Heart failure (HF) is a common disease that affects approximately 5 million patients in the United States and is responsible for 20% of hospital admissions.1,2 The incidence of HF doubles for every decade of life, and the overall 5-year survival rate is only 30% to 40%. Numerous medications in various combinations are now being used to treat HF, and clinical trials provide support for their utility.1-3
This article will focus on the pharmacotherapy of systolic dysfunction, described by decreased contractility with an ejection fraction of <40%. Treatment of diastolic dysfunction, described as impaired ventricular relaxation with a normal ejection fraction, has less clinically defined treatment options and will not be discussed.4
Acute Decompensated Heart Failure
Acute decompensated heart failure (ADHF) requires a more emergent paradigm of care, as opposed to chronic therapy.5 Aggressive use of diuretics (Table 1), usually intravenous (IV) loop types, commonly are administered in the acute setting. Major goals involved in the treatment of ADHF include reduction of preload and afterload and improvements in renal perfusion. Agents utilized to reduce preload include nitroglycerin products, which have no effect on afterload. The use of the positive inotropic agents, dobutamine and milrinone, both of which may improve cardiac output, also may provide benefits in some patients.3,5,6
A newer therapeutic option, nesiritide, an endogenous brain natriuretic peptide, has been reported to improve cardiac output and to have positive effects on renal function, although clinical trials have not reported significant benefits of this drug versus IV nitroglycerin. Due to cost concerns, nesiritide probably should be reserved for patients who have failed nitroglycerin infusions and are refractory to diuretic therapy.7 Standard oral therapy should be reinitiated and acute therapy titrated down and discontinued as the patient becomes hemodynamically stable.3,5
Chronic Pharmacotherapy of Heart Failure
Diuretics are used to treat both the peripheral and pulmonary edema associated with HF, and they may be continued along with other chronic therapies to prevent recurrences of edema symptoms. Loop diuretics are the most commonly used type, although thiazides (Table 1) may be used in mild fluid overload or with loop diuretics to counteract diuretic resistance.8 Major side-effect concerns with the thiazides and loop diuretics include hypokalemia and excessive volume depletion.2,3,5
Studies conducted during the last few years with the aldosterone antagonist class of diuretics (Table 1) have reported their benefits in HF.9,10 The theoretical mechanisms include diuresis, in addition to blocking the potentially detrimental effects of the neurohormone aldosterone. This action may be important in patients who are already taking angiotensin-converting enzyme inhibitors (ACEIs) due to the concept of aldosterone escape. Side effects with these agents include hyperkalemia and unwanted hormonal side effects, including gynecomastia, breast pain, and impotence, especially with spironolactone.9,10
Angiotensin-converting Enzyme Inhibitors
ACEIs have become the mainstay of chronic pharmacotherapy of HF (Table 2). Clinical trials support their benefits in reducing both morbidity and mortality.11-13 ACEIs cause both venous and arterial dilation, resulting in reductions in preload and afterload. ACEIs should be used in all patients with left ventricular systolic dysfunction unless there is an absolute contraindication. Multiple mechanisms have been proposed and continue to be studied. ACEIs primarily work by inhibiting the formation of the potent vasoconstrictor angiotensin II, in addition to blocking the detrimental effects of cardiac remodeling.
Adverse effects may include hyperkalemia and acute renal failure. ACEIs are considered to be contraindicated in patients with bilateral renal artery stenosis, history of angioedema, or intolerable ACEI-related cough. Alternatives for patients who experience an ACEI cough are the angiotensin II receptor blockers (ARBs). If other contraindications exist, the combination of isosorbide dinitrate and hydralazine may be a potential alternative.2,3,5
Angiotensin II Receptor Blockers
ARBs are a class of agents (Table 3) with clinical effects similar to those of the ACEIs, and, theoretically, they should be used in the same capacity. Their mechanism, however, involves actual blocking of the angiotensin receptors. Although these agents have been studied in HF, there is less practical clinical experience with them, and they usually are recommended as second-line therapy. As mentioned previously, they are excellent alternatives for patients who develop an intolerable cough while taking ACEIs.2,3,5 Studies that utilized the combination of ACEIs and ARBs in HF continue to be evaluated.14,15
Beta-blockers (BBs) are another class of drugs (Table 4) that have a clinically significant role in HF.3 They have demonstrated reductions in morbidity and mortality in patients already on standard HF therapies in numerous clinical trials.16-18 Patients with stable systolic dysfunction are candidates for BB therapy, initiated at low doses and titrated over several weeks to target doses. If BBs are given to unstable patients or titrated too rapidly, a worsening of HF symptoms may occur.
The principal mechanism of BBs is to inhibit the detrimental effects of the sympathetic nervous system, which are activated in HF due to compensatory influences of the neurohormonal system. Side effects of the BBs may include bradycardia, hypotension, and sexual dysfunction in males.2,3,5
Digitalis Glycosides (Digoxin)
Digoxin has a long history of use in HF and still has a role in some patients in combination with other chronic HF agents. The theory behind its use and mechanism of action may be related more to its effects on neurohormones than its inotropic effects.3 Although clinical trials with digoxin have reported benefits in reducing morbidity, this drug appears to have a neutral effect on mortality.19 Although it is not a firstline agent, patients who are stable on digoxin may show signs of HF progression if digoxin is discontinued.
Adding digoxin usually is recommended only in patients who are symptomatic on other chronic HF therapies. If digoxin is utilized in HF patients, the data suggest the use of low doses in most patients, and adjustments for renal impairment are important. Side effects may include nausea/vomiting, cardiac effects (arrhythmias), and central nervous system effects. The use of digoxin is widely supported in patients with left ventricular systolic dysfunction and comorbid conditions such as atrial fibrillation or flutter.2,3,5
Role of the Pharmacist
HF is a chronic disease that has a significant influence on both morbidity and mortality. Pharmacists can play a role in ensuring that optimal chronic pharmacotherapy is being utilized in order to provide maximum symptomatic relief, reduction in episodes of acute decompensation (hospitalization), and improved survival. Chronic treatment options encompass ACEIs, ARBs, BBs, digoxin, and diuretics, including aldosterone antagonists. Other agents that also may have a role in HF include combinations such as isosorbide dinitrate (nitrates) and hydralazine, especially in patients who are intolerant of ACEIs or ARBs.20 The use of these agents in various combinations requires careful titration and monitoring in order to maximize benefits.
Dr. DeMaagd is an associate professor of pharmacy practice at Ferris State University, and a clinical pharmacist at KCMS Geriatric Assessment Clinic and Bronson Methodist Hospital Adult Medical (Geriatric Unit), Kalamazoo, Mich. At the time of completion of this article, Ms. Brazo was a PharmD candidate at Ferris State University.
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