Contemporary Medical Therapy for Heart Failure Patients with Reduced Ejection Fraction

Heart failure (HF) is a complex clinical syndrome that represents a final common pathway for many types of cardiovascular disease. Multiple overlapping frameworks for classifying HF exist ( see also Chapters 18, Chapter 31 ). HF can be viewed as a continuum that is comprised of four interrelated stages as defined by the American College of Cardiology and the American Heart Association (ACC/AHA) Guidelines ( Fig. 37.1 ). Stage A patients represent the largest group, defined as patients who are at high risk for developing HF, but who do not yet have evidence of structural heart disease or symptoms of HF (e.g., patients with diabetes or hypertension; see also Chapter 35 ). Stage B includes patients who have structural heart disease, but without symptoms of HF (e.g., patients with a previous myocardial infarction [MI], left ventricular [LV] hypertrophy, or asymptomatic LV dysfunction). Stage C includes patients who have structural heart disease and have developed symptoms of HF. Stage D includes patients with refractory HF requiring special interventions (e.g., patients who may be candidates for advanced surgical therapies (LV assist devices or cardiac transplantation; see also Chapters 44, Chapter 45 ) or palliative care and hospice ( see also Chapter 50 ).

Epidemiologically, a large (and growing) proportion of patients with symptomatic HF have normal or near normal ejection fraction (EF), so-called heart failure with preserved ejection fraction, or HFpEF. This clinical entity, for which effective therapies have yet to be developed with the possible exception of mineralocorticoid receptor antagonists (MRAs) in appropriately selected patients, is covered in detail in Chapter 39 . Similarly, acute decompensated HF leading to hospitalization is a major public health problem and is covered in detail in Chapter 36 . In the current chapter, we will focus on contemporary medical therapy for patients with symptomatic heart failure and reduced ejection fraction (HFrEF), with a focus on both the biologic rationale and the clinical evidence supporting contemporary treatment. Notably, few areas in medicine have seen as much progress in the development of effective new therapies over recent decades as has the treatment of HFrEF, with multiple classes of agents and devices (which are covered separately in Chapter 38 ) having demonstrated major improvements in morbidity and mortality over this period. Cumulatively, contemporary guideline-directed medical therapy has reduced mortality in HFrEF by more than 60% over the last 30 years ( Fig. 37.2 ).

Goals of Therapy in Heart Failure and Reduced Ejection Fraction

The main goals of treatment in HF are to reduce symptoms, improve quality of life and functional capacity, prevent disease progression, and prolong survival. Although different therapies may impact each of these to varying degrees, collectively contemporary medical therapy for HFrEF has made a significant impact on each of these outcomes, as detailed later.

General Measures

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.

Diuretics and Management of Volume Status

Many of the cardinal clinical manifestations of HF result from excessive salt and water retention that leads to an inappropriate volume expansion of the vascular and extravascular space. Most patients with symptomatic chronic HF therefore require diuretic therapy to maintain appropriate volume status and to control symptoms related to fluid retention.

A number of classification schemes have been proposed for diuretics on the basis of their mechanism of action and their anatomic locus of action within the nephron. The most common classification for diuretics employs an admixture of chemical (e.g., “thiazide” diuretic), site of action (e.g., “loop” diuretics), or clinical outcomes (e.g., “potassium-sparing” diuretics).

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.

Fig. 37.4, (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.

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).

TABLE 37.1

Pharmacokinetics of the Loop Diuretics

From Felker GM, Mentz RJ. Diuretics and ultrafiltration in acute decompensated heart failure. J Am Coll Cardiol . 2012;59:2145–2153.

Property	Furosemide	Bumetanide	Torsemide
Relative IV potency	40 mg	1 mg	20 mg
Bioavailability (%)	10–100 (average = 50)	80–100	80–100
PO to IV conversion	2:1	1:1	1:1
Initial outpatient PO dose (mg)	20–40	0.5–1	5–10
Maintenance outpatient PO dose (mg)	40–240	1–5	10–20
Maximum daily IV dose (mg)	400–600	10	200
Onset (min)
Oral	30–60	30–60	30–60
Intravenous	5	2–3	10
Peak serum concentration after PO administration (hr)	1	1–2	1
Affected by food	Yes	Yes	No
Metabolism	50% renal conjugation	50% hepatic	80% hepatic
Half-life (hr)
Normal	1.5–2	1	3–4
Renal dysfunction	2.8	1.6	4–5
Hepatic dysfunction	2.5	2.3	8
Heart failure	2.7	1.3	6
Average duration of effect (hr)	6–8	4–6	6–8

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.

Neurohormonal Antagonists in the Management of Heart Failure

Maladaptive chronic activation of the renin-angiotensin-aldosterone axis and sympathetic nervous system is central to modern understanding of the pathophysiology of HF ( see Chapters 5, Chapter 6 ). The clinical development of drugs that antagonize these axes has been the most fundamental and important development in the management of chronic HF, establishing for the first time the ability of medical therapy to change the natural history of the disease process. In this regard, inhibitors of the RAAS (ACE inhibitors, ARBs [with and without neprilysin inhibition], and MRAs) and β-blockers have emerged as cornerstones of modern HF therapy for patients with HFrEF (see Fig. 37.1 ). The ability of therapies to effectively intervene on ventricular remodeling has been consistently shown to be the most reliable surrogate for predicting subsequent efficacy in improving clinical outcomes ( Fig. 37.5 ). These classes of agents, often collectively referred to as neurohormonal antagonists, have been shown to arrest, prevent, and even (particularly for β-blockers) potentially reverse the process of progressive ventricular remodeling that is associated with disease progression in HF ( Fig. 37.6 ). As described in detail later, these agents have a large evidence base definitively establishing their efficacy in improving morbidity and mortality in patients with chronic HF and reduced EF, which is summarized in the current ACC/AHA guidelines as “guideline-directed evaluation and management,” or GDEM (see Fig. 37.1 ).

Fig. 37.5, Relationship between drug effect on ventricular remodeling and mortality in randomized trials. Quantitative relationship between drug effects on end-diastolic volume and mortality: each data point represents a placebo-corrected change in end-diastolic volume (EDV) from an individual remodeling trial plotted against the mortality odds ratio (OR) for the specific therapy. Interventions were classified as favorable (blue circles) if the upper limit of the 95% confidence interval (CI) of the OR for death from the mortality trials was less than 1, neutral (black circles) if the 95% CI crossed 1, and adverse (red circles) if the lower limit of the 95% CI was greater than 1. There were significant correlations between short-term therapeutic effects on EDV and longer-term therapeutic effect on mortality. RCTs, Randomized clinical trials.

Fig. 37.6, The effect of angiotensin-converting enzyme (ACE) inhibitors and β-blockers on ventricular remodeling.

Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers

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.

Angiotensin-converting enzyme inhibitors

ACE inhibitors were the first agents clinically available for inhibiting the RAAS and continue to be the most widely used in clinical practice. ACE inhibitors interfere with the renin-angiotensin system by inhibiting the enzyme that is responsible for the conversion of angiotensin I to angiotensin II. These agents act by inhibiting one of several proteases responsible for cleaving angiotensin I to form angiotensin II. However, alternative enzymatic pathways have become recognized as playing a major role in angiotensin II production in humans. For example, in the failing human heart, angiotensin II formation is only partially inhibited by an ACE inhibitor but almost completely blocked by an inhibitor of chymase, another protease that catalyzes the formation of angiotensin II from angiotensin I. Accordingly, ACE inhibitor therapy achieves only partial inhibition of angiotensin II production.

To the extent that ACE inhibitors reduce production of angiotensin II, effects attributable to angiotensin II are diminished regardless of which receptor mediates the particular effect (i.e., both AT ₁ and AT ₂ receptors). ACE not only cleaves angiotensin I to form angiotensin II, but is also the principal protease that degrades bradykinin; thus ACE inhibition leads to increased levels of bradykinin within the circulation and at the tissue level. The hemodynamic effects of ACE inhibitors may be mediated in part through increases in regional bradykinin levels. Bradykinin stimulates endothelial release of nitric oxide (NO) and vasodilator prostaglandins, contributing to the vasodilator effects of ACE inhibitors. In some animal models of myocardial injury or pressure overload, the beneficial effects of ACE inhibitors mitigating cardiomyocyte hypertrophy and fibroblast hyperplasia within the myocardium are blocked by a bradykinin antagonist. Thus, reduction of bradykinin metabolism, resulting in potentiation of local bradykinin levels, potentially contributes to the therapeutic benefit of ACE inhibitors.

Angiotensin Receptor Blockers

Although ACE inhibitors and ARBs both inhibit RAAS, they do so by different mechanisms. ARBs block the effects of angiotensin II on the angiotensin type 1 receptor, the receptor subtype that is responsible for virtually all the adverse biologic effects relevant to angiotensin II on cardiac remodeling. In contrast to ACE inhibitors, effects of angiotensin II receptor antagonists limit the responses specifically mediated by that receptor. Because most of the clinically relevant effects of angiotensin II appear to be mediated through the AT ₁ receptor, AT ₁ receptor antagonists mirror the actions anticipated through the blockade of angiotensin II production. However, loss of feedback inhibition results in increased angiotensin II levels after administration of an AT ₁ receptor antagonist, which leads to overstimulation of alternative angiotensin II receptors. The unopposed activation of non-AT ₁ receptors may mediate some of the clinically relevant effects attributable to AT ₁ receptor blockade. For example, stimulation of the AT ₂ receptor may be responsible for the antiproliferative and antifibrotic effects of AT ₁ antagonists within the cardiovascular system, although unopposed activation of the AT ₂ receptor may also promote apoptosis.

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

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