.[28] The highest quartile of the daily diuretic dose (>160 mg furosemide or equivalent) had the highest risk-adjusted mortality rate. The association between loop diuretic use and worse outcomes at higher doses must be tempered by the fact that data supporting this link are observational in nature. It is often difficult to control for numerous clinical variables that increase patients' risk for worse outcomes (e.g., advanced HF, renal insufficiency, multiple co-morbidities) and result in the need for higher doses of diuretics. One of the major challenges encountered with i.v. loop diuretics is how to care for patients who have not responded to initial doses, as evidenced by continued volume overload. Both the ACCF/AHA and HFSA guidelines present three treatment options for these patients: increase the dosage of the loop diuretic, add a second type of diuretic (e.g., metolazone), or switch to a continuous infusion of a loop diuretic.[1,5] Potential pharmacodynamic advantages to using a continuous infusion include a more constant delivery of medication to the renal tubule, thus avoiding fluctuations in serum levels. Higher levels may be associated with ototoxicity, whereas lower levels may lead to rebound sodium reabsorption.[29] A Cochrane review evaluating eight trials found greater urine output and less ototoxicity with continuous infusions compared with intermittent bolus injections of diuretics.[30] Results from the Diuretic Optimization Strategies Evaluation in Acute Heart Failure (DOSE) study were recently presented.[31] The objective of the study was to better understand the potential negative implications of high-dose diuretics as well as the optimal dosage and duration. Approximately 300 patients with chronic HF receiving oral daily doses of loop diuretics (furosemide 80–240 mg or equivalent) were randomized to i.v. treatment in a 2 × 2 factorial design (every 12 hours i.v. bolus versus continuous i.v. infusion, plus low intensification to a daily i.v. dose equivalent to the oral dose versus high intensification to a daily i.v. dose 2.5 times the oral dose of furosemide). It is important to point out that patients who required i.v. vasodilators or inotropes or who had a SCr concentration of <3 mg/dL were excluded. The main efficacy endpoint was patient global assessment of symptom relief as assessed by visual analogue scale area under the curve over 72 hours. Change in SCr level was the primary safety endpoint. Overall, neither global symptom relief nor change in SCr concentration was significantly different in either comparison of administration technique or dose. Furthermore, continuous infusion dosing was not associated with improvements in any of the secondary endpoints, including net diuresis, change in weight, and treatment failure. Dose intensification, however, did improve the aforementioned secondary endpoints. One of the limitations of this trial was that medical therapy for HF could be adjusted based on clinical response 48 hours after randomization. Therefore, evaluation of the 48-hour endpoint may provide more insight into potential differences. Vasodilators When managing patients in the early phase of AHFS, the key goals of management include hemodynamic stabilization and symptom improvement. The vasodilators have been shown to meet both needs by reducing preload, afterload, or both. The agents decrease BP, PCWP, and SVR to reduce dyspnea and improve peripheral oxygen delivery. The efficacy of high-dose nitroglycerin in this setting is demonstrated by prompt resolution of symptoms, including decreased pulmonary congestion, decreased need for mechanical ventilation, and a reduction in intensive care unit (ICU) admission.[18] Similar to the beneficial role of nitroglycerin, data regarding the early initiation of nesiritide in patients with AHFS have shown positive results.[17] Observations from the ADHERE registry showed increased overall survival with the use of nitroglycerin or nesiritide compared with inotropic therapy with dobutamine or milrinone; however, it is possible that patients requiring inotropic therapy had a more-advanced form of HF than did those receiving vasodilators.[16] Although clinical trial evidence is limited, recommendations addressing the role of vasodilators in patients with AHFS are provided. HFSA and ACCF/AHA guidelines recommend considering nitroglycerin, sodium nitroprusside, or nesiritide as an adjunct to diuretics for rapid resolution of congestive symptoms in the normotensive or hypertensive patient.[1,5] Likewise, ESC guidelines recommend i.v. nitrates or sodium nitroprusside at an early stage for AHFS patients with a systolic BP of >90 mm Hg and without serious obstructive valvular disease.[6] Nitroglycerin Nitroglycerin is an organic nitrate that exerts its pharmacologic actions through nitric-oxide-mediated smooth muscle vasodilation. It produces venous vasodilation at lower doses and, as the rate is increased, arterial vasodilation may also occur. Nitroglycerin reduces preload (PCWP, central venous pressure) and arterial BP. Nitroglycerin is an effective therapy to assist with the management of patients with AHFS by ultimately decreasing cardiac filling pressures and increasing CO. In the setting of AHFS, nitroglycerin is best used in a patient who fits a clinical profile displaying volume overload with a normal to elevated BP and a lack of response to i.v. diuretic therapy. Nitroglycerin is also preferred in the setting of acute coronary syndromes and AHFS due to coronary vasodilation. The hemodynamic responses to i.v. nitroglycerin are rapid and short acting, which allows for frequent dose escalation. Dosing and monitoring recommendations for nitroglycerin and other vasodilators are provided in Table 3. The usual dosage required varies significantly by patient but generally should not be increased beyond 200 μg/min. Patients who do not achieve hemodynamic improvement with a dosage of approximately 200 μg/min can be considered nonresponders.[5] Tachyphylaxis can occur in patients receiving continuous-infusion nitroglycerin for greater than 24 hours but may be apparent more quickly in patients receiving higher dosages. Potential adverse effects associated with nitroglycerin include headache, hypotension, abdominal discomfort, reflex tachycardia, and paradoxical bradycardia. Table 3. Dosing of I.V. Vasodilators and Inotropesa Medication Initial Dosage Typical Dosage Range Adjustment Increment Nitroglycerin 10 g/min 5–200 g/min 10–20 g/min every 5–15 min Sodium nitroprusside 0.2 g/kg/min 0.5–5 g/kg/min 0.25–0.5 g/kg/min every 5–15 min Nesiritide Loading dose: 2 ìg/kgb Infusion: 0.01 g/kg/min 0.01–0.03 g/kg/min 0.005 g/kg/min; bolus: 1 g/kg every 3 hr to maximum dose Dobutamine hydrochloridec 2.5–5 g/kg/min 2.5–20 g/kg/min 2.5–5 g/kg/min every 5–15 min Milrinone lactatec Loading dose: 50 g/kgb Infusion: 0.25 g/kg/min 0.25–0.75 g/kg/min Adjustment usually not recommended aAdapted from references 6, 32, and 36. bMay omit loading dose if there is a concern for hypotension. expressed in terms of the base. cDosage Although clinical trial data evaluating the efficacy of nitroglycerin are minimal, the drug remains a cornerstone of therapy for patients with ischemic heart disease and AHFS. One randomized trial conducted in patients with earlyphase AHFS compared the effects of two different treatment regimens: nitrates and diuretics.[20] One group of patients received high-dose furosemide with low-dose isosorbide dinitrate, and the comparator group used high-dose isosorbide dinitrate with low-dose furosemide. The main goal of treatment was to rapidly reduce pulmonary edema without compromising BP. The main outcome measures evaluated were inhospital death, need for mechanical ventilation within 12 hours of admission, and development of MI within 24 hours of admission. While relief of pulmonary congestive symptoms was accomplished in both treatment groups, the effect of high-dose nitrate therapy was superior in terms of need for mechanical ventilation and development of MI. However, there was no significant difference between the two treatment groups in the rate of inhospital death. Sodium Nitroprusside Sodium nitroprusside is a potent, direct-acting vasodilator with a similar mechanism of action to nitroglycerin. However, sodium nitroprusside provides rapid and pronounced venous and arterial vasodilation at usual dosages. The reductions in preload, afterload, and arterial BP make it particularly useful for patients with AHFS and advanced HF. CO also can increase to near-normal levels because of the effects on cardiac filling pressures.[5,32,33] In most institutions, the use of sodium nitroprusside requires invasive monitoring of BP and central hemodynamics. Sodium nitroprusside dosages can be adjusted rapidly until hemodynamic goals are met, and SVR can be used to help guide dosing. However, slow weaning to discontinuation is advised because of the potential for rebound vasoconstriction.[5] Sodium nitroprusside is converted to both nitric oxide and cyanide and initially cleared through nonenzymatic mechanisms. The liver converts cyanide to thiocyanate, whereas the kidneys eliminate thiocyanate.[33] One of the main concerns of using sodium nitroprusside is the risk of cyanide and thiocyanate toxicities, especially in patients who have hepatic or renal insufficiency or patients maintained on sodium nitroprusside 3 μg/kg/min for more than 72 hours.[32] While the risk of toxicity in patients with AHFS is rare when lower dosages are used, health care providers should be cognizant of the development of its signs and symptoms. The presentation of cyanide toxicity may include mental status changes (e.g., confusion, psychosis), muscle spasm, convulsions, cardiovascular instability, or unexplained metabolic or lactic acidosis. Thiocyanate toxicity can present in a similar fashion, along with other nonspecific symptoms such as nausea, vomiting, tinnitus, and fatigue.[32,33] Like other i.v. vasodilators, sodium nitroprusside can also produce hypotension in some patients. Consequently, the absence of systemic hypotension is paramount before the initiation of therapy for AHFS.[1,5,6] Lastly, sodium nitroprusside is not recommended for patients with ischemia due to the risk of the coronary steal phenomenon, in which blood is shunted away from ischemic areas to small resistance vessels.[32,33] Similar to the other agents in this class, clinical trial data evaluating the efficacy of sodium nitroprusside are limited. However, the drug does appear to serve a role in patients with AHFS and evidence of increased afterload and decreased CO. One retrospective study evaluating the safety and efficacy of sodium nitroprusside in patients with AHFS and a low CO found that patients treated with sodium nitroprusside achieved greater improvement in cardiac index (CI), significantly lower all-cause mortality, and fewer clinical adverse effects at long-term follow-up than did patients not receiving sodium nitroprusside.[34] One limitation of this study was its nonrandomized design, which may have introduced selection bias. The majority of patients selected to receive sodium nitroprusside tended to have higher BP and lower CO, the population that would benefit most from the use of a vasodilator. Another single-center study evaluating the role of sodium nitroprusside in patients with severe aortic stenosis and left ventricular dysfunction concluded that the drug rapidly and significantly improved the CI from a baseline mean of 1.6 to 2.22 L/min/m2 at 6 hours, along with a further increase to 2.52 L/min/m2 at 24 hours.[35] The investigators concluded that sodium nitroprusside is a valid option for optimizing cardiac function before aortic valve replacement in patients with left ventricular failure or for converting to an oral vasodilator regimen in patients not undergoing surgery. Nesiritide Nesiritide, or recombinant human brain-type natriuretic peptide (BNP), is labeled for the treatment of patients with acute de-compensated HF who have dyspnea at rest or with minimal physical activity.[36] BNP is an endogenous hormone produced in the ventricular myocardium in response to increased wall stress, hypertrophy, and volume overload. The hemodynamic effects of BNP include arterial and venous vasodilation, natriuresis, diuresis, and attenuation of the renin– angiotensin–aldosterone and sympathetic nervous systems.[37] Nesiritide has been shown to reduce PCWP, pulmonary vascular resistance, and mean and systolic pulmonary artery pressures and significantly improve CO compared with nitroglycerin and placebo.[38] One potential advantage of using nesiritide is its ability to rapidly reduce hemodynamic markers, especially PCWP, by achieving 90% of its peak effect within 30 minutes.[36] Nesiritide is generally infused for a total duration of 72 hours or less, and, in the largest clinical trial to date, the median duration of use was 24 hours.[38] Because nesiritide has a longer half-life (median of 20 minutes) than the previously discussed vasodilators, adverse effects such as hypotension can persist for a significantly longer period of time. If symptomatic hypotension occurs, the infusion should be discontinued until resolution of symptoms and until the systolic BP is greater than 90 mm Hg.[36] Once BP is corrected, nesiritide may be restarted at a 30% lower infusion rate without a bolus dose. Conservative dosing by omitting the initial bolus dose has been proposed as a means of minimizing hypotension.[1] The package insert information states that nesiritide should not be used in patients with a systolic BP of <90 mm Hg.[36] In addition, nesiritide should not be used as first-line treatment for patients in cardiogenic shock. The Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) trial was the largest prospective randomized trial of patients with AHFS conducted to date.[38] This study randomized 489 patients to receive nesiritide, nitroglycerin, or placebo for 24 hours. The primary endpoints of the study were change in PCWP and dyspnea improvement at 3 hours. Results of this trial found the difference in PCWP (from baseline to 3 hours) between nesiritide and nitroglycerin to be statistically significant, with a mean reduction of 5.8 mm Hg versus 3.8 mm Hg, respectively (p = 0.03). However, the nitroglycerin doses used were relatively small and could account for some of the differences observed. Patients' self-assessment of dyspnea at 3 hours was similar with nesiritide and nitroglycerin but significantly improved compared to placebo (p = 0.03). Since the marketing approval of nesiritide in 2001, controversy has existed as to whether its use is beneficial for preserving or improving renal function. The evidence to support these effects are conflicting.[39,40] In addition, metaanalyses found that treatment with nesiritide may be associated with worsening of renal function and short-term mortality.[41,42] Since the publication of these studies, there has been a dramatic decline in the use of nesiritide in clinical practice.[43] An expert panel committee has since convened to review all available data surrounding the safety of nesiritide in response to publication of the aforementioned meta-analyses.[44] The committee did note a dosedependent increase in SCr levels, indicating renal dysfunction, at dosages within the normal range. The panel also noted that completed trials have shown a trend toward increased mortality at 30 days, but not at 180 days, with the use of nesiritide. The overall findings of the meta-analyses remain inconclusive due to the varying methodologies and patient characteristics within each of the studies included. In summary, the expert panel reiterated that nesiritide should not be used to replace or enhance diuretics or to improve renal function. Nesiritide also should not be used for scheduled repetitive or intermittent outpatient use. Data from the Second Follow-Up Serial Infusions of Nesiritide (FUSION II) trial underscored this recommendation, as there was no benefit with nesiritide in outpatients at high risk for decompensation.[45] Likewise, the use of nesiritide in an emergency department or observation unit did not improve outcomes, including the need for hospitalization.[46] The Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) will further evaluate the efficacy and safety of nesiritide and will be the largest trial ever conducted for AHFS.[47] In this randomized, double-blind, placebo-controlled, multicenter trial, approximately 7000 patients with AHFS will be randomized to receive nesiritide or placebo for a minimum of 24 hours and up to seven days. This study is designed to assess whether nesiritide plus standard care compared with placebo and standard care will provide significant improvements in symptoms, HF rehospitalizations, and mortality after admission to the hospital. Other specific endpoints to be addressed in this study include renal function and overall safety. Morphine The role of morphine in the setting of AHFS is uncertain. Morphine's use in the early stabilization of patients with AHFS has been accepted for many years based on its hemodynamic and sedative properties. Morphine has been reported to reduce preload, heart rate, and possibly afterload, the net effect of which is a reduction in myocardial oxygen demand. Evidence supporting its use is very limited despite its widespread application.[6] A recent observational analysis from the ADHERE registry suggested that the use of morphine is associated with worse outcomes in AHFS, including the need for mechanical ventilation, a longer length of stay, a higher ICU admission rate, and a higher overall risk-adjusted mortality.[48] Although HFSA guidelines do not provide a formal recommendation for the use of morphine, they do state that it should be used with caution, especially in patients with altered mental status and impaired respiratory drive.[5] ESC guidelines state that morphine should be considered for patients with severe symptoms of AHFS plus restlessness, dyspnea, anxiety, or chest pain.[6] I.V. bolus doses of morphine sulfate (2.5–5 mg) can be considered and repeated as necessary; however, careful attention must be made to monitoring of respiratory status. Caution must also be exercised when using morphine in patients with hypotension, bradycardia, advanced atrio-ventricular block, or carbon dioxide retention. Nausea is a well-known adverse effect of morphine and may require treatment with an antiemetic.[6] ACCF/AHA guidelines do not address morphine use for AHFS. Angiotensin-converting-enzyme Inhibitors Angiotensin-converting-enzyme (ACE) inhibitors do not have a clear role in the early management of AHFS, as randomized, controlled trial data are lacking. However, ACE inhibitors may be considered in the setting of acute coronary syndromes with evidence of left ventricular dysfunction and HF.[6] Caution is warranted in patients with a marginal BP, and i.v. ACE inhibitors in particular should be avoided in such patients.[49] ESC guidelines do not endorse the early use of ACE inhibitors, though the American College of Emergency Physicians advises that they may be used based on favorable hemodynamic effects (decreased preload and afterload). Vigilant monitoring for first-dose hypotension is needed.[50] ACCF/AHA and HFSA guidelines do not address the early use of ACE inhibitors for AHFS. The role of oral ACE inhibitors for chronic HF is well established. Digoxin Digoxin has beneficial neurohormonal and hemodynamic effects in the setting of HF, including vagomimetic effects, attenuation of the renin–angiotensin–aldosterone system, reduced PCWP and SVR, increased CO, and improved LVEF.[51] Accordingly, digoxin has been viewed as a favorable therapeutic alternative for the management of AHFS, even though studies examining clinical outcomes have yet to be conducted.[52] ESC guidelines briefly discuss the role of digoxin for AHFS in the context of its modest inotropic effects, ability to reduce filling pressure, and ability to decrease ventricular rate in patients with atrial fibrillation (class IIb, level C recommendation).[6] Digoxin is not addressed in either ACCF/AHA or HFSA guidelines for AHFS. Inotropes Inotropes may be considered for hospitalized patients with AHFS and low output syndrome. Dobutamine or milrinone, in particular, may be considered for relief of symptoms and to improve end-organ function in patients with severe systolic dysfunction. Inotropes may also be of value in patients who have marginal systolic BP or symptomatic hypotension and are intolerant to vasodilators due to hypotension and in patients who have not adequately responded to vasodilator therapy.[53] Data from the ADHERE registry illustrate that out of greater than 150,000 patients, fewer than 3% had a systolic BP of <90 mm Hg, and approximately 50% had a preserved systolic function.[15] However, approximately 14% of the patients in ADHERE were treated with an i.v. inotropic agent. These patients had a higher mortality rate (19%) than all other non-inodilator-treated patients (14%).[16] The HFSA, ACCF/AHA, and ESC all deemphasize the role of inotropes compared with vasodilators for adjunctive management of AHFS due to a lack of controlled studies establishing a clear benefit and the adverse-event risk profile including arrhythmias, hypotension, and myocardial ischemia. Current guidelines suggest the use of inotropic agents for symptom relief and end-organ function improvement in patients with low systolic BP (<90 mm Hg) and evidence of low output.[1,5,6] Some patients may continue to require an inotrope to maintain sufficient CO beyond their hospitalization. In these cases, inotropes are also used as a "bridge" to more definitive or destination therapy, including cardiac transplantation, mechanical circulatory support (ventricular assist device), or revascularization. For patients who are not candidates for these options and have end-stage HF, inotropes may be offered for palliation of symptoms.[5] Dobutamine Dobutamine is a synthetic catecholamine that has both inotropic and vasodilatory effects. Its mode of action is mediated via stimulation of both 1- and 2-adrenergic receptors. By working on these receptors, it produces a dosedependent increase in CO and a decrease in PCWP. A reduction in SVR may be seen secondary to its effects at the [54] The favorable inotropic and vasodilatory effects of dobutamine make it a preferred agent for the 2-receptor management of patients with AHFS and low output syndrome. Dobutamine begins to work within 1–2 minutes but may take up to 10 minutes to exert its peak effect. Tachyphylaxis may occur in patients using dobutamine for greater than 24–72 hours; therefore, upward dosage adjustment may be needed in patients when a decline in CO is noted. Notable adverse effects of dobutamine include hypotension and tachyarrhythmias (e.g., atrial fibrillation, ventricular tachycardia). Long-term use of dobutamine has been associated with decreased survival, mainly attributable to sudden cardiac death.[55] The Prospective Randomized Evaluation of Cardiac Ectopy with Dobutamine or Natrecor Therapy (PRECEDENT) was a multicenter, randomized, open-label, active-control trial designed to compare the safety of dobutamine at a dosage of at least 5 μg (as the hydrochloride salt)/kg/min and two fixed doses of nesiritide (0.015 and 0.030 μg/kg/min, with no bolus dose) for their effects on heart rate and ventricular arrhythmias in patients with AHFS.[56] Results of this study found that dobutamine significantly increased all measures of ventricular ectopy. In addition, nesiritide reduced the frequency of ventricular tachycardia at 24 hours. With regard to improvement of signs and symptoms of congestive HF, both drugs were comparable. Although additional studies evaluating the efficacy of dobutamine in patients with AHFS are lacking, it remains a first-line option for patients with marginal BP and reduced CO requiring inotropic support. Milrinone Milrinone is a phosphodiesterase (PDE) type-3 inhibitor that has similar effects to dobutamine. PDE type 3 is an enzyme that breaks down intracellular cyclic adenosine monophosphate (cAMP) to its inactive metabolite.[53] Inhibition of this conversion allows for increased intracellular calcium concentration and contractility and myocardial relaxation. An increased cAMP in the periphery produces arterial and venous vasodilation, leading to decreased systemic and pulmonary vascular resistance, decreased left and right filling pressure, and increased CO.[53] In contrast to other catecholamines, milrinone exerts its effects without stimulating -adrenergic receptors; subsequently, tachyphylaxis due to downregulation of -receptors is not a concern. Milrinone has also been shown to have a greater vasodilatory effect than dobutamine, as demonstrated by further reductions in key hemodynamic markers (pulmonary artery pressures, PCWP, and SVR). Conversely, dobutamine may have a greater degree of effect on CO than milrinone but at the expense of greater increases in heart rate and myocardial oxygen consumption.[55] The adverse-effect profile of milrinone is an extension of its hemodynamic effects. Hypotension is of greater concern with milrinone due to its vasodilatory effects, which can be compounded by its prolonged half-life (one to three hours) and renal elimination.[54] Consequently, dosing strategies typically omit the initial bolus dose and advise against dosage adjustment. In fact, bolus-free dosing has been shown to provide significant hemodynamic changes within 30 minutes and becomes similar to bolus dosing by three hours.[57] Similar to dobutamine, milrinone can potentiate atrial or ventricular arrhythmias, and long-term use is associated with decreased survival due to sudden cardiac death.[55] The use of milrinone in AHFS has been evaluated in limited randomized controlled trials. The largest trial of these is the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIMECHF), which assessed the effects of short-term use of milrinone in addition to standard therapy.[14] The primary efficacy endpoint was the total number of days hospitalized for cardiovacsular causes within 60 days after randomization. The main secondary endpoint included the proportion of cases failing therapy because of adverse events or worsening HF 48 hours after initiating therapy. The results of this trial concluded that the use of milrinone for patients with AHFS did not significantly decrease days of hospitalization compared with placebo. Furthermore, use of milrinone resulted in a significant increase in adverse events related to sustained hypotension and atrial arrhythmias. Consequently, the authors concluded that the routine use of milrinone in AHFS is not supported.[14] Comparisons with dobutamine are sparse, but one retrospective analysis demonstrated no difference in clinical outcomes.[58] Dobutamine may be an initial choice over milrinone in patients with severe renal dysfunction to lessen the potential for adverse effects (e.g., hypotension) with drug accumulation. Milrinone, however, would be preferred as maintenance therapy with -blockade, as it retains its hemodynamic effects by acting on post- -receptor mechanisms.[59] Finally, milrinone may be considered as first-line therapy over dobutamine for patients with AHFS and evidence of severe pulmonary hypertension due to more-pronounced vasodilatory properties.[58] Vasopressin Antagonists Vasopressin concentrations are known to be elevated in HF, correlate with its severity, and contribute to both fluid retention and hyponatremia.[60] In addition, hyponatremia is a known predictor of mortality in patients hospitalized with HF.[61] As a mediator of ongoing neurohormonal activation in HF, vasopressin has become a pharmacotherapeutic target of interest. Antagonism of V1A receptors located in the systemic vasculature results in vasodilation, whereas inhibiting the V2 receptors in the kidneys leads to an increase in free water clearance (aquaresis) and serum sodium level and a decrease in urine osmolality. The currently available vasopressin antagonists include conivaptan and tolvaptan. Conivaptan is a dual V1A/V2-receptor antagonist given via the i.v. route, whereas tolvaptan is a selective V2receptor antagonist given orally. Both agents are labeled for hypervolemic and euvolemic hyponatremia; however, only tolvaptan is labeled for patients with HF in either of these settings. Key monitoring values for these agents include serum sodium levels in the hospital setting due to the potential for overly rapid correction of sodium (>12 meq/L/day) resulting in osmotic demyelination syndrome. Common adverse effects include thirst, dry mouth, and (for conivaptan) infusion-site reactions. Both agents are extensively metabolized by the cytochrome P-450 isoenzyme system; therefore, strong inhibitors and inducers of this pathway should generally be avoided.[62,63] HFSA guidelines recommend water restriction and optimization of ACE inhibitors or angiotensin receptor blockers for the treatment of hyponatremia.[5] For refractory hyponatremia, the guidelines advise seeking alternative causes (e.g., hypothyroidism, hypoaldosteronism, syndrome of inappropriate antidiuretic hormone). HFSA does acknowledge vasopressin antagonists as being effective at increasing serum sodium and state that it may be reasonable to add a nonselective vasopressin antagonist to treat patients with significant cognitive symptoms in the setting of hyponatremia. However, the guidelines provide no clear role for this class and reinforce that long-term therapy does not improve outcomes. The largest-scale trial to date of vasopressin antagonists was the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST).[64] In EVEREST, no differences were found in terms of all-cause mortality, cardiovascular death, or hospitalizations for HF with tolvaptan in addition to standard therapies versus placebo among 4133 patients. Neither the ACCF/AHA nor the ESC guidelines provide any recommendations regarding the use of vasopressin antagonists.[1,6] Special Considerations in AHFS Management BNP-guided Pharmacotherapy Current guidelines acknowledge the value of BNP or N-terminal proBNP (NT-proBNP) for both diagnostic and prognostic purposes.[1,5,6] Consequently, there has been increasing interest in using natriuretic peptide levels to guide pharmacotherapy and improve outcomes for patients with HF. The Trial of Intensified vs. Standard Medical Therapy in Elderly Patients with Congestive Heart Failure (TIME-CHF) compared 18-month survival free of any hospitalization and quality of life among 622 patients with chronic HF randomized to either intensified NT-proBNP-guided therapy or standard symptom-guided therapy.[65] Patients age 60–74 years were further compared with those age 75 years or older. All patients had to have at least New York Heart Association (NYHA) functional class II symptoms, history of HF hospitalization within the past year, and a minimum NT-proBNP level ( 400 pg/mL for patients age 60–74 years; 800 pg/mL for patients age 75 years or older). Goals of therapy were to reduce symptoms to NYHA functional class II or less or symptoms and NT-proBNP levels to less than two times the normal value. Medical therapy recommendations were provided based on current guidelines but were ultimately at the discretion of the individual physician. Ultimately, no difference in the primary outcome of survival-free hospitalization of any cause between groups was seen. Qualityof-life metrics improved in both groups to a similar degree. However, there was a significant association between age and clinical outcomes, demonstrating that patients younger than 75 years conferred benefit with NT-proBNP-guided therapy as opposed to older patients. The BATTLESCARRED (NT-proBNP-Assisted Treatment To Lessen Serial Cardiac Readmissions and Death) trial compared three treatment strategies: (1) usual care, (2) intensive, standardized, clinically guided care, and (3) NTproBNP-guided care.[66] Patients enrolled had symptomatic congestive HF with a recent hospital admission, and an NT-proBNP level of >400 pg/mL. Medical therapy in the clinically guided care and NT-proBNP groups was adjusted based on an HF score with a preset algorithm. Therapy in the NT-proBNP group was also targeted to reduce levels of NT-proBNP to less than 1300 pg/mL. The primary outcome was all-cause mortality and the composite of death plus hospitalization for HF. A total of 364 patients were randomized. Overall, mortality at 1 year was significantly improved in both the NT-proBNP and clinically guided care groups compared with the group receiving usual care. Three-year mortality was improved with NT-proBNP compared with both clinically guided and usual care but only for patients age 75 years or younger. For the primary endpoints of death and hospitalization for HF, a similar pattern was observed, except that the benefit at 1 and 3 years was only seen in the younger group of patients. The addition of NT-proBNP levels to guide medical therapy of patients with HF may be beneficial in certain populations. This strategy appears to be most useful in younger patients (<75 years). The reasons for this are not entirely clear but may reflect a greater prevalence of comorbidities, including renal insufficiency, among older patients. In addition, older patients may be less likely to reach target dosages of certain medications (e.g., ACE inhibitors, blockers) and have more HF with preserved systolic function, for which the importance of these medication classes and target dosages are less clear. In both the TIME-CHF and BATTLESCARRED trial, NT-proBNP levels fell to a similar degree between hormone-guided and control groups. In many cases, medical therapy was adjusted even in the absence of worsening symptoms. This suggests that there may be opportunities to further optimize the management of HF with or without NT-proBNP guidance.[67] While the BNP or NT-proBNP level itself may be of value in guiding initial therapy, some authors have suggested that the manner in which these levels are reduced may be even more important.[67] ACCF/AHA guidelines state that the value of serial measurements of BNP to guide therapy is not well established (class IIb, level C).[1] HFSA guidelines state that it is not possible to recommend the use of natriuretic peptides to guide therapy for HF in either the inpatient or outpatient setting until further data become available.[5] Maintenance Therapies While the medical management of AHFS largely focuses on symptomatic and hemodynamic improvement, none of the medications used in this setting have shown an improvement in long-term outcomes. Consequently, clinical practice guidelines have recently addressed the importance of initiating and optimizing evidence-based oral medications for long-term use (e.g., ACE inhibitors, angiotensin-receptor blockers [ARBs], -blockers, aldosterone antagonists) at some point during the patient's hospital stay.[1,5,6] This is a particularly salient point, given that patients are often discharged on the same pre-admission medications. Aside from diuretic dosage adjustments, initiation of new or escalation of evidence-based therapies (e.g., ACE inhibitors, -blockers) occurs in less than 10% of patients.[4] HFSA guidelines recommend that at least near-optimal pharmacologic therapy (e.g., ACE inhibitor and -blocker for patients with reduced LVEF) is achieved for all HF patients before hospital discharge. Specifically, HFSA recommends initiating -blocker therapy at a low dose before discharge in stable patients (after optimization of volume status and successful discontinuation of i.v. diuretics and vasoactive agents; strength of evidence = B). Upward adjustment of dosages should be gradual (typically every two weeks). For patients who have been receiving long-term maintenance therapy with a -blocker, HFSA recommends continuation in most patients experiencing a symptomatic exacerbation of HF (strength of evidence = C) unless there is evidence of cardiogenic shock, refractory volume overload, or symptomatic bradycardia.[5] Even in this setting, it may be appropriate in some situations to temporarily lower the blocker dosage by half. Beta-blocker therapy should not be abruptly discontinued unless the situation is life threatening (strength of evidence = C).[5] ACCF/AHA guidelines provide similar recommendations, stating that oral therapies known to improve outcomes (ACE inhibitors, ARBs, -blockers) should be initiated in stable patients before hospital discharge (class I, level B). Particular caution is warranted before starting a -blocker in patients who required an inotrope during their hospital stay. For patients who have been receiving maintenance oral therapies known to improve outcomes, it is recommended that these be continued in most patients in the absence of hemodynamic instability or contraindications (class I, level C).[1] The ESC guidelines are consistent with other guidelines in that ACE inhibitors or ARBs should be initiated before hospital discharge and continued as maintenance therapy, even for an admission for worsening HF (class I, level A).[6] After the patient has been stabilized on an ACE inhibitor or ARB, a -blocker should be initiated before hospital discharge. ESC suggests that the -blocker should generally not be stopped in patients with AHFS, but the dosage may need to be reduced temporarily or omitted in unstable patients with low output or in cases of severe HF and inadequate response to initial therapy (class IIa, level B). Although the use of -blockers in patients with AHFS has historically been controversial, several recent trials and registry data have shown improved outcomes with both predischarge initiation and continuation of therapy during hospitalization.[68–71] Finally, only the ESC guidelines address digoxin as a consideration for AHFS as a means of producing a small increase in CO, reducing filling pressure, and slowing ventricular rate in rapid atrial fibrillation (class IIb, level C).[6] Despite a lack of data on the role of digoxin in AHFS, some authors have advocated for its reevaluation in this setting on the basis of favorable hemodynamic, neurohormonal, and symptomatic benefits.[52] Investigational Therapies Several therapies with novel mechanisms of action are under investigation for the management of AHFS.[8,9,72] Table 4 provides an overview of select agents that have been studied the most extensively in clinical trials. A host of vasodilator classes are under development, including adenosine antagonists (rolofylline), atrial natriuretic peptides (ularitide), peptide hormones (relaxin), and direct renin inhibitors (aliskiren). Rolofylline is an adenosine A1-receptor antagonist that has been evaluated in the Study of the Selective A1 Adenosine Receptor Antagonist KW-3902 for Patients Hospitalized With Acute HF and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT-2).[73] This trial showed no benefit of rolofylline over placebo among 2033 patients with AHFS and impaired renal function in terms of the primary endpoint (treatment success, patient unchanged, or treatment failure). Higher rates of neurologic events were also seen with rolofylline, including seizures and strokes. Other adenosine antagonists remain under investigation; paradoxically, adenosine agonists are concurrently in development. In addition to the investigational agents addressed, the direct renin inhibitor aliskiren is under study for the management of AHFS. Table 4. Overview of Select Investigational Therapies for Acute Heart Failure Syndromesa Agent Classification Mechanism of Action Levosimendan Calcium sensitizer Stabilizes calcium–troponin C Increased contractility and vasodilation; complex, opens smooth muscle similar effect on mortality vs. dobutamine; potassium ion channels approved in Europe Adenosine Inhibits adenosine A1-receptor Rolofylline Comments Increased diuresis and natriuresis; no change or increased GFR; no improvement antagonist in afferent arterioles of kidneys in symptoms or clinical outcome vs. placebo Ularitide ANP Binds to ANP receptors in kidneys Increased diuresis and natriuresis; similar activity to nesiritide Relaxin Peptide hormone Releases nitric oxide, inhibits endothelin and angiotensin II Decreased cardiac filling pressure and increased cardiac output aAdapted from references 8, 9, and 72. GFR = glomerular filtration rate, ANP = atrial natriuretic peptide. Inotropic therapies continue to be explored, including calcium sensitizers (levosimendan), cardiac myosin activators, metabolic modulators, and Na/K-ATPase inhibitors (istaroxime). Levosimendan has been the most extensively studied inotropic agent thus far. However, primary results from the Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) trial showed no difference in mortality at 180 days between levosimendan and dobutamine among 1327 patients.[74] Adverse effects were also more common with levosimendan, including hypotension, tachyarrhythmias, hypokalemia, and headache. Conclusion Drug therapy of AHFS may include diuretics, vasodilators, morphine, ACE inhibitors, digoxin, inotropes, and vasopressin antagonists. Clinical practice guidelines for patients with AHFS provide a useful mechanism to incorporate available evidence and standards of practice into patient care. Appendix—Comparison of Guidelines for Management of Acute Heart Failure Syndromes [1,5,6] American College of Cardiology Foundation/American Heart Association,[1,a] Diuretics z z z Start i.v. loop diuretics in the emergency department or clinic setting for significant fluid overload (class I, level B). The initial i.v. dose should equal or exceed the long-term oral daily dose. Adjust dose according to symptom relief and to reduce extracellular fluid volume excess (class I, level C). When diuresis is inadequate to relieve congestion, the regimen should be intensified by using higher doses of loop diuretic, adding a second diuretic (e.g., metolazone, spironolactone, chlorothiazide), or using a continuous infusion of loop diuretic (class I, level C). Vasodilators z I.V. nitroglycerin, sodium nitroprusside, or nesiritide added to diuretics or in patients not responding to diuretics alone for evidence of severely symptomatic fluid overload in the absence of systemic hypotension (class IIa, level C). Inotropes z z I.V. inotropic or vasopressor drugs should be administered for clinical evidence of hypotension with hypoperfusion and obvious evidence of elevated cardiac filling pressure (class I, level C). Dopamine, dobutamine, or milrinone might be reasonable for patients with severe systolic dysfunction, low z blood pressure (BP), and evidence of low cardiac output, with or without pulmonary congestion (class IIa, level C). Use of i.v. inotropes in normotensive patients without evidence of decreased organ perfusion is not recommended (class III, level B). Heart Failure Society of America,[5,b] Diuretics z z z z Loop diuretic (usually given i.v.) for evidence of fluid overload is recommended (strength of evidence = B). Use of diuretic doses needed to achieve optimal volume status with relief of signs and symptoms of pulmonary congestion without causing a rapid reduction in intravascular volume or serum electrolytes (strength of evidence = C). Patients with moderate-to-severe renal dysfunction and evidence of fluid retention should continue to be treated with diuretics. In the presence of severe fluid overload, renal dysfunction may improve with diuresis (strength of evidence = C). When congestion fails to improve with diuretics, the following pharmacologic options should be considered: increasing doses of loop diuretic, continuous infusion of loop diuretic, and the addition of a second type of diuretic (e.g., metolazone, spironolactone, chlorothiazide) (strength of evidence = C). Vasodilators z z z z I.V. nitroglycerin, sodium nitroprusside, or nesiritide added to diuretics for rapid improvement of congestive symptoms in the absence of symptomatic hypotension may be considered. Frequent BP monitoring is recommended (strength of evidence = B). Reintroduction of i.v. vasodilators in increasing doses may be considered once symptomatic hypotension is resolved (strength of evidence = C). I.V. nitroglycerin or sodium nitroprusside and diuretics for rapid symptom relief in patients with acute pulmonary edema or severe hypertension are recommended (strength of evidence = C). Sodium nitroprusside, nitroglycerin, or nesiritide in patients with persistent severe heart failure (HF) despite aggressive treatment with diuretics and standard oral therapies may be considered (sodium nitroprusside: strength of evidence = B; nitroglycerin and nesiritide: strength of evidence = C). Inotropes z z z z z z Milrinone or dobutamine to relieve symptoms and improve end-organ function in advanced HF, particularly with marginal systolic BP (<90 mm Hg), symptomatic hypotension despite adequate filling pressure, or lack of response or intolerance to i.v. vasodilators may be considered (strength of evidence = C). Milrinone or dobutamine with evidence of fluid overload if poor response to i.v. diuretics or diminished/worsening renal function may be considered (strength of evidence = C). Vasodilators should be considered over inotropes for adjunctive therapy (strength of evidence = C). Inotropes are not recommended unless left heart filling pressure is known to be elevated or cardiac index is severely impaired based on direct measurement or clear clinical signs (strength of evidence = C). Continuous or frequent BP and cardiac rhythm monitoring with i.v. inotropes is recommended (strength of evidence = C). Discontinuation or dose reduction of i.v. inotropes should be considered if symptomatic hypotension or worsening tachyarrhythmias develop (strength of evidence = C). European Society of Cardiology,[6,c] Diuretics z I.V. loop diuretic in the presence of symptoms secondary to congestion and volume overload (class I, level B). Vasodilators z I.V. nitrates and sodium nitroprusside in patients with systolic BP of >110 mm Hg (or with caution in patients with systolic BP of 90–110 mm Hg) (class I, level B). Inotropes z z z Inotropes should only be administered in patients with low systolic BP or cardiac index in the presence of signs of hypoperfusion or congestion (class IIa, level B). Dobutamine or dopamine (class IIa, level B). Milrinone (class IIb, level C). a Classes of recommendations: I = treatment should be administered, IIa = reasonable to administer treatment although additional studies with focused objectives needed, IIb = treatment may be considered although additional studies with broad objectives needed, III = treatment should not be administered since it is not helpful and may be harmful. Levels of evidence: A = multiple (3–5) population strata evaluated and general consistency of direction and magnitude of effect, B = limited (2–3) population risk strata evaluated, C = very limited (1–2) population risk strata evaluated. b Levels of evidence: A = randomized, controlled, clinical trials, B = cohort and case–control studies, C = expert opinion. Strength of recommendations: "is recommended" = part of routine care, "should be considered" = majority of patients should receive the intervention, "may be considered" = individualization of therapy is indicated, "is not recommended" = therapeutic intervention should not be used. c Classes of recommendations: I = evidence and/or general agreement that a given treatment is effective, IIa = weight of evidence/opinion in favor of efficacy, IIb = efficacy is less well established by evidence/opinion, III = evidence or general agreement that the treatment is not effective and in some cases may be harmful. Levels of evidence: A = data derived from multiple randomized clinical trials or meta-analyses, B = data derived from a single randomized trial or large nonrandomized studies, C = consensus of opinion of the experts and/or small studies, retrospective studies, and registries. References 1. 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