Heart failure (HF) is defined as the inability of
the heart to provide adequate blood supply throughout the body. This may lead
to several different vascular (e.g., edema) and metabolic (e.g., angina)
conditions. There is no one cause of HF, and each cause may have unique
symptoms. With over five million current cases of HF in the
Pharmacists are in a unique position to help treat patients with HF, since the majority of effective treatments involve the use of medications. Data indicating the effectiveness of pharmacists as part of a team of health care practitioners in the management of patients with heart failure continue to grow. The Pharmacists in Heart Failure Assessment Recommendation and Monitoring (PHARM) Study showed that adding a clinical pharmacist to a health care team consisting of physicians had a significant mortality benefit.2 In addition, patients seen by clinical pharmacists were more likely to be prescribed the most effective dose of angiotensin-converting enzyme (ACE) inhibitors. Pharmacist-managed clinics focusing on patients with HF have been effective in increasing compliance with prescribed medications and educating patients about the disease state as well as the importance of exercise, weight management, and avoidance of high-salt foods.3 As would be expected, patient outcomes, including all-cause mortality and heart failure events, also improved. One study showed that pharmacists who were not located inside a clinic with the prescribers were effective in increasing diuretic compliance in patients with HF.4 Although this study was conducted in a community pharmacy, the results are relevant to pharmacists in any setting.
This article will provide the reader with a background on ADHF and an update on the current guidelines for treating this condition.
The ventricular dysfunction that occurs with HF can be either systolic, diastolic, or a combination of both. Systolic dysfunction occurs when there is a decrease in myocardial contractility, which can lead to a reduction in stroke volume and cardiac output, as well as insufficient ventricular emptying, cardiac dilation, and, possibly, elevated ventricular diastolic pressure. In contrast, diastolic dysfunction is characterized by impaired relaxation and filling of the ventricle, which causes an increase in ventricular diastolic pressure, regardless of diastolic volume. In patients with both systolic and diastolic dysfunction, the left ventricle empties and fills abnormally.5
When the heart has suffered from loss of contractility or myocardium, or when it has experienced increases in hemodynamic load (e.g., increased pressure or volume overload), the body has various mechanisms to try to compensate for these changes. In the short term, these changes are often beneficial; however, over time, the compensatory mechanisms can become maladaptive, leading to episodes of ADHF.5,6 During an episode of ADHF, patients may experience shortness of breath, sudden fluid overload, and/or an irregular heartbeat caused by elevated left and right ventricular filling pressures, decreased cardiac output, and increased systemic resistance. An increase in preload, the volume of blood that remains in the ventricle after diastole, and afterload, the amount of pressure needed to eject blood from the ventricle, occurs to compensate for changes in arterial pressure.7
Neurohormonal systems that play a role in the pathogenesis of ADHF include the sympathetic nervous system, the renin-angiotensin-aldosterone system (RAAS), and natriuretic peptides.5,6 Patients with chronic HF or ADHF may have an elevation in plasma norepinephrine levels, which is proportional to the degree of cardiac dysfunction. Chronic adrenergic response may increase afterload and cause cardiac arrhythmias. Long-term adrenergic response is also toxic to cardiomyocytes and responsible for down-regulation of beta-1 receptors and uncoupling of beta-2 receptors. Changes to beta-1 receptors may lead to myocardial hypertrophy.5,6 Declining cardiac output can trigger the RAAS, causing increases in angiotensin II levels that lead to aldosterone release. The release of angiotensin II increases sodium reabsorption, stimulates vasoconstriction, and may promote progressive loss of myocardial function due to effects on myocardial cellular hypertrophy. The release of aldosterone increases both sodium and water retention.6 Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are vasodilator peptides released when the heart is dilated; they act on natriuretic peptide receptors to increase production of cyclic guanosine monophosphate (cGMP). This increase in cGMP leads to volume and sodium excretion changes, reduced vascular resistance, and reduced renin and aldosterone secretion.5 Research has shown that both ANP and BNP levels are elevated in HF, and BNP levels play a major role in diagnosis, treatment, and predicting outcomes. Both ANP and BNP decrease ventricular filling pressures. BNP produces afferent arteriolar vasodilation while inhibiting both sodium reabsorption and renin and aldosterone release. This process is important in decreasing fluid retention.6 In addition to these neurohormonal systems, both endothelin and tumor necrosis factor–alpha are elevated in HF patients; however, their blockade has not been associated with improved outcomes.5
Currently there are two sets of guidelines concerning HF. The American Heart Association/American College of Cardiology guidelines address the prevention of HF, as well as the treatment of chronic HF, but do not address ADHF.8 In 2005, the Heart Failure Society of America (HFSA) published guidelines addressing ADHF.
The HFSA guidelines recommend initial treatment with loop diuretics for fluid overload. Doses needed to reach optimal volume status and relief of congestive symptoms without causing hypotension or renal dysfunction should be used. Another recommendation made by the HFSA is the monitoring of side effects, including renal dysfunction, electrolyte abnormalities, and symptomatic hypotension. Pharmacists can have an important role assisting in the monitoring of adverse effects.
The HFSA guidelines recommend considering the use of intravenous nitroglycerin (NTG), nitroprusside, or nesiritide with diuretic therapy for rapid relief of congestive symptoms for patients without symptomatic hypotension. Although the guidelines recommend decreasing the dosage or discontinuing the use of intravenous vasodilators if symptomatic hypotension develops, the agents may be reintroduced in increasing doses once the hypotension is resolved. According to the HFSA guidelines, the positive inotropic agents milrinone and dobutamine may be considered to relieve symptoms and improve end-organ damage in patients with left ventricular dilation, reduced left ventricular ejection fraction, and diminished peripheral perfusion or end-organ dysfunction. This is especially true in patients who have a systolic blood pressure of less than 90 mmHg, have symptomatic hypotension despite adequate filling pressure, or are unresponsive or unable to tolerate intravenous vasodilators. If adjunctive therapy is needed in patients other than those previously mentioned, intravascular vasodilators should be considered instead of milrinone or dobutamine. In addition, milrinone and dobutamine are not recommended unless left heart filling pressures are known to be elevated.
The goals of treatment for ADHF according to the HFSA guidelines include optimizing chronic oral therapy, minimizing side effects, and educating patients about their medications.9 Helping attain these treatment goals is an area in which a pharmacist can be effectively utilized when part of a multidisciplinary team.
Pharmacotherapy for ADHF
Pharmacotherapy for ADHF includes the use of diuretics, positive inotropes, nitrate vasodilators, and natriuretic peptides. Recommended dosages, adverse effects, and monitoring parameters are listed in Table 1.
Diuretics: Diuretic therapy has an integral role in fluid removal for patients with ADHF, although data on the effects of diuretic use are lacking. Frequently, the initial symptom upon presentation of ADHF is fluid overload; thus the use of diuretics is a practical one. Although the morbidity and mortality effects of loop diuretics are unknown, clinical practice has shown that effective management of ADHF cannot take place without their use.10 According to the 2006 Acute Decompensated Heart Failure National Registry (ADHERE), furosemide was administered to approximately 84% of patients admitted to the hospital for ADHF.11
Diuretics should be given intravenously to ADHF patients to bring about short-term vasodilation, which leads to decreased cardiac preload, a fall in pulmonary artery wedge pressure, and symptomatic relief. Caution is needed when administering these agents, because an activation of the sympathetic nervous system may lead to increased afterload and diminished cardiac function.12 In addition to the immediate vasodilating effects of diuretics, which occur within five to 15 minutes of administration, sodium and water excretion also contributes to the decrease in preload; this effect occurs within 20 minutes of adminstration.13
Diuretic resistance is a problem in HF, affecting approximately 33% of patients. Diuretic resistance may occur as a result of consuming large amounts of dietary sodium, using nonsteroidal anti-inflammatory drugs (NSAIDs), insufficient intraluminal concentrations, and RAAS activation.10,14 Ways to counteract resistance include restricting dietary sodium, avoiding use of NSAIDs, and/or employing a sequential nephron blockade using a loop diuretic in combination with a carbonic anyhdrase inhibitor (acetazolamide) and a thiazide diuretic (hydrochlorothiazide)--or, most frequently, a thiazide-like diuretic (metolazone). If available, the continuous infusion (instead of bolus administration) of loop diuretics has also been shown to reduce resistance to diuresis.10,14
Positive Inotropes: Positive inotropic medications such as dobutamine and dopamine have been widely available for patients with ADHF for some time. Newer agents such as milrinone and amrinone have been used to some extent, though evidence suggests their use should be limited. The decision to initiate a positive inotrope must be weighed against the associated severe adverse events. Inotropic agents work by increasing intracellular cyclic adenosine monophosphate (cAMP), resulting in an increase of intracellular calcium and causing an increase in myocardial contractility.15
Dopamine and dobutamine are both catecholamines that work on specific adrenergic receptors. Dopamine has affinity for beta-receptors at low doses and for beta- and alpha-receptors at higher doses. This agent also has dose-dependent positive inotropic and chronotropic effects. Limitations of dopamine include decreased cardiac output, tachycardia, and increased myocardial oxygen demand.16 Dobutamine, a synthetic catecholamine, acts primarily on beta-1 receptors but has some affinity for beta-2 and alpha-2 receptors when given at high doses. Dobutamine is primarily inotropic with mild vasodilatory effects; however, patients may experience symptomatic hypotension.16
Milrinone and amrinone belong to a class of agents known as phosphodiesterase inhibitors. By inhibiting phosphodiesterase, these medications enhance the entry of calcium into the myocardium, which leads to increased contractility.16 Routine use of milrinone is no longer recommended based on results from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study.17 During this study, patients received the normal standard of care for an HF exacerbation, which may have included diuretics, ACE inhibitors, beta-blockers, calcium channel blockers, or angiotensin receptor blockers and the study intervention of either milrinone or placebo. The results of this study showed no significant difference in length of hospital stay for cardiovascular causes within 60 days (the primary objective), in-hospital mortality, 60-day mortality, or composite incidence of death or readmission. In addition, the milrinone group had significantly more hypotension requiring intervention and new atrial arrhythmias, compared with the placebo group.17
According to ADHERE, dopamine, dobutamine, and milrinone were the most commonly used positive inotropic agents between January 2001 and March 2006.11
Nitrate Vasodilators: NTG and nitroprusside are the two most commonly used intravenous vasodilators in ADHF. Approximately 9% of patients hospitalized with ADHF receive intravenous NTG.11 Data supporting the use of nitrate vasodilators are limited, but their use is considered standard care. Nitroprusside, a mixed arteriovenous vasodilator, causes rapid vasodilation and reduces cardiac preload. Hypotension is a dose-limiting side effect of this drug. Patients may also experience reflex tachycardia when nitroprusside is administered. 13,15 Another potential concern is nitroprusside's metabolite, thiocyanate, which can lead to toxicity when used for more than 24 hours, especially in patients with renal dysfunction.16
Low cost, patient comfort, and a proven safety profile contribute to NTG being the most commonly used vasodilator. Limitations of NTG include hypotension and tolerance, which can develop within 12 to 72 hours of continuous treatment. Due to the short half-lives of both of these agents, they must be administered via continuous infusion.13 The Vasodilation in the Management of Acute CHF (VMAC) trial evaluated the effects of a natriuretic peptide compared to intravenous NTG when added to standard care for hospitalized patients with ADHF. Patients receiving NTG had a greater reduction in pulmonary capillary wedge pressure and pulmonary vascular resistance than those in the placebo group.18
Natriuretic Peptides: Nesiritide is a recombinant form of human BNP that is identical to endogenous BNP, which is secreted in response to volume overload. Nesiritide exerts both vasodilatory and natriuretic actions when given intravenously. While patients are tolerant to NTG, they are intolerant to nesiritide.13
Controversy exists over the effect of nesiritide on renal function. Two meta-analyses raised questions about the safety of nesiritide due to a noticeable decline in kidney function after its use; however, patients in these studies received higher than recommended doses of nesiritide.13-20 The VMAC trial reported significantly reduced pulmonary capillary wedge pressures with nesiritide compared with NTG and placebo at 24 hours.18 In addition to this vasodilatory effect, nesiritide also promotes diuresis and natriuresis.16 The Prospective, Randomized Evaluation of Cardiac Ectopy with Dobutamine or Nesiritide Therapy (PRECEDENT) trial showed that although both agents exhibited effectiveness in the management of ADHF, nesiritide demonstrated significantly fewer serious ventricular arrhythmias and no increases in heart rate compared with dobutamine.
Anticoagulation: Thrombus formation leading to stroke is frequently associated with atrial fibrillation; however, it is also a concern in patients with ADHF. The rate of venous thromboembolism is about 50% higher for medically ill patients admitted for ADHF.21 For patients in ADHF, there are multiple factors leading to the risk of thrombi being formed. Increases in the amount of fluid in the extremities along with possible decreases in peripheral perfusion may lead to clot formation in patients with ADHF. In addition to these effects, patients with ADHF are less likely to be ambulatory and are thus at a higher risk of clots. Thrombus formation in the heart is a concern if the patient has a significantly depressed ejection fraction, as this could indicate a pooling of blood inside the heart, thereby placing the patient at higher risk.
Patients admitted for care who are already on warfarin therapy should continue to receive warfarin unless another factor limiting the use of warfarin arises. If the patient was not on anticoagulation therapy prior to being admitted for care, warfarin may be started; however, the use of unfractionated or low-molecular-weight heparin is recommended to provide immediate anticoagulation.22 Anticoagulation therapy should continue throughout the hospital stay and may need to be continued once the patient has been discharged.
Treatment of ADHF involves the use of several medications that modulate the disease state and improve patient outcomes. In addition to choosing the correct medication to use during an exacerbation, it is just as important to know which medications to avoid. The clinical pharmacist is in a position to help the health care team make correct decisions regarding treatment of the patient. The pharmacist should have a firm understanding of the disease state and medications' effect on the disease. In addition, the pharmacist also has the knowledge and skills to effectively counsel the patient about their disease state. The pharmacist must stress adherence, as HF medication regimens are very complex. In addition, medications that should be avoided, such as NSAIDs and metformin, must be made known to the patient. Sodium restriction is also a quick counseling point that a pharmacist may make that will help the patient.
Pharmacists need to ensure that they are part of the health care team treating patients with ADHF. The pharmacist provides a benefit in three ways: (1) by providing expert knowledge on medications; (2) by having training in counseling patients about their medications and disease state; and (3) by working in collaboration with the health care team.
1. Munger MA. Management of acute decompensated heart failure: treatment, controversy and future directions. Pharmacotherapy. 2006;26(8 pt 2):131S-138S.
2. Gattis WA, Hasselblad V, Whellan DJ, O'Conner CM. Reduction in heart failure events by the addition of a clinical pharmacist to the heart failure management team. Arch Intern Med. 1999;159:1939-1945.
3. Varma S, McElnay JC, Hughes CM, et al. Pharmaceutical care of patients with congestive heart failure: interventions and outcomes. Pharmacotherapy. 1999;19:860-869.
4. Bouvy ML, Heerdink ER, Urquhart J, et al. Effect of a pharmacist-led intervention on diuretic compliance in heart failure patients: a randomized controlled study. J Card Fail. 2003;9:404-411.
5. Braunwold E. Normal and abnormal myocardial function. In: Kasper DL, Braunwald E, Fauci AS, et al, eds. Harrison's Principals of Internal Medicine. 16th ed. New York: McGraw-Hill; 2005.
6. Shah M, Ali V, Lamba S, Abraham WT. Pathophysiology of clinical spectrum of acute congestive heart failure. Rev Cardiovas Med. 2001;2(suppl 2):s2-s6.
7. Fonarow GC. The treatment targets in acute decompensated heart failure. Rev Cardiovas Med. 2001;2(suppl 2):s7-s12.
8. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). Circulation. 2001;104:2996.
9. Adams KF, Lindenfel J, et al. HFSA 2006 Comprehensive Heart Failure Practice Guideline. J Card Fail. 2006;12:e1-e122.
10. Ravnan SL, Ravnan MC, Deedwania PC. Pharmacotherapy in congestive heart failure: diuretic resistance and strategies to overcome resistance in patients with congestive heart failure. Congest Heart Fail. 2002;8:80-85.
11. Acute Decompensated Heart Failure National Registry (ADHERE).1st Quarter Final Cumulative National Benchmark Report. 2006. Available at: www.adhereregistry.com. Accessed January 28, 2007.
12. Brater DC. Pharmacology of diuretics. Am JMedical Sci. 2000;319:38-50.
13. Parker RB, Patterson JH, Johnson JA. Heart failure. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy. 6th ed. New York: McGraw-Hill; 2005:219-260.
14. Hill JA, Yancy CW, Abraham WT. Beyond diuretics: management of volume overload in acute heart failure syndromes.Am J Med Sci. 2006;119:S37-S44.
15. Havey RA, Champe PC, Howland RD, and Mycek MJ. Lippincott's Illustrated Review: Pharmacology. 3rd ed. Baltimore: Lippincott Williams and Wilkins; 2006.192;225.
16. Buccelletti F, Hermann L. Acute decompensated heart failure: formulating an evidence-based approach to diagnosis and treatment (part II). Mt Sinai J of Med. 2006;73:516-527.
17. Cuffe MS, Califf RM, Adams KF, et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure. JAMA. 2002;287:1541-1547.
18. Publication Committee for the VMAC Investigators (Vasodilation in the Management of Acute CHF). Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA. 2002;287:1531-1540.
19. Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation. 2005;111:1487-1491.
20. Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K. Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials. JAMA. 2005;293:1900-1905.
21. Edelsburg J, Hagiwara M, Taneja C, Oster G. Risk of venous thromboembolism among hospitalized medically ill patients. Am J Health Syst Pharm. 2006;63:(20 suppl 6):S16-S22.
22. Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:(3 suppl):338S-400S.
23. Lexi-Comp Online Database.
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