Introduction

Acute decompensated HF is a life-threatening condition generally defined as a first occurrence ( de novo ) or, more frequently a presentation of acute worsening of preexisting chronic HF with prior reported admissions for decompensation. It affects primarily the elderly and often requires urgent evaluation and hospitalization ( Table 3.1 ).

Patients with de novo ADHF usually have a sudden presentation, with pulmonary edema or cardiogenic shock, while those with acute decompensation of chronic HF tend to show progressive signs and symptoms before acute presentation. These differences are explained by compensatory mechanisms, the capacity of the pulmonary lymphatic system and preexisting use of diuretic therapy. Also, although acute decompensation of chronic HF can happen without known precipitants, most patients have identifiable triggers such as infection, arrhythmia, anemia, pulmonary embolism, acute coronary syndrome (ACS), and nonadherence.

Although prehospital management is recommended, it should not delay transfer to an appropriate medical environment. The assessment includes discrimination of severity and adjudication of the relative contribution of either congestion or perfusion to the bedside clinical profile. In the absence of cardiogenic shock, immediate echocardiography is not mandatory, since initial treatment of ADHF is similar for patients with HFrEF or HFpEF, which centers around decongestion with diuretic therapy and maintenance of adequate peripheral perfusion using either vasodilators or in selected situations, inotropic support. There is some controversy as to whether chronic therapies for HF should be reduced or stopped during acute decompensations. Current guidelines suggest that patients should continue long-term HF therapies in the setting of ADHF, except in the presence of hemodynamic instability, hyperkalemia or severely impaired renal function. The clinical supposition in such cases is that the neurohormonal activation may be necessary during acute decompensation to maintain cardiorenal hemodynamics. In these cases, daily dosages of neurohormonal antagonists may be down-titrated or withheld temporarily until stabilization, with rapid reexposure once the acute state abates. The choice of drug therapy will need to take prognostic variables into account and parameters such as an elevated blood urea nitrogen (BUN) level ≥ 43 mg/dL, low systolic blood pressure (BP) < 115 mmHg, high serum creatinine level ≥ 2.75 mg/dL, and increased troponin I level signify elevated risk. Permanent signs of congestion and renal dysfunction have been shown to be among the most important prognostic variables. The routine use of a pulmonary artery catheter is not recommended and should be restricted to hemodynamically unstable patients with an unknown mechanism of deterioration and influences the therapy which in such cases tends to be targeted towards the hemodynamic aberration. A clinical approach that may act as a surrogate to invasive hemodynamic parameters has been widely used to classify patients into therapeutic categories ( Fig. 3.1 ). Patients with a “wet” profile have correlated higher pulmonary capillary wedge pressure (PCWP ≥ 18 mmHg) while those with a “cold” profile have lower cardiac indexes (CI ≤ 2.2 L/min/m ² ). Fig. 3.2 summarizes the 2016 European Society of Cardiology (ESC) algorithm for management of patients admitted with ADHF based on clinical profiles.

Clinical profiles based on the presence of symptoms and signs of congestion and peripheral hypoperfusion. CI , Cardiac index; PCWP , pulmonary capillary wedge pressure; S3 , third heart sound; SVR , systemic vascular resistance.

(Based on data from Nohria A, Tsang SW, Fang JC, et al. Clinical assessment identifies hemodynamic profiles that predict outcomes in patients admitted with heart failure. J Am Coll Cardiol 2003;41(10):1797–1804.)

Algorithm for management of patients admitted with acute heart failure (AHF) based on clinical profiles.

(Data from Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: The task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016.)

Diuretics

Congestion is the leading cause of hospitalization in patients with ADHF. Although robust evidence is lacking, clinical experience has demonstrated that diuretics effectively improve hemodynamics and congestive symptoms, even in the setting of de novo ADHF, in which pulmonary edema may occur without significant volume overload. During ADHF hospitalization, net changes in weight and fluid balance are commonly used to assess response to decongestive therapies.

Diuretics are classified according to their major site of action, chemical structure, or type of diuresis. Table 3.2 summarizes the doses and site of action of most diuretics commonly used in patients with acute and chronic HF. The optimal regimen is often influenced by renal function, preexisting diuretic therapy and urgency of decongestion. Loop diuretics, such as furosemide, torsemide, and bumetanide, have the most potent diuretic effect and remain the diuretic of choice for treating ADHF. These agents act by directly inhibiting the sodium–potassium–chloride cotransporter (NKCC) at the thick ascending limb of the loop of Henle. They also inhibit a second cotransporter isoform that is widely expressed throughout the body, including the ear, which probably explains the side effect of ototoxicity associated with their use.

Loop diuretics are organic anions that are heavily bound to proteins as they circulate, reaching the tubular lumen predominantly by active secretion rather than glomerular filtration and thus maintain efficacy unless renal function is severely impaired. While structurally similar as a class, these agents have substantial differences in pharmacokinetics. The oral bioavailability of furosemide ranges from 10% to 90% and is determined by absorption from the gastrointestinal tract into the bloodstream, which is decreased in patients with severe ADHF-associated bowel edema. In contrast, the oral bioavailability of torsemide and bumetanide remain high (> 90%), making oral and intravenous (IV) doses similar. In addition, torsemide has a longer half-life when compared to furosemide or bumetanide. In healthy individuals, an oral dose of a loop diuretic may be as effective as an IV dose because the diuretic bioavailability that is above the natriuretic threshold is approximately equal. However, the natriuretic threshold increases in patients with HF and the oral dose may not provide a high enough serum level to elicit a significant natriuresis. Therefore, IV therapy is recommended in patients with ADHF to achieve a higher and consistent bioavailability, allowing rapid onset of action within few minutes.

Diuretic dosing should be individualized and titrated according to hemodynamic response. Patients on chronic loop diuretic therapy may need higher doses in the setting of acute decompensation of chronic HF. The DOSE trial prospectively compared diuretic strategies in patients with ADHF and suggested that 2.5 times the usual home dose is associated with better symptom improvement than low dose, at the cost of some renal impairment. The DOSE trial also showed no difference in outcomes between continuous IV infusion and intermittent bolus strategies, suggesting that both approaches could be considered when managing significant volume overload or diuretic resistance. Clinical experience, however, has demonstrated that when the effect of high-dose loop diuretic is suboptimal, a continuous infusion may be superior to reduce toxicity and maintain stable serum drug levels. Given the steep dose-response curve of loop diuretics, prompt doubling of dose at 2-hour intervals might allow the attainment of a ceiling dose earlier. Increasing the dose above the ceiling can lead to additional natriuresis by extending the time during which serum drug levels exceeds the natriuretic threshold, which makes it appear as if a ceiling does not exist.

Impaired diuretic response is a common complication in patients with ADHF and is associated with increased rehospitalization and mortality. Although not fully understood, diuretic resistance is thought to result from a complex interplay between cardiac and renal dysfunction, specific renal adaptation, and escape mechanisms. In fact, the magnitude of natriuresis following a given dose of diuretics declines over time as a result of the braking phenomenon, an appropriate homeostatic response that prevents excessive volume depletion during continued diuretic therapy. However, in patients with secondary hyperaldosteronism, such as those with HF, this phenomenon can be pronounced, leading to an increased reabsorption of sodium and contributing to diuretic resistance. Furthermore, chronic treatment with a loop diuretic results in compensatory hypertrophy of the distal tubular cells, which bypasses the proximal effect of the loop diuretic.

The coexistence of HF and impaired renal function is another common cause of diuretic resistance, as decreased renal blood flow and impaired tubular secretion may lead to insufficient therapeutic urinary drug concentrations. Among these patients, it is important to distinguish between underlying kidney disease and cardiorenal syndrome, which is being increasingly recognized as a complication of ADHF. The pathways to these distinct conditions involve not only hemodynamic deterioration but also neurohormonal, inflammatory, and intrinsic renal mechanisms. It is hypothesized that the cardiorenal syndrome may represent a backward failure, with elevated right-sided filling pressures contributing more to renal dysfunction than low cardiac output (CO). Traditional therapy with diuretics can contribute to cardiorenal syndrome, probably by further neurohormonal activation and worsening intrarenal hemodynamics, while vasodilator or inotropic therapy has not been shown to help. In most cases, however, worsening of renal function in the setting of aggressive diuresis may reflect hemodynamic or functional changes in glomerular filtration rather than actual renal tubular injury. Because residual clinical congestion is a predictor of poor outcomes in HF, a small to moderate increase in the BUN/creatinine ratio should not prevent further diuretic therapy if clinical evidence of congestion is still present in patients with ADHF.

A useful approach for overcoming diuretic resistance is by sequential nephron blockade, which is the concurrent use of diuretics acting upon different segments of the nephron to produce an additive or synergistic diuretic response. There is some evidence that a stepped pharmacologic strategy with early assessment of urinary output and sequential nephron blockade might result in equal decongestion when compared to mechanical ultrafiltration (UF), without significant renal impairment. A post hoc analysis of the CARRESS-HF, DOSE, and ROSE-ADHF trials compared the efficacy of a urine-output guided diuretic adjustment versus standard high-dose loop diuretics therapy for the management of cardiorenal syndrome in patients with ADHF. Compared with standard therapy, the stepped pharmacologic algorithm dosed to maintain urine output between 3 and 5 L/day resulted in greater weight change and more net fluid loss after 24 hours with slight improvement in renal function. A practical stepped pharmacologic algorithm to diuretic assessment in ADHF is reflected in Fig. 3.3 .

A practical stepped pharmacologic algorithm to diuretic assessment in acute heart failure.

Total loop diuretic dose can be administered either as continuous infusion or bolus infusion. SGLT-2i , Sodium-glucose cotransporter 2 inhibitor; UF , ultrafiltration; UO , urine output.

(Modified from Mullens W, Damman K, Harjola VP, et al. The use of diuretics in heart failure with congestion—a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2019;21(2):137–155.)

Combined diuretic therapy using any of several thiazide-type diuretics can more than double daily natriuresis, although care must be taken for symptomatic hypotension, renal dysfunction, and electrolyte abnormalities. Both IV chlorothiazide and oral metolazone have been shown to provide significant increases in urine-output when added to furosemide monotherapy, with chlorothiazide inducing a larger diuretic effect but at higher costs and greater need for potassium replacement. There are no randomized controlled trials to establish whether a preferable thiazide exists in the treatment of ADHF.

Potassium-sparing diuretics, such as spironolactone, eplerenone, amiloride, and triamterene, should be considered to prevent hypokalemia associated with loop and thiazide diuretics use. Spironolactone and eplerenone are synthetic mineralocorticoid-receptor antagonists (MRAs) with a strong recommendation for patients with symptomatic chronic HFrEF, while amiloride and triamterene are epithelial sodium channel blockers that do not affect the mineralocorticoid receptor.

Carbonic anhydrase inhibitors, such as acetazolamide, potently inhibit sodium bicarbonate reabsorption in the proximal tubules, resulting in increased sodium levels in the loop of Henle where loop diuretics may exert their natriuretic action. These agents may be particularly useful during concomitant metabolic alkalosis, but, when used repeatedly, can lead to metabolic acidosis and hypokalemia. Other potential drugs for further decongestion, such as the arginine vasopressin (AVP) antagonists, have been investigated as adjuncts to standard HF therapies and will be addressed in other sections.

Other approaches that may also be helpful in patients with diuretic resistance are UF or hypertonic saline solution (HSS 3%) administration. The potential benefit of veno-venous UF is the removal of isotonic fluid without neurohormonal activation seen with diuretics. A trial comparing UF to diuretic therapy in patients with ADHF showed that UF was associated with greater weight loss by 48 hours but no difference in dyspnea score when compared to the control group. UF was associated with a reduction in rehospitalization and unscheduled office visits. By contrast, other trials have observed a higher frequency of adverse events in patients treated with UF, including worsening of renal function in the CARRESS-HF and venous access complications in the AVOID-HF, which was not completed by the sponsor. Based on these concerns, current HF guidelines do not recommend routine use of UF, which should be restricted to patients with congestion not responding to a stepped-care diuretic strategy. HSS 3% administration along with high-dose furosemide in selected hyponatremic patients with systemic congestion and renal dysfunction may be associated with greater clinical response and renal function preservation. However, routine use of HSS 3% is controversial and further studies are needed before use can be endorsed.

Organic Nitrates

Organic nitrates, such as nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate, reduce ventricular preload primarily via venodilation. At higher doses, especially in the presence of vasoconstriction, these agents can decrease systemic vascular resistance (SVR) and left ventricular (LV) afterload, consequently increasing stroke volume (SV) and CO. Nitrates are also partially selective for epicardial coronary arteries, thus justifying use in ADHF associated with ACS.

Nitrate indication is largely based upon hemodynamic response and expert opinion, as evidence is scarce and has relatively limited methodological quality. Intravenous administration is recommended for greater bioavailability and ease of titration. Low initial doses of nitroglycerin (NTG) are recommended, with rapid up-titration increments every 5 minutes as required and tolerated. Aggressive early up-titration of NTG is associated with a significant reduction in pulmonary capillary wedge pressure (PCWP) that reaches a maximum effect at 2 to 3 hours and declines subsequently within the following 24 hours due to tachyphylaxis. Tachyphylaxis is described as a rapid and significant attenuation of hemodynamic effects, limiting NTG usefulness in the treatment of patients with ADHF. The most common side effects of NTG are hypotension, headache, and nausea.

Sodium Nitroprusside

In contrast to NTG, sodium nitroprusside (SNP) causes balanced arterial and venous dilation, therefore reducing both the preload and the afterload. The use of SNP in patients with ADHF results in a significant decrease in systemic BP, right atrial pressure (RAP), pulmonary arterial pressure (PAP), PCWP, SVR, and pulmonary vascular resistance (PVR). SNP has a very short half-life, of seconds to a few minutes, and is particularly effective in the setting of ADHF secondary to elevated afterload such as acute aortic or mitral regurgitation, ventricular septal rupture, or hypertensive emergency.

Administration of SNP requires close hemodynamic monitoring due to its potent hemodynamic effects. Although severe hypotension is rare and resolves quickly, significant vasodilation of the intramyocardial vasculature may cause a “coronary steal” phenomenon. Therefore, SNP is not recommended in the setting of ACS. Also, sudden withdrawal may cause a “rebound hypertension” effect and gradual tapering is advised, ideally transitioning to oral vasodilators.

The major limitation to the use of SNP is its metabolism to cyanide. When doses > 400 μg/min are used for long periods of time, especially in patients with renal and/or hepatic dysfunction, the accumulation of SNP metabolites can lead to the development of cyanide, or rarely thiocyanate, toxicity, which may be fatal. The first sign of cyanide toxicity is lactic acidosis, and the most common side effects of thiocyanate toxicity are mental status changes, nausea, and abdominal pain. Thiocyanate can be removed with dialysis, and cyanide toxicity has been successfully managed with infusions of thiosulfate, sodium nitrate, and hydroxycobalamin. There are no randomized clinical trials of SNP in patients with ADHF and, as with NTG, their indication is based upon hemodynamic response and expert opinion.

Nesiritide

Nesiritide is a synthetic analogue form of the human B-type natriuretic peptide (BNP), manufactured from Escherichia coli with recombinant DNA technology. It causes balanced arterial and venous dilation, resulting in significant reductions in filling pressures and mild increases in CO.

In patients with ADHF, the administration of nesiritide has been investigated more extensively than both NTG and SNP. The VMAC trial tested the safety and efficacy of nesiritide in patients with ADHF and reported a significantly greater decrease in PCWP compared to both NTG and placebo, with no evidence of tachyphylaxis. Nesiritide, but not NTG, was also associated with significant improvements in patient-reported dyspnea at 3 hours. The ASCEND-HF trial tested nesiritide in a broad population of patients with ADHF and demonstrated a modest improvement in dyspnea when compared to placebo, but no difference in the composite outcome of death or HF hospitalization at 30 days. While there was no increase in renal failure with nesiritide, the incidence of symptomatic hypotension was higher with nesiritide. Those findings were consistent with the latter ROSE-ADHF trial, which assessed the effects of low-dose nesiritide in patients with ADHF and showed no benefits on urine output, congestion, renal function, or clinical outcomes, but more symptomatic hypotension.

Because of its high cost and lack of clear clinical benefit beyond other vasodilator therapies, such as NTG or SNP, nesiritide is not recommended as a first-line drug for patients with ADHF. Neither should it be used for the indication of replacing diuretic therapy, enhancing natriuresis, preventing cardiorenal syndrome, or improving survival. However, in selected patients who remain symptomatic despite standard therapy, a trial of nesiritide may be helpful.

Dobutamine

Dobutamine is the most widely used β-adrenergic agent for inotropic support. It is a synthetic analog of dopamine, with strong β ₁ agonist activity as well as minor effects on β ₂ -and α ₁ -receptors. It has been suggested that the inotropic activity of dobutamine results from combined β ₁ and α ₁ stimulation in the myocardium. β ₁ -stimulation enhances cardiac contractility through increases in intracellular cyclic adenosine monophosphate (cAMP) and calcium. At low doses, β2-stimulation generally offsets α1-adrenergic activity, resulting in peripheral artery vasodilation that occasionally may lead to symptomatic hypotension. At higher doses, though, peripheral vasoconstriction predominates through vascular α ₁ -receptor stimulation. Since it has no dopaminergic effects, dobutamine is less prone to induce hypertension than is dopamine.

Dobutamine provides hemodynamic support with a dose-dependent increase in SV and CO and modest decreases in SVR and PCWP, referred to as an inodilatory effect. Lower doses might improve perfusion in patients with cardiogenic shock, but higher doses are generally recommended for more profound hypoperfusion states.

Dobutamine may induce serious atrial and ventricular arrhythmias at any infusion dose, particularly in the context of myocarditis and electrolyte imbalance. It also increases heart rate (HR) and myocardial oxygen demand and should be used cautiously in patients with recent myocardial ischemia. Hypersensitivity to dobutamine is a rare and unrecognized cause of eosinophilic myocarditis after prolonged infusion. Also, β-receptors may be downgraded or therapeutically blocked in patients with advanced HF so that intolerance to dobutamine may ensue. In the absence of cardiogenic shock, either levosimendan or milrinone could be alternatives for treating ADHF when β-blockade is thought to be contributing to hypoperfusion.

Clinical trials and HF registries have documented excess mortality in patients receiving intermittent or continuous dobutamine infusion, despite its beneficial hemodynamic effects. Thus, dobutamine should be restricted to HF patients with pulmonary congestion and low CO syndrome. In this setting, dobutamine appears to be as effective as milrinone.

Dopamine

Dopamine is a catecholamine-like agent, with complex effects that vary greatly with dose. At low doses, dopamine acts primarily on dopamine-1 receptors to dilate renal, splanchnic, and cerebral arteries. Although it has been proposed that dopamine might improve renal blood flow promoting natriuresis through direct distal tubular effects, data supporting such a potential benefit are limited. The DAD-HF study suggested that a combination of low-dose furosemide and low-dose dopamine as a continuous infusion for 8 hours was equally effective as high-dose furosemide but associated with improved potassium homeostasis and preservation of renal function. The follow-up DAD-HF II trial, however, found no differences in mortality rates, HF hospitalization, or overall dyspnea relief with the combined therapy. These findings are consistent with the ROSE-ADHF trial, which found that neither low-dose dopamine nor low-dose nesiritide enhanced decongestion or improved renal function in patients with ADHF. Notably, both DAD-HF II and ROSE-ADHF studies showed a higher incidence of tachycardia in the dopamine group.

At intermediate doses, dopamine acts as a precursor in the synthesis of norepinephrine (NE), an agonist of both adrenergic and dopaminergic receptors, and an inhibitor of NE reuptake, increasing SV and CO with variable effects on HR. Both the β ₁ -stimulation and the rapid release of NE can precipitate tachycardia as well as atrial and ventricular arrhythmias. Tachyphylaxis to the inotropic effects of dopamine may develop, in part, because myocardial NE stores often become depleted in patients with advanced HF.

At higher doses, dopamine also stimulates α-receptors leading to pulmonary and peripheral artery vasoconstriction. In the treatment of shock, dopamine compares similarly to NE as the first-line vasopressor agent with respect to 28-day mortality but is associated with an increased risk of arrhythmias. Also, vasoconstriction dosages carry significant risk of precipitating limb and end-organ ischemia and should be used with caution. Discontinuation from high infusion rates should be done gradually to no less than 3 μg/kg/min, to minimize potential hypotensive response of low-dose dopamine.

Epinephrine

Epinephrine is the first-line vasopressor for cardiac arrest and anaphylactic shock. It acts as a complete β-receptor agonist, with dose-dependent α-agonism effect at higher doses. At lower doses, epinephrine acts predominantly on β ₁ -receptors, with less prominent effects on β ₂ and α ₁ , resulting in an overall increase in CO with balanced vasodilator and vasoconstrictor effects. At higher doses, it increases SVR and BP, with combined inotropic and vasopressor effect. Common side effects, particularly at high doses, include tachycardia, arrhythmias, poor peripheral perfusion, headaches, anxiety, cerebral hemorrhage, and pulmonary edema. There is also a risk of local tissue necrosis with extravasation.

Isoproterenol

This relatively pure β-stimulant should be considered in cardiogenic shock secondary to bradycardia or when excessive β-blockade is thought to be contributing to hypoperfusion. It increases inotropy and chronotropy through β ₁ -stimulation, with a variable response on BP, depending upon the degree of concomitant β ₂ -vasodilator stimulation. The cardiac effects of isoproterenol may lead to palpitations, sinus tachycardia, and more serious arrhythmias. Other common side effects are hypotension, angina pectoris, flushing, headache, restlessness, and sweating. Patients with IHD may be at higher risk of further myocardial ischemia due to increased oxygen consumption. Also, there are some concerns regarding cost effectiveness of isoproterenol when compared to significantly cheaper alternative chronotropic agents.

Omecamtiv Mecarbil

Omecamtiv mecarbil is a direct cardiac myosin activator that enhances effective actin-myosin cross-bridge formation and creates a force-producing state that is not associated with cytosolic calcium accumulation. Thus, omecamtiv mecarbil is believed to act as a calcium-sensitizer with pure inotropy action and no pleiotropic effects. Earlier studies have shown that it is safe, well tolerated, and produces dose-dependent increases in systolic ejection time, SV, EF, and fractional shortening. In the ATOMIC-AHF trial, IV omecamtiv mecarbil did not meet the primary outcome of dyspnea improvement in patients with ADHF compared to placebo, except in the higher-dose group. It did, however, increase systolic ejection time and decrease LV end-systolic diameter.

Istaroxime

Istaroxime is an investigational drug that mediates lusitropism through inhibition of sodium-potassium ATPase and stimulation of the sarcoendoplasmic reticulum calcium ATPase type 2a (SERCA2a). In the phase 2 HORIZON-HF trial, the addition of istaroxime to standard therapy lowered PCWP and HR and increased systolic BP in patients with ADHF. Also, higher doses of istaroxime appeared to be associated with more improvement in diastolic function. The role of this agent remains uncertain at this time.

Acute Coronary Syndromes

The acute onset of severe myocardial ischemia, with or without infarction, can result in decreased CO and/or elevated filling pressures. The coexistence of ADHF within ACS identifies a high-risk cohort, for whom aggressive therapy aiming at reperfusion should be rapidly instituted. Primary angioplasty is the strategy of choice for patients with ST-elevation MI. Inopressor therapy can offer pharmacological support to improve hemodynamics during cardiogenic shock but should be administered at the lowest possible doses to avoid further ischemia. Inodilator agents are not recommended in the absence of shock.

Hypertensive Emergency

Hypertensive ADHF accounts for approximately 10% of all ADHF cases, being most common in patients with HFpEF. ADHF precipitates in the setting of markedly elevated afterload, and typically manifests as acute pulmonary edema. Aggressive BP reduction with IV vasodilators and diuretics is recommended. Calcium channel blockers (CCBs) without significant myocardial depressant effects, such as nicardipine and clevidipine, may be helpful in patients presenting with hypertensive ADHF. Intravenous clevidipine has a rapid onset of action, high clearance, and no effect on ventricular contractility or central venous pressure (CVP), and is currently approved for the acute management of severe hypertension. Intravenous esmolol, a β-blocker, may be also used, but it is contraindicated in severe bradycardia heart block, cardiogenic shock, and overt HF.

Right Ventricular Heart Failure

Isolated right-sided or right ventricular (RV) HF is generally caused by acute RV infarction, severe pulmonary hypertension, or acute pulmonary embolism. Acute RV infarction should be approached as any other ACS, including early reperfusion and primary angioplasty when indicated. However, patients with RV infarction are very preload-dependent and can develop severe hypotension in response to nitrates or other preload-reducing agents. Hemodynamic stabilization with careful volume loading to a goal CVP of 10–12 mmHg can be beneficial, especially in patients with MAP < 60 mmHg. After ensuring adequate filling pressures, inotropic support can further augment RV CO. However, these principals do not apply to chronic right-sided HF.

The RV is also sensitive to increases in afterload, which is affected by the PVR. Selective pulmonary artery vasodilation includes treatment with NO, prostacyclin analogues, endothelin receptor antagonists, or, less frequently, certain CCBs. Hemodynamically unstable patients due to acute pulmonary embolism should be treated with immediate reperfusion either with thrombolysis, catheter-based approach, or surgical embolectomy.

Cardiogenic Shock

Cardiogenic shock is defined as a state of sustained hypotension (systolic BP < 90 mmHg for ≥ 30 min) and a reduced CI (< 2.2 L/min/m ² ) in the presence of normal or elevated PCWP (> 15 mmHg) and inadequate tissue perfusion (e.g., elevation in lactate levels). Acute MI with LV dysfunction is the most frequent cause of cardiogenic shock. In patients with a recent ACS, mechanical complications such as papillary muscle rupture, ventricular septal defect, and free wall rupture may present as cardiogenic shock within 24 hours of hospitalization. Also, around 2%–6% patients may develop postcardiotomy cardiogenic shock following cardiac surgery. Therefore, immediate echocardiography is mandatory in all individuals presenting with cardiogenic shock. Other, less common etiologies include advanced valvular heart disease, arrhythmias, cardiac tamponade, cardiac constriction, pulmonary embolism, peripartum cardiomyopathy, acute coronary dissection, acute myocarditis, and drug poisoning.

Fluid challenge for up to 30 minutes, either with saline or ringer lactate, is recommended as the first-line treatment if there is no sign of overt fluid overload. Pharmacological therapy with inotropic and vasopressor agents aims to improve organ perfusion by increasing CO and BP. Despite their frequent use, few clinical outcome data are available to guide the initial selection of such therapies in patients with cardiogenic shock. Dobutamine is the most used inotrope, while levosimendan may be an alternative to patients already on oral β-blockade. Norepinephrine is recommended as the first-line vasopressor agent in the treatment of shock, as the use of dopamine is associated with a greater number of adverse events, such as arrhythmia. Short-term MCS, including extracorporeal membrane oxygenation (ECMO), may be considered as a bridge to heart transplantation or to other mechanical intervention in refractory cases. Currently, the intra-aortic balloon pump (IABP) is still the most widely used MCS device in cardiogenic shock. However, among patients with MI and cardiogenic shock, the use of an IABP did not improve mortality or any long-term secondary outcome in the IABP-SHOCK II trial. Therefore, routine use of an IABP cannot be recommended.

Introduction

There has been substantial progress in the pharmacological management of chronic HF over the past three decades. The positive results of successive landmark clinical trials are reflected in clinical practice guidelines, which, in turn, have become standard of HF care. In general, the goals of treatment are to improve symptoms, functional capacity, and general quality of life, prevent disease progression and recurrent admissions, and prolong survival. To accomplish these goals, HFrEF should be viewed as a continuum that comprises four interrelated stages with incremental therapy at each stage aimed at modifying risk factors (A), treating structural heart disease (B-D), and reducing morbidity and mortality.

Currently, the recommendation for patients with stage A HF is largely preventive and should focus on risk factor modification and treatment of atherosclerotic vascular disease. There is robust evidence showing that the onset of HF may be delayed or prevented through interventions aimed at modifying risk factors or treating asymptomatic LV systolic dysfunction. The SPRINT trial showed that intensive BP control in subjects with a high CV risk was associated with a 38% relative risk reduction in the development of overt HF. In patients with stable coronary artery disease (CAD) without LV dysfunction, meta-analyses of randomized clinical trials have shown a modest benefit of angiotensin converting–enzyme (ACE) inhibitors, with a reduction in major CV outcomes, including HF. The antidiabetic sodium-glucose cotransporter 2 (SGLT-2) inhibitors reduced the composite risk of CV death or HF hospitalization in patients with type 2 diabetes mellitus (T2DM), regardless of established CV disease or HF. There is also reasonable evidence that intensive statin therapy, but not aspirin or other antiplatelet agents, may prevent or delay the onset of HF after ACS, with the most gain in patients with elevated levels of BNP.

Several mechanisms contribute to the progression of HF, such as neurohormonal activation, endothelial dysfunction, venous congestion, and myocardial remodeling. Once patients have established structural heart disease, the choice of pharmacotherapy will depend on their NYHA functional class. For patients with structural heart disease but without signs or symptoms of HF (stage B), the therapeutic goal should be the prevention of further cardiac remodeling. In asymptomatic patients with chronically reduced LV ejection fraction (LVEF), an ACE inhibitor should be used to prevent the risk of HF hospitalization. In all patients with a recent or remote history of MI or ACS, β-blockers and ACE inhibitors should be used, regardless of LVEF. It is noteworthy that β-blocker therapy should only be initiated after acute MI has resolved to avoid the risk of cardiogenic shock.

Symptomatic patients (stages C and D) have a worse prognosis, particularly after hospital admission for ADHF. The major goals of treatment in patients with structural heart disease and previous or current symptoms (stage C) are to alleviate symptoms and reduce morbidity by reversing or slowing the cardiac and peripheral dysfunction. Neurohormonal antagonists, such as ACE inhibitors, angiotensin receptor blockers (ARBs), β-blockers, MRAs, and ARNIs, have been shown to improve outcomes in HFrEF and are recommended, unless contraindicated or not tolerated. More recently, the SGLT-2 inhibitor dapagliflozin was also associated with improved clinical outcomes among patients with symptomatic HFrEF, irrespective of T2DM status, signaling a new approach in the treatment of HF.

Additional pharmacological agents, such as hydralazine plus nitrate, ivabradine, and digoxin, should be considered in selected patients. Patients with refractory end-stage HF (stage D) may be eligible for specialized, advanced treatments, such as LV assist devices (LVADs) and heart transplantation.

Neurohormonal Activation

HFrEF classically develops after an index event that could be an acute injury to the heart, a long-standing hemodynamic overload, or a response to genetic variations that disrupt contractile function or lead to myocyte death. The circulatory changes that arise from impaired cardiac pumping and/or filling trigger a series of compensatory mechanisms referred to as neurohormonal activation. This historical term reflects early observations that many of the molecules that are elaborated in response to HFrEF are produced by the neuroendocrine system. However, most neurohormones such as NE and angiotensin II are now known to be synthesized directly within the myocardium and, therefore, act in an autocrine or paracrine manner.

The sympathetic nervous system (SNS) and the renin–angiotensin–aldosterone system (RAAS) are the major neurohormonal systems, working collectively to maintain CO through increased retention of salt and water, peripheral vasoconstriction, and increased contractility. The activation of inflammatory mediators also contributes to maintain early CV homeostasis through cardiac repair and remodeling. However, sustained and chronic neurohormonal activation has deleterious effects and leads to progressive ventricular remodeling and worsening HF. Further activation of the natriuretic peptide (NP) system briefly offsets these harmful effects but is unable to sustain compensation for chronic neurohormonal activation over time.

Neuroendocrine modulation with β-blockers targeting the SNS and ACE inhibitors, ARBs, and MRAs targeting the RAAS have become the cornerstone of medical therapy to reduce morbidity and mortality in patients with chronic HFrEF. Most recently, the ARNIs further improved clinical outcomes by targeting both the RAAS and the NP system.

β -Blockers

SNS activation is one of the earliest responses to a decrease in CO, resulting in both increased release and decreased reuptake of catecholamines at adrenergic nerve endings. It plays a complex role in HF, with both beneficial and adverse effects. In the short term, catecholamine-mediated chronotropic and inotropic responses help to maintain CO while increased SVR and venous tone preserve BP and preload. NE and angiotensin II also mediate constriction of the efferent arterioles, allowing for stable glomerular filtration rate (GFR) despite a low renal perfusion, and stimulate sodium retention and volume expansion, improving SV via the Frank–Starling law.

Over time, however, these responses become detrimental, resulting in disruptions of β-adrenergic signaling and impaired mobilization of intracellular calcium. As a consequence, increased SNS activation has been implicated in the development and progression of HF through multiple mechanisms, involving cardiac, renal, and vascular function. In the heart, it may lead to downregulation and functional desensitization of β-adrenergic receptors, cardiomyocyte hypertrophy, necrosis, apoptosis, and fibrosis. In the kidneys, SNS activation stimulates salt and water retention, attenuates response to natriuretic factors, and activates the RAAS, which in turn promotes a positive feedback loop that adversely affects hemodynamic and cardiac remodeling. In the peripheral vessels, it also mediates neurogenic vasoconstriction and vascular hypertrophy.

The association between SNS activation, reflected by an increase in the plasma NE concentration, and mortality in patients with HFrEF raised the possibility of therapeutic efficacy for sympathetic inhibition. The potential mechanisms by which β-blockers improve outcomes in HFrEF are likely related to reducing the detrimental effects of sustained SNS activation by competitively antagonizing β-adrenergic receptors. Particular benefits might include decreased myocyte death from catecholamine-induced necrosis, antiarrhythmic and HR-lowering effects, upregulation of β ₁ -receptors, and inhibition of renin secretion. In addition, β-blockers directly reduce myocardial oxygen consumption and BP, revert production of fetal protein isoforms, and prevent proapoptotic and cardiotoxic effects of cAMP-mediated calcium overload.

β-Blockers also strongly modulate cardiac remodeling, improve symptoms, reduce hospitalizations, and prolong survival in patients with HFrEF. Recommendations for their use are mainly based on the outcomes of large randomized placebo-controlled trials. The three β-blockers that have been shown to reduce the risk of death in patients with chronic HFrEF are carvedilol, bisoprolol, and extended-release metoprolol succinate (CR/XL). Nebivolol was also associated with a reduction in the composite outcome of mortality or CV hospitalizations, but it did not reduce mortality alone and is not approved by the US Food a Drug Administration (FDA) for the treatment of HFrEF.

The MDC was the first randomized clinical trial testing a β-blocker, the short-acting metoprolol tartrate, in subjects with idiopathic dilated cardiomyopathy (DCM) and NYHA class II-III. At 12 months, the metoprolol group had significant improvement in quality-of-life assessments, LVEF, and exercise capacity. There was also a nonsignificant 34% relative risk reduction in the combined outcome of death or need for cardiac transplantation, which was driven entirely by the reduction in transplantation, since there was no difference in all-cause mortality. The following MERIT-HF trial also investigated the impact of metoprolol on mortality in subjects with symptomatic HFrEF. However, it was larger, included patients with IHD as well as idiopathic DCM, and used the metoprolol succinate, which has a better pharmacological profile than metoprolol tartrate because of its extended-release formulation (CR/XL) and longer half-life. The MERIT-HF trial was stopped early at a mean follow-up of 12 months after an interim analysis demonstrated a 34% relative risk reduction in all-cause mortality in subjects with NYHA class II–IV HF and LVEF ≤ 40% with metoprolol CR/XL compared to placebo. Additional secondary outcomes showed a reduction in all-cause hospitalization and CV events. Of note, metoprolol CR/XL reduced mortality from both sudden cardiac death and progressive pump failure while nearly 95% of the study population was already taking a concomitant ACE inhibitor or ARB at baseline.

The first study performed with bisoprolol in HFrEF was the CIBIS trial, which showed a nonsignificant trend toward 20% lower mortality and 30% fewer HF hospitalizations at a mean follow-up of 1.9 years in the bisoprolol group. The subsequent follow-up CIBIS-II trial had greater statistical power to detect a mortality benefit and included approximately four times as many subjects as did CIBIS. The CIBIS-II was stopped early, at about 16 months, after the second interim analysis demonstrated a 34% relative risk reduction in all-cause mortality in patients with NYHA class III–IV HF and LVEF ≤ 35% with bisoprolol compared to placebo. At the time of CIBIS-II publishing, standard HFrEF therapy included diuretics, ACE inhibitors, nitrates, and digoxin. Other benefits of bisoprolol therapy, such as a reduction in the risk of sudden cardiac death, HF hospitalizations, and all-cause hospitalizations, were observed regardless of the HF etiology.

Of the three FDA-approved β-blockers for the treatment of HFrEF, carvedilol has been the most studied. The US Carvedilol Heart Failure Program was designed as a stratified clinical program consisting of four component trials to evaluate nonfatal outcomes in subjects with mild to severe HF and LVEF ≤ 35%. Although mortality was not a predefined primary outcome for the combined trials, it was prospectively measured by a safety committee, which prematurely stopped the program at a mean follow-up of 6.5 months due to a highly significant 65% relative risk reduction in mortality associated with the use of carvedilol across all four trials. The following ANZ-Carvedilol trial was conducted primarily to determine the effect of carvedilol therapy on LVEF and exercise tolerance in subjects with HF due to ischemic heart disease. The study concluded that carvedilol therapy for 12 months reduced LV volumes and preserved exercise performance at a lower rate-pressure product. At 19 months, there was also a significant 26% relative risk reduction in the clinical composite of death or hospitalization with carvedilol compared to placebo. However, the ANZ-Carvedilol trial was not powered to determine statistically significant effects on mortality, and therefore, the 24% relative risk reduction in mortality alone did not achieve statistical significance.

Taken together, the outcomes of the US Carvedilol HF Program and the ANZ-Carvedilol trial provided a strong rationale for other large, randomized mortality studies, such as the COPERNICUS and the CAPRICORN trials. The COPERNICUS trial was specifically designed to evaluate the impact of carvedilol in a population with more advanced HF than was studied in previous trials, including subjects with NYHA class III–IV and severely reduced LVEF < 25%. After a mean follow-up of 10.4 months, carvedilol was associated with a 34% relative risk reduction in annual mortality rates, as well as reductions in rehospitalizations, hospital length of stay, and cardiogenic shock when compared to placebo. In addition, subjects in the carvedilol group felt better and were less likely to develop any serious adverse event. The CAPRICORN trial tested the effects of carvedilol in patients with acute MI and LV dysfunction with LVEF ≤ 40% and showed no difference in the prespecified primary composite outcome of mortality and CV hospitalization when compared to placebo. However, all-cause mortality was reduced by 23% in the carvedilol group, a magnitude nearly identical to the results of the BHAT trial, which tested propranolol in patients with acute MI and was published two decades before. Importantly, almost all subjects in CAPRICORN were taking an ACE inhibitor, while approximately one-half had received thrombolysis and/or primary angioplasty.

Differences in β-blockers clinically used in HFrEF are associated to β ₁ -receptor selectivity, presence of α ₁ -receptor antagonism, antioxidant properties, and vasodilating effects. Both metoprolol and bisoprolol are second-generation agents that block β ₁ -receptors to a much greater extent than β ₂ -receptors, without antioxidant properties or vasodilating effects. Metoprolol is 75-fold selective, whereas bisoprolol has approximately 120-fold higher affinity for human β ₁ -versus β ₂ -receptors. This is important because their effects are mainly restricted to areas containing β ₁ receptors, especially the heart and part of the kidney. Also, side effects linked to β ₂ -blockade, such as bronchospasm, peripheral vasoconstriction, and abnormalities of glucose and lipid metabolism, are less common with β ₁ -selective agents, although receptor selectivity weakens at higher doses. Conversely, carvedilol is a third-generation nonselective β-blocker that competitively blocks β ₁ -, β ₂ -, and α-receptors with some antioxidant properties. Approximately 80% of adrenergic receptors in the normal myocardium are β ₁ -receptors. However, due to β ₁ downregulation in HF, β ₂ may rise up to 40% of the total adrenergic receptors. Interestingly, β ₂ also mediates the effects of catecholamines in the heart, and as a result, it becomes a relatively important mediator of inotropic support and arrhythmogenic effects of sympathetic stimulation in patients with HF. The human heart also expresses α ₁ -receptors, although at much lower levels than β-receptors. The importance of cardiac α ₁ -receptors in the pathophysiology of HF is still controversial, but their role in the vasoconstriction of major arteries, such as the aorta, pulmonary arteries, mesenteric vessels, and coronary arteries, is well known. Consequently, carvedilol blockade of α ₁ -receptors causes vasodilation of blood vessels and might help to improve afterload while posing a higher risk for hypotension.

The hypothesis that multiple adrenergic blockade is more effective than selective β ₁ -adrenergic blockade was tested in the COMET trial, which remains the largest and most well-designed head-to-head trial of β-blockers in HF. The COMET trial randomized subjects with NYHA class II–IV HF and LVEF ≤ 35% to carvedilol or short-acting metoprolol tartrate in addition to other standard therapies and showed that carvedilol was more effective in reducing all-cause mortality. The generalizability of these findings is limited given that the degree of β-blockade may not have been equivalent in the two arms of COMET. The mean dose of metoprolol achieved in COMET was lower than the ones given in the MDC and MERIT-HF trials, which resulted in significantly lesser HR reductions when compared to carvedilol. Another potential concern is that metoprolol tartrate differs from the extended-release metoprolol succinate (CR/XL) used in MERIT-HF, the main trial showing a survival benefit of metoprolol compared with placebo in HFrEF patients. Metoprolol tartrate produces a less sustained β ₁ -blockade because of its shorter half-life and has not been shown to reduce mortality in the MDC trial. There have been no trials directly comparing outcomes on carvedilol and extended-release metoprolol succinate (CR/XL).

The COMET trial supports the hypothesis that meaningful differences exist in the clinical effects of different β-blockers, suggesting that their beneficial effects in HFrEF may not necessarily be a class effect. For instance, some β-blockers with intrinsic sympathomimetic activity, such as xamoterol, have been shown to increase, rather than reduce, mortality in patients with HFrEF. Other β-blockers, such as bucindolol and nebivolol, had a neutral effect on overall mortality rates in the BEST and SENIORS trials. Bucindolol is a third-generation nonselective β-blocker, with additional weak α-blocking properties and some intrinsic sympathomimetic activity. Although it failed to reduce total mortality in the BEST trial, a prespecified subanalysis suggested a survival benefit restricted to white participants that might be secondary to a polymorphism in β ₁ -receptors in that population. Nebivolol is a selective β ₁ -receptor antagonist with some vasodilatory effects that are partially mediated by NO production via activation of β ₃ -adrenergic receptors. It is approximately 3.5 times more β ₁ -selective than bisoprolol and, along with carvedilol, is one of the few β-blockers to cause vasodilation. The SENIORS trial tested the effects of nebivolol on mortality and morbidity in patients ≥ 70 years old with stable HF. At a mean follow-up of 21 months, nebivolol therapy resulted in a significant 14% relative risk reduction in the primary composite outcome of all-cause mortality or CV hospitalizations compared to placebo but did not reduce all-cause mortality. In the United States, nebivolol is only approved for the treatment of hypertension, while in Europe it is registered for use in hypertension and HF as well.

Overall, the results of the COMET, BEST, and SENIORS trials highlight the importance of using doses and formulations of β-blockers with proven benefit in clinical trials. In accordance with clinical practice guidelines recommendations, β-blockers should be up-titrated to reach maximally tolerated doses whenever possible. Evidence-based doses for recommended β-blockers are listed in Table 3.5 . However, the abrupt withdrawal of adrenergic support may lead to exacerbation of congestive HF and significant negative chronotropy. Thus, therapy with β-blockers is recommended for clinically stable patients and should be initiated at very low doses and up-titrated gradually, with dose doubling no earlier than every 2 weeks as tolerated. Nevertheless, patients may experience some fluid retention within the first 3–5 days of treatment and should be advised to weigh themselves on a daily basis. Fluid retention can be managed by increasing the diuretic dose until weight returns to baseline and should not prevent future up-titration of the β-blocker.

Other commonly mentioned noncardiac side effects of β-blockers include exacerbation of reactive airway disease, increased peripheral vascular resistance, depression, fatigue, insomnia, and sexual dysfunction. Hence, despite extensive evidence of clinical efficacy, several HF registries have shown that the use and dose of β-blockers is often suboptimal, possibly due to side effects or intolerance. Reasons for β-blocker discontinuation have differed across registries, but generally include worsening of HF symptoms, bradycardia, hypotension, dizziness, and fatigue.

β-Βlocker selection may affect tolerability, as patients with reactive airway disease may benefit from β ₁ -selective blockers, while those with peripheral vascular disease may benefit from carvedilol, given its vasodilatory effects. The CIBIS-ELD trial was designed to compare the tolerability of bisoprolol and carvedilol during attempted titration to guideline-recommended target doses after 12 weeks of treatment in elderly subjects with chronic HF. It showed that adverse bradycardia was more common with bisoprolol, whereas pulmonary events were more common with carvedilol. Lipophilic β-blockers, such as metoprolol, can cause sleep disturbances, insomnia, vivid dreams, and nightmares, due to the high penetration across the blood–brain barrier. Furthermore, intolerance may not be a class effect, as 80% of subjects considered intolerant to one β-blocker might be successfully changed to another. Actually, contrary to early reports, β-blocker therapy is well tolerated by 90% of HF patients, including those with diabetes mellitus, chronic obstructive lung disease, and peripheral vascular disease.

Severe bradycardia and asthma with active bronchospasm remain the most important contraindications to β-blockade. The dose of β-blocker should be adjusted if HR decreases to < 50 beats/min or in the setting of second- or third-degree heart block. Symptomatic hypotension can be managed by decreasing the diuretic dose. Finally, continuation, but not introduction, of β-blocker treatment during an episode of ADHF is safe, although dose reduction may be necessary.

Angiotensin-converting Enzyme Inhibitors or β -Blockers First

Although the combination of an ACE inhibitor and a β-blocker is more effective in HFrEF than monotherapy with either, the order of initiation is important in clinical practice because patients often cannot tolerate optimum doses of both agents. There are theoretical considerations suggesting it may be more beneficial to initiate the treatment with a β-blocker, as the SNS is systemically activated at an earlier stage than is the RAAS. The CIBIS-III trial addressed this important question and showed that initiating treatment with the selective β ₁ -receptor blocker bisoprolol is as effective and well tolerated as beginning treatment with the ACE inhibitor enalapril.

In clinical practice, drug initiation and up-titration could be tailored to individual patients and their unique clinical circumstances. The initial treatment strategy with β-blockers first may be better for subjects with ischemic cardiomyopathies and tachycardia, while the strategy of using an ACE inhibitor first should be indicated for patients with hypertension and fluid overload. Current clinical practice guidelines recommend starting with an ACE inhibitor, followed by the addition of a β-blocker. In most cases, β-blockers are then up-titrated to their maximum recommended dose before further increase in the dose of ACE inhibitors.

Diuretics

Diuretics are the cornerstone of therapy for the treatment of volume overload in patients with HF, relieving clinical symptoms and signs more rapidly than any other drug. They can reduce CVP, pulmonary congestion, peripheral edema, and body weight within hours or days of initiation of therapy, whereas the clinical effects of digoxin, ACE inhibitors, or β-blockers may require weeks or months to become apparent. Additionally, in the intermediate term, diuretics have also been shown to improve cardiac function and exercise tolerance in HF patients. However, the effects of diuretic therapy with long-term follow-up in chronic HFrEF have not been studied in large prospective randomized controlled trials. A Cochrane meta-analysis suggested that in patients with chronic HF, conventional diuretic therapy might reduce the risk of death and worsening of HF compared to placebo and appear to improve exercise capacity compared to active control. However, this meta-analysis included only small-size studies with limited follow-up and cannot be used as formal evidence to recommend the use of diuretics to reduce HF mortality.

Patients at higher risk for fluid overload would benefit from long-term therapy with oral loop diuretics. However, the use of loop diuretics might associate with electrolyte disturbances, arrhythmias, neurohormonal activation, accelerated renal function decline, and hypotension. The latter might be particularly relevant, as it could limit optimal target doses of neurohormonal antagonists. Therefore, it is advised to use the lowest possible dose of loop diuretic, which should be adjusted individually. As previously stated, diuretics do not have a smooth dose-response curve, and natriuresis will only occur when the threshold rate of drug excretion, which is often higher in HF patients, is attained. Hence, if there is little or no response to the initial dose, it is recommended to double it rather than giving the same dose twice a day. Additionally, for patients presenting with an ADHF episode while previously taking a loop diuretic, a higher dose at discharge should be considered.

Thiazide diuretics are widely used for the management of hypertension. Despite structural variation among the heterogeneous group of agents with similar physiological properties, including the thiazide-like diuretics, the term “thiazide diuretic” comprises all diuretics believed to have a primary action in the distal convoluted tubule. Metolazone, a quinazoline sulfonamide, is a thiazide-like diuretic that can be used in combination with furosemide in patients with diuretic resistance. The chronic use of sequential nephron blockade with thiazide diuretics should be avoided in stable patients, as it often induces electrolyte disorders that could go unseen in the ambulatory setting.

Since sodium retention occurs in more proximal tubular sites, potassium-sparing diuretics are ineffective in achieving a net negative sodium balance when given alone in HF patients. Besides, the benefit of MRAs in patients with HF is thought to be relatively independent of their diuretic properties and may be due to their ability to antagonize the RAAS.

Vasopressin receptor antagonists modulate the renal actions of AVP by directly blocking its receptors V1A, V1B, and V2. The inappropriate elevation of AVP in HF plays a key role in mediating vasoconstriction, water retention, and electrolyte imbalance. Combined V1A and V2 antagonism causes a decrease in SVR and prevents dilutional hyponatremia. The AVP antagonists, or “vaptans,” can either selectively block the V2-receptor or nonselectively block both the V1A- and the V2-receptors. The EVEREST-Outcomes trial randomized subjects admitted with ADHF to the selective V2-receptor antagonist tolvaptan or placebo and showed no difference in long-term mortality or HF-related morbidity at a median follow-up of 9.9 months. Currently, conivaptan and tolvaptan are FDA-approved for the treatment of clinically significant hypervolemic and euvolemic hyponatremia, but they are not officially approved for HF. Although it is reasonable to use these agents after traditional measures to hyponatremia have failed, including fluid restriction and optimal target doses of angiotensin inhibitors, their widespread use might be limited by high costs.

Patients receiving diuretics should be monitored regularly for complications, including electrolyte and metabolic disturbances, volume depletion, and worsening renal function. Even when successful in controlling symptoms and fluid retention, diuretics alone are unable to maintain the clinical stability of patients with chronic HF for long periods of time. Therefore, they should be combined with standard guideline recommended HFrEF therapies, including neurohormonal antagonists.