Diet and Fluid Restriction

Dietary restriction of sodium (2–3 g daily) is commonly recommended in all patients with symptomatic HF, based on the rationale that sodium and fluid retention are a central aspect of HF pathophysiology. Although the recommendation for sodium restriction has been a long-standing cornerstone of HF management, the body of evidence on which these recommendations are based is relatively scant, and the level of evidence for fluid restriction in recent guidelines is based primarily on expert opinion only (class IIa recommendation, level of evidence C). Indeed, some studies have suggested that sodium restriction may actually worsen the neurohormonal profile and may lead to worsened outcomes. Strict fluid restriction is generally unnecessary in most patients unless the patient is hyponatremic (<130 mEq/L), a condition that may develop because of activation of the renin-angiotensin system, excessive secretion of arginine vasopressin (AVP), or loss of salt in excess of water from prior diuretic use. Fluid restriction (<2 L day) should be considered in hyponatremic patients or for those patients whose fluid retention is difficult to control despite high doses of diuretics and sodium restriction.

Activity

Regular physical activity or exercise training is recommended for HF patients (class I, level of evidence A) by the current ACC-AHA guidelines. This recommendation is based on studies and meta-analyses suggesting that exercise training improves functional capacity, quality of life, and clinical outcomes in patients with HF. Unlike many lifestyle interventions, exercise training has been rigorously studied in a large randomized outcomes trial of patients with HFrEF. HF-ACTION (A Controlled Trial Investigating Outcomes of Exercise Training) was a large multicenter randomized controlled study of exercise training that enrolled patients with an EF of 35% or less and New York Heart Association (NYHA) class II to IV symptoms with a primary endpoint of all-cause mortality and all-cause hospitalization. In this study, structured exercise training demonstrated a modest improvement in all-cause mortality and hospitalizations after adjustment for other variables, as well as improvements in functional capacity and quality of life. Notably, in the HF-ACTION study there was no evidence that exercise training in HF was unsafe, even in patients with relatively severe HF symptoms. Based on the results of HF-ACTION, cardiac rehabilitation for patients with HF is covered by the Centers for Medicare and Medicaid Services in the United States.

Therapies to Avoid

Several common classes of medications may exacerbate symptoms of HF, potentially lead to disease progression, and thus should be avoided in patients with heart failure. Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the synthesis of prostaglandins, lead to sodium and fluid retention, and may lead to worsening HF. Thiazolidinediones are a class of antidiabetic agents that may lead to fluid retention and have been shown to increase the rate of HF events in previous clinical trials. The antidiabetic therapy saxagliptin in the DPP-4 inhibitor medication class has also been shown to increase HF hospitalization, and similar concerns have also been raised about alogliptin. In general, the area of antidiabetes therapies in patients at risk for or with HF is in rapid evolution, and is discussed in more detail in Chapter 48 . Calcium channel blockers, which are frequently used for the management of hypertension and angina, have negative inotropic properties that may worsen HF and should generally not be used in patients with HF. The dihydropyridine calcium channel blockers (e.g., amlodipine) have been studied in HF, and although not efficacious as a HF therapy, appear to be safe in HF patients if needed for management of hypertension or angina. The use of dietary supplements should generally be avoided in the management of symptomatic HF because of the lack of proven benefit and the potential for significant interactions with proven HF therapeutics.

Loop Diuretics

The loop diuretics are the primary form of diuretic used in patients with HF. These agents increase sodium excretion by up to 20% to 25% of the filtered load of sodium, enhance free water clearance, and maintain their efficacy unless renal function is severely impaired. The agents in this class, which include furosemide, bumetanide, and torsemide, act by reversibly inhibiting the Na ⁺ -K ⁺ -2Cl ⁻ symporter (cotransporter) on the apical membrane of epithelial cells in the thick ascending loop of Henle ( Fig. 37.3 ), resulting in decreased urine sodium and chloride reabsorption with natriuresis and diuresis. The increase in delivery of Na ⁺ and water to the distal nephron segments also markedly enhances K ⁺ excretion, particularly in the presence of elevated aldosterone levels. Loop diuretics have a sigmoidal-shaped dose response relationship ( Fig. 37.4 ). Importantly, in both HF and renal insufficiency, the dose response for the loop diuretics curve shifts downward and to the right, thereby necessitating a higher dose to achieve the same effect and diminishing the likely maximal diuretic effect. The plasma concentration of loop diuretics also varies in peak value and duration of effect whether given intravenously or orally.

Mechanisms of Loop Diuretic Action and Resistance. As shown in panel A, loop diuretics circulate bound to protein. As shown in panel B, they are secreted into the tubule lumen by organic anion transporters (OAT1 and OAT2) at the basolateral membrane and by multidrug resistance–associated protein 4 (and others) at the apical membrane. As shown in panel C, diuretics compete with chloride for binding to sodium–potassium–chloride cotransporter 2 (NKCC2), which is also present at the macula densa. Abnormalities at each step can mediate diuretic resistance.

From Ellison DH, Felker GM. Diuretic treatment in heart failure. N Engl J Med . 2017;377:1964–1975.

(A) Dose response curves of loop diuretics in normal versus patients with heart failure. (B) Comparison of pharmacokinetics of oral versus intravenous loop diuretics (LD ) . (C) An example of the braking phenomenon, whereby each additional dose of LD results in progressively less natriuresis. Each period of natriuresis is followed by a period of postdiuretic sodium retention. ADHF, Acute decompensated heart failure.

From Ellison DH, Felker GM. Diuretic treatment in heart failure. N Engl J Med . 2017;377:1964–1975.

Because furosemide, bumetanide, and torsemide are bound extensively to plasma proteins, delivery of these drugs to the tubule by filtration is limited. However, these drugs are secreted efficiently by the organic acid transport system in the proximal tubule and thereby gain access to their binding sites on the Na ⁺ -K ⁺ -2Cl ⁻ symporter in the luminal membrane of the ascending limb. Thus the efficacy of loop diuretics is dependent upon sufficient renal plasma blood flow and proximal tubular secretion to deliver these agents to their site of action. Although these drugs have similar mechanisms of action, they differ in terms of bioavailability and pharmacokinetics in ways that may have important clinical implications ( Table 37.1 ).

Thiazides and Thiazide-Like Diuretics

Thiazide-type diuretics inhibit the Na/Cl cotransporter in the distal tubule, thus blocking sodium resorption. Commonly used drugs in this class include hydrochlorothiazide, chlorthalidone, chlorothiazide, and metolazone (which is not technically a thiazide but has similar properties). Thiazides have been shown to be a potentially powerful adjunct to loop diuretics (so-called sequential nephron blockade), especially in patients demonstrating a substantial degree of diuretic resistance and/or with significant renal dysfunction. The potential benefits imparted by the addition of a thiazide-type diuretic must be balanced against the potential risks, specifically the risk of resulting electrolyte and metabolic abnormalities. Hypokalemia in particular is a frequent consequence of the sequential nephron blockade that results from combining a thiazide-type diuretic with a loop diuretic. Other electrolyte abnormalities, such as hyponatremia and hypomagnesemia, are also common and may be severe. Use of these agents as an adjunct to loop diuretics in the outpatient setting should generally be done with caution and only with careful monitoring.

Mineralocorticoid Receptor Antagonists and Potassium-Sparing Diuretics

MRAs, such as spironolactone and eplerenone, are relatively weak diuretics at commonly used doses, but are generally used in HF patients as neurohormonal antagonists rather than for their diuretic properties (as described in detail later). High doses of MRAs (e.g., doses of spironolactone of 100 mg/day or more) may induce substantial diuresis, and can be considered for use as a therapy for refractory diuretic resistance, although careful monitoring of potassium and renal function is required. A recent study of high-dose spironolactone for 96 hours in the acute HF setting was safe but did not improve natriuretic peptide levels, congestion, or clinical outcomes. Potassium-sparing diuretics such as triamterene are mild diuretics, but are typically not effective in HF patients and are seldom used clinically in this population.

Vasopressin Antagonists

Increased circulating levels of the pituitary hormone AVP contribute to increased systemic vascular resistance and positive water balance in HF patients. The cellular effects of AVP are mediated by interactions with three types of receptors: V _1a , V _1b , and V ₂ . Selective V _1a antagonists block the vasoconstricting effects of AVP in peripheral vascular smooth muscle cells, whereas V ₂ selective receptor antagonists inhibit recruitment of aquaporin water channels into the apical membranes of collecting duct epithelial cells, thereby reducing the ability of the collecting duct to resorb water. The AVP antagonists or vaptans were developed to selectively block the V ₂ receptor (tolvaptan) or nonselectively block both the V _1a /V ₂ receptors (conivaptan). These agents are not diuretics per se, but have been termed aquaretics because they lead to excretion of free water rather than natriuresis. Long-term therapy with the V ₂ selective vasopressin antagonist tolvaptan did not improve mortality but appears to be safe when given chronically after a HF hospitalization. Several recent studies explored a potential role for improved short-term symptoms of dyspnea and measures of congestion with tolvaptan in the setting of acute HF, but these were neutral. The two vasopressin antagonists (conivaptan and tolvaptan) that are currently approved by the US Food and Drug Administration (FDA) are not specifically approved for HF, but are approved for the treatment of hyponatremia in patients with HF.

Practical Issues in the Use of Diuretics in Heart Failure

Patients with evidence of volume overload or a history of fluid retention should be treated with a diuretic to relieve their symptoms. In patients who have moderate to severe HF symptoms and/or renal insufficiency, a loop diuretic is generally required. Diuretics should generally be titrated as needed to relieve signs and symptoms of fluid overload. One commonly used method for finding the appropriate dose is to double the dose until the desired effect is achieved or the maximal dose of diuretic is reached. Patients with chronic HF can be instructed on parameters for self-adjustment of diuretics based on daily weights and symptoms ( see also Chapter 47 ). Although furosemide is the most commonly used loop diuretic, bumetanide or torsemide may be preferable in selected patients because of their increased bioavailability (see Table 37.1 ) and the potential antifibrotic effect of torsemide. Changing to torsemide in particular may induce diuresis in patients seemingly refractory to oral furosemide. With the exception of torsemide, the commonly used loop diuretics are short acting (<3 hours). For this reason, loop diuretics are usually more effective when given at least twice daily to minimize periods where the concentration in the tubular fluid declines below a therapeutic level, which may produce postdiuretic sodium retention or “rebound.” Infrequent dosing may therefore lead to sodium retention that exceeds natriuresis, especially if dietary sodium intake is not restricted. An ongoing large outcomes trial is investigating the strategy of torsemide versus furosemide in a broad population of patients with HF (ClinicalTrials.gov Identifier: NCT03296813).

Risks of Diuretic Use

Observational studies have shown associations between loop diuretics, especially at higher doses, and adverse clinical outcomes in patients with HF. These observations are confounded by the fact that patients receiving higher doses of diuretics tend to have greater disease severity or comorbidity, making it difficult to determine whether higher doses of diuretics are simply a marker for greater HF severity or are actually causing harm in HF patients. Postulated mechanisms for worse outcomes with loop diuretics include stimulation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system, electrolyte disturbances, and deterioration of renal function. Although randomized data on the use of diuretics in HF are limited, the largest randomized study to date of diuretics in patients with acute decompensated HF (the DOSE study) did not suggest that higher doses of diuretics were associated with significant harm ( see also Chapter 36 ).

Patients with HF who are receiving diuretics should be monitored for complications of diuretics on a regular basis. The major complications of diuretic use include electrolyte and metabolic disturbances, volume depletion, and worsening azotemia. The interval for reassessment should be individualized based on severity of illness and underlying renal function; the use of concomitant medications such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and MRAs; the past history of electrolyte imbalances; and/or need for more aggressive diuresis.

Diuretic use can lead to potassium depletion, which can predispose the patient to significant cardiac arrhythmias and sudden death. Renal potassium losses from diuretic use can also be exacerbated by the increase in circulating levels of aldosterone observed in patients with advanced HF, and by the marked increases in distal nephron Na ⁺ delivery that follow use of loop or distal nephron diuretics. Serum potassium levels should generally be maintained between 4.0 and 5.0 mEq/L. Hypokalemia can be prevented by increasing the dietary intake of KCL, although most patients on significant doses of loop diuretics will require oral potassium supplementation. Diuretics may be associated with multiple other metabolic and electrolyte disturbances, including hyponatremia, hypomagnesemia, metabolic alkalosis, hyperglycemia, hyperlipidemia, and hyperuricemia.

Diuretic Resistance and Management

One inherent limitation of diuretics is that they achieve water loss via excretion of solute at the expense of glomerular filtration, which in turn activates a set of homeostatic mechanisms that ultimately limit their effectiveness. The term diuretic resistance typically defines a clinical scenario with progressively diminished responsiveness to diuretics despite persistent signs and/or symptoms of volume excess. One common cause of diuretic resistance is the so-called braking phenomenon to the effect of loop diuretics—this results from hemodynamic changes at the glomerulus mediated by the RAAS and sympathetic nervous system and adaptive changes in the distal nephron. Additionally, as mentioned previously, most loop diuretics, with the exception of torsemide, are short-acting drugs. Accordingly, after a period of natriuresis, the diuretic concentration in plasma and tubular fluid declines below the diuretic threshold. In this situation, renal Na ⁺ reabsorption is no longer inhibited and a period of antinatriuresis or postdiuretic NaCl retention ensues. If dietary NaCl intake is moderate to excessive, postdiuretic NaCl retention may overcome the initial natriuresis in patients with excessive activation of the adrenergic nervous system and renin-angiotensin system. Other potential contributors to apparent diuretic resistance include changes in cardiac or renal function or patient noncompliance with their diuretic regimen or diet. Concurrent use of drugs that adversely affect renal function, such as NSAIDs and cyclooxygenase-2 (COX-2) inhibitors, may contribute to diuretic resistance.

Management of patients with progressive resistance to diuretics requires careful consideration of potential causes. Increasing doses of diuretics to ensure that therapeutic concentrations are achieved in the tubule is the typical initial step. Another common method for treating the diuretic-resistant patient is to administer two classes of diuretic concurrently (“sequential nephron blockade”). Most commonly, this involves adding a thiazide-like diuretic to a loop diuretic. Many clinicians choose metolazone because its half-life is longer than that of some other distal collecting tubule diuretics, and because it has been reported to remain effective even when the glomerular filtration rate is low. As noted previously, careful monitoring of fluid status, renal function, and electrolytes is critical with this approach, because sequential nephron blockade can be associated with dramatic fluid shifts and electrolyte disturbances.

Rationale/Pathophysiologic Basis for Use

Activation of the RAAS plays a key role in the pathophysiology of the development and progression of HF. The fundamental biology of this neurohormonal axis as it relates to HF is covered in Chapter 5 . The RAAS may be inhibited at many levels: renin inhibition, inhibition of the conversion of angiotensin I to angiotensin II, antagonism of one or more angiotensin II receptors, and blockade of the primary target of aldosterone, the mineralocorticoid receptor.

Effects on Hemodynamics

The primary acute hemodynamic effect of both ACE inhibitors and ARBs is vasodilation. Early investigations of ACE inhibitors demonstrated that these agents produced dose-dependent decreases in right atrial pressure, pulmonary capillary wedge pressure, and systemic vascular resistance, with a resultant increase in cardiac index. In addition, inhibition of neurohormonal activation over time is evident from decreases in heart rates and plasma catecholamine levels at rest and with exercise. Similarly, ARBs produce dose-dependent decreases in right atrial pressure, pulmonary capillary wedge pressure, and systemic vascular resistance in association with increased cardiac index, which are sustained over time in the absence of tachyphylaxis. These hemodynamic effects of ARBs occur without increases in heart rate or neurohormonal activation. Beneficial hemodynamic and clinical effects of irbesartan were reported by Havranek and colleagues in patients already taking ACE inhibitors.

Effects on Ventricular Structure

In addition to a wealth of experimental evidence supporting the important role of the RAAS in the pathophysiologic processes of ventricular remodeling ( see Chapter 5 ), clinical evidence also supports this premise. Sharpe and associates demonstrated that captopril initiated within 48 hours after Q wave MI reduced the increase in LV end-diastolic volume after only 3 months of therapy. Similarly, in the multicenter Survival and Ventricular Enlargement (SAVE) trial, captopril improved survival among patients after MI with reduced left ventricular ejection fraction (LVEF) (<40%) and mitigated the degree of LV chamber dilation after the first year of therapy. ACE inhibitors prevent progressive LV remodeling in patients with LV systolic dysfunction with or without symptoms of HF (see Fig. 37.6 ). In a substudy of the Studies of Left Ventricular Dysfunction (SOLVD) trial, the placebo recipients exhibited LV dilation over the span of this study (1 year), whereas the enalapril recipients exhibited the opposite, which was consistent with a decrease in LV chamber size for a given LV pressure. This study demonstrated clinically that ACE inhibition prevents, and perhaps reverses, the extent of ventricular remodeling in patients with LV systolic dysfunction.

The precise effect of AT ₁ receptor antagonists on ventricular remodeling is not as well studied. In the Evaluation of Losartan in the Elderly (ELITE) radionuclide substudy, researchers compared the effect of losartan, an AT ₁ antagonist, with that of the ACE inhibitor captopril on LV remodeling in elderly patients with HF and systolic dysfunction (EF < 40%). After 48 weeks of therapy, captopril and losartan demonstrated statistically equivalent effects in reducing LV end-diastolic and end-systolic volumes, although there was a trend toward a greater beneficial effect of captopril in this study. Perhaps the largest study of whether combination therapy with an ACE inhibitor and ARB produces greater reduction in LV remodeling has been the Valsartan in Acute Myocardial Infarction Trial (VALIANT), in which investigators examined the effect of valsartan alone, captopril alone, and their combination in patients after an acute MI complicated by HF, LV dysfunction, or both. Although the patient population in this trial differed from that in HF trials (after MI, mean LVEF among the groups was 39%), the degree of LV remodeling (increase in LV end-diastolic volume and change in LVEF) was similar among all three groups of patients. The results of the VALIANT substudy do not support the view that combination therapy in patients with HF or LV dysfunction after MI exerts a greater effect in limiting LV remodeling than either class of agent alone.

Effects on Functional Capacity and Symptoms

Effects on Morbidity and Mortality

Although the hemodynamic and clinical effects of ACE inhibitors are notably similar to those of ARBs, these two classes of agents should not be considered interchangeable, inasmuch as they possess both overlapping and distinct effects. Clinical evidence for the benefit of ACE inhibitors exceeds that for ARBs, a finding that is strongly influenced by the earlier development of ACE inhibitors. Results of clinical trials, both early and more recent, have helped determine whether, and under what circumstances, these agents can be used interchangeably or in combination.

Mechanisms Underlying These Effects

The original hypothesis behind investigation of ACE inhibitors in patients with HF was that these agents would reduce the progression of clinical HF through vasodilation. As noted previously, direct comparison between ACE inhibitors and other vasodilatory regimens (e.g., nitrates and hydralazine in the V-HeFT studies) support the concept that ACE inhibitors alter the natural history of HF via mechanisms distinct from their hemodynamic effects, including direct effects on the cellular mechanisms responsible for progressive changes in the myocyte and the interstitium. Beyond an effect on clinical events linked to progressive HF, both the SOLVD and SAVE studies demonstrated significant reductions in the incidence of MI, which potentially contributed to the overall influence of ACE inhibitors on mortality. Furthermore, within the SOLVD population, enalapril caused a significant reduction in the number of patients hospitalized for unstable angina. These findings provided, for the first time, evidence of an influence of ACE inhibitors on the pathogenesis of acute coronary syndromes, an influence potentially mediated by effects on the arterial wall, on the balance between thrombosis and thrombolysis, or on both.

Angiotensin Receptor Blockers

In symptomatic HF patients who were intolerant of ACE inhibitors, the aggregate clinical data suggest that ARBs are roughly as effective as ACE inhibitors in reducing HF morbidity and mortality. Candesartan significantly reduced all-cause mortality, cardiovascular death, or hospitalization in ACE-intolerant patients in the Candesartan Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM-Alternative) trial. Similar findings were shown with valsartan in the small subgroup of patients not receiving an ACE inhibitor in the Valsartan Heart Failure Trial (Val-HeFT) ( Fig. 37.7 ). A direct comparison of ACE inhibitors and ARBs was assessed in the Losartan Heart Failure Survival Study (ELITE-II), which showed that losartan was not associated with improved survival in elderly HF patients when compared with captopril, but was significantly better tolerated. Two trials have evaluated ARBs compared to ACE inhibition in post-MI patients who developed LV dysfunction or signs of HF. The direct comparison of losartan with captopril indicated that losartan was not as effective as captopril on all-cause mortality, whereas valsartan was shown to be noninferior to captopril on all-cause mortality in the VALIANT study. ²⁷ The combination of captopril and valsartan produced no further reduction in mortality in VALIANT, although the number of adverse events increased. When given in addition to ACE inhibitors in general cohorts of patients with symptomatic HF, the effects of ARBs were shown to have a modest beneficial effect in the CHARM-Added trial. However, the addition of valsartan to ACE inhibitors had no beneficial effect on mortality in Val-HeFT, although the combined endpoint mortality and morbidity was significantly (13.2%) lower with valsartan than with the placebo because of a reduction in the number of patients hospitalized for HF. The question of high-dose versus low-dose angiotensin receptor antagonism on clinical outcomes was evaluated in the Heart Failure Endpoint Evaluation of Angiotensin II Antagonist Losartan (HEAAL) trial. This study showed that the use of a high-dose losartan was not associated with a significant reduction in the primary endpoint of all-cause death or admission for HF (hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.84–1.04, P = .24) when compared with low-dose losartan, but was associated with a significant reduction in HF admissions (HR 0.94, 95% CI 0.84–1.04, P = .24), suggesting that uptitration of ARBs may confer clinical benefit.

Outcomes with ARBs compared with the placebo in heart failure. (A) Kaplan-Meier curves for mortality in the valsartan (dotted line) and placebo (solid line) groups ( n = 185 and 181, respectively) without angiotensin-converting enzyme (ACE) inhibitor background therapy ( P = .017 by log-rank test) in the Valsartan Heart Failure Trial (Val-HeFT). (B) Kaplan-Meier cumulative event curves for the primary outcome (all-cause mortality, cardiovascular death, or hospitalization) in the Candesartan Heart Failure: Assessment of Reduction in Mortality and Morbidity trial (CHARM-Alternative) in ACE-intolerant patients.

A, From Maggioni AP, Anand I, Gottlieb SO, et al. Effects of valsartan on morbidity and mortality in patients with heart failure not receiving angiotensin-converting enzyme inhibitors. J Am Coll Cardiol. 2002;40:1414–1421; B, From Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003;362:772–776.

Although one meta-analysis suggests that ARBs and ACE inhibitors have similar effects on all-cause mortality and HF hospitalizations, and although ARBs may be considered as initial therapy rather than ACE inhibitors following MI, the general consensus is that ACE inhibitors remain the first-line therapy for the treatment of HF, whereas ARBs are recommended for ACE inhibitor-intolerant patients. Importantly, a recent ACC/AHA/Heart Failure Society of America (HFSA) guideline update highlights that ACE inhibitors, ARBs, and now also angiotensin receptor-neprilysin inhibitors (ARNIs) have a class I recommendation for use in patients with chronic HFrEF in conjunction with other GDEMs (see further discussion later). Combination therapy with ACE inhibitors and ARB can be considered in persistently symptomatic patients, although the risk of side effects is higher (see later discussion), particularly in patients also treated with MRAs (the triple combination of ACE inhibitors, ARBs, and MRAs is specifically discouraged; class III recommendation for harm) in current guidelines.

Side Effects, Complications, and Drug Interactions

Practical Tips

Angiotensin-Converting Enzyme Inhibitors

Starting and target doses for commonly used ACE inhibitors and ARBs are shown in Table 37.3 . Because fluid retention can attenuate the effects of ACE inhibitors, it is preferable to optimize the dose of diuretic first before starting the ACE inhibitor. However, it may be necessary to reduce the dose of diuretic during the initiation of an ACE inhibitor to prevent symptomatic hypotension. ACE inhibitors should be initiated in low doses, followed by increments in dose if lower doses have been well tolerated. Titration is generally achieved by doubling doses every 3 to 5 days. The dose of ACE inhibitors should be increased until the doses used are similar to those that have been shown to be effective in clinical trials or to the maximally tolerated dose. Higher doses are more effective than lower doses in preventing hospitalization based on the ATLAS trial. For stable patients, it is acceptable to add therapy with β-blocking agents before full target doses of ACE inhibitors are reached. Blood pressure (including postural changes), renal function, and potassium should be evaluated within 1 to 2 weeks after initiation of ACE inhibitors, especially in patients with preexisting azotemia, hypotension, hyponatremia, diabetes mellitus, or in those taking potassium supplements. Abrupt withdrawal of treatment with an ACE inhibitor may lead to clinical deterioration and should therefore be avoided in the absence of life-threatening complications (e.g., angioedema, hyperkalemia).

TABLE 37.3

Starting and Target Doses for Guideline-Recommended Drugs for Heart Failure and Reduced Ejection Fraction

Drug	Initial Daily Dose(S)	Maximum Dose(S)	Mean Doses Achieved IN Clinical Trials
ACE Inhibitors
Captopril	6.25 mg 3 times	50 mg 3 times	122.7 mg/day
Enalapril	2.5 mg twice	10–20 mg twice	16.6 mg/day
Fosinopril	5–10 mg once	40 mg once	N/A
Lisinopril	2.5–5 mg once	20–40 mg once	32.5–35.0 mg/day
Perindopril	2 mg once	8–16 mg once	N/A
Quinapril	5 mg twice	20 mg twice	N/A
Ramipril	1.25–2.5 mg once	10 mg once	N/A
Trandolapril	1 mg once	4 mg once	N/A
ARBs
Candesartan	4–8 mg once	32 mg once	24 mg/day
Losartan	25–50 mg once	50–150 mg once	129 mg/day
Valsartan	20–40 mg twice	160 mg twice	254 mg/day
Aldosterone Antagonists
Spironolactone	12.5–25.0 mg once	25 mg once or twice	26 mg/day
Eplerenone	25 mg once	50 mg once	42.6 mg/day
β-Blockers
Bisoprolol	1.25 mg once	10 mg once	8.6 mg/day
Carvedilol	3.125 mg twice	50 mg twice	37 mg/day
Carvedilol CR	10 mg once	80 mg once	N/A
Metoprolol succinate extended release (metoprolol CR/XL)	12.5–25 mg once	200 mg once	159 mg/day
Hydralazine and Isosorbide Dinitrate
Fixed-dose combination	37.5 mg hydralazine/20 mg isosorbide dinitrate 3 times daily	75 mg hydralazine/40 mg isosorbide dinitrate 3 times daily	≈175 mg hydralazine/90 mg isosorbide dinitrate daily
Hydralazine and isosorbide dinitrate	Hydralazine: 25–50 mg, 3 or 4 times daily and isosorbide dinitrate: 20–30 mg 3 or 4 times daily	Hydralazine: 300 mg daily in divided doses and isosorbide dinitrate: 120 mg daily in divided doses	N/A

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