The Clinical Challenge of Heart Failure: Comprehensive, Evidence-Based Management of the Hospitalized Patient With Acute Myocardial Decompensation
Part II: Outcome-Effective Treatment and Prophylaxis Against Venous Thromboembolic Disease (VTED)
Authors: W. Frank Peacock, MD, FACEP, Emergency Department Clinical Operations Director, The Cleveland Clinic, OH; Benjamin J. Freda, DO, Department of Internal Medicine, Cleveland Clinic Foundation, OH.
Peer Reviewers: Charles L. Emerman, MD, Chairman, Department of Emergency Medicine, MetroHealth Medical Center, Cleveland Clinic Foundation, OH; Gregory A. Volturo, MD, FACEP, Vice Chairman and Professor, Department of Emergency Medicine, University of Massachusetts Medical School, Worcester.
The approach to managing heart failure (HF) is multi-factorial, and includes hemodynamic support; close monitoring of vital signs, metabolic status, and cardiac rhythm; and administration of pharmacologic agents belonging to a number of therapeutic classes. Historically, the pharmacotherapeutic approach to HF has focused on a number of agents—both oral and intravenous—with the capacity to decrease intravascular volume, reduce afterload, and/or improve left ventricular (LV) function.
To achieve both hemodynamic and symptomatic goals in a broad group of patients, ranging from those with decompensated HF to individuals with pulmonary edema and cardiogenic shock (CS), a number of so-called workhorse agents for managing HF have been pressed into service in the emergency department (ED) setting. They include diuretics, oxygen, morphine, nitroglycerin (NTG), nitroprusside, angiotensin-converting enzyme inhibitors (ACEIs), digoxin, vasodilators, beta-blockers (b-blockers), angiotensin receptor blockers (ARBs), and inotropic agents.
Recently, the therapeutic options for managing HF have expanded to include such newer agents as nesiritide, a recombinant DNA manufactured form of endogenously synthesized b-type natriuretic polypeptide. In addition to managing deteriorations in cardiac function and ejection fraction, clinicians are focusing on the need to prevent VTED, in particular, deep venous thromboembolism (DVT) and pulmonary embolism (PE), as part of the overall management approach to hospitalized patients.
Part II of this two-part series outlines a systematic approach to managing patients with HF in the ED setting. Initial stabilization approaches are outlined in detail, and a systematic approach to pharmacologic therapy is highlighted. The benefits, risks, and indications for newer therapeutic options are discussed in detail, with a focus on improving clinical outcomes and reducing length of hospital stay.
Initial Stabilization Measures
Stabilization measures aimed at maintaining airway control and ensuring adequate ventilation should take precedence during the initial phase of patient management. Clearly, any patient with signs or symptoms of heart failure (HF) is a candidate for supplemental oxygen, which should be administered promptly on an empiric basis. Patients who appear to be in impending respiratory failure, who are unable to oxygenate, are ventilating poorly, or cannot protect their airways should be evaluated promptly for eligibility regarding endotracheal or nasotracheal intubation.
As emphasized, oxygen administration may improve clinical status and should be considered for all patients with suspected decompensated HF. Therapy may be guided by the results of pulse oximetry. Supplemental oxygen also can accelerate relief of dyspnea and frequently relieves the anxiety of hypoxia. Because hypoxia presents a more immediate risk than hypercarbia, oxygen should not be withheld due to concerns about carbon dioxide retention. When carbon dioxide retention is likely to complicate management (i.e., patients with chronic obstructive pulmonary disease [COPD]), arterial blood gas analysis is helpful for guiding subsequent therapy, including the need for intubation in patients with acute carbon dioxide retention. Selecting an appropriate oxygen delivery device is based on patient needs. Patients with minimal dyspnea may be able to oxygenate adequately with a nasal cannula, whereas patients with CS and/or extreme respiratory distress may require endotracheal intubation.
Non-invasive positive pressure ventilation (NPPV) can be a temporizing measure in properly selected patients. Bilevel positive airway pressure (BiPAP) and continuous positive airway pressure (CPAP) are the most commonly used modalities. BiPAP involves delivery of separately controlled inspiratory and expiratory pressures via face mask, while CPAP delivers constant pressure throughout the respiratory cycle. To be eligible for a trial of NPPV, patients must be monitored closely and hemodynamically stable and mentally appropriate. In addition, they must be able to protect their airway and clear secretions.
NPPV has been studied most extensively in patients with COPD exacerbation. In this setting, NPPV may offer a mortality benefit over invasive mechanical ventilation. The data is controversial in acute cardiogenic pulmonary edema. The use of NPPV may result in decreased rates of endotracheal intubation; however, mortality appears to be unchanged. In addition, one study showed that patients treated with CPAP had higher rates of myocardial infarction (MI) than patients treated with BiPAP.1 Consequently, there is no consensus regarding the precise role of NPPV in patients with acute pulmonary edema (APE).
Intravenous (IV) access is mandatory for all HF patients. Significant electrolyte abnormalities can occur as the result of aggressive diuretic therapy. Since HF patients are at risk for ventricular arrhythmia, prompt treatment may be required. Delaying therapy to attempt vascular access may have adverse consequences.
The initial approach to the patient with HF requires simultaneous assessment of vital signs, cardiovascular laboratory parameters, radiographic studies, and overall evaluation of the patient’s clinical status. Initial treatment decisions are based on the acuity of presentation, determination of volume status, and systemic perfusion. Although most patients presenting to the ED are symptomatic, patients who present with minimal symptoms may undergo an initial period of evaluation before treatment is initiated. Typically, initial evaluation should include the following steps:
1. Evaluation of airway, degree of respiratory distress, and need for mechanical ventilation;
2. Assessment of circulation by blood pressure (BP), mentation, pulses, and skin temperature;
3. Expeditious physical exam and history with attention to cardiopulmonary systems;
4. Evaluation of oxygenation and ventilation by pulse oximetry and arterial blood gas (ABG), if indicated;
5. Assessment of cardiac rhythm by monitoring, and evaluation for ischemia by 12-lead electrocardiogram (ECG);
6. Chest x-ray—portable if necessary;
7. Blood drawn for complete blood cell count (CBC), electrolytes, B-natriuretic peptide level (BNPL), cardiac enzymes, and possibly digoxin levels (especially with worsening renal function or drug interaction); and
8. Placement of a urinary catheter to monitor fluid output in seriously ill and unstable patients;
Management Strategies for Specific Categories and Patient Risk Groups with Heart Failure
Cardiogenic Shock. CS requires immediate intervention, which will be concurrent with the clinical challenge of gathering historical, physical, and diagnostic data. Although unavailable in the ED, Swan-Ganz catheterization may be necessary to guide therapy and confirm myocardial dysfunction as the cause of shock. Urgent cardiology consultation is mandatory and will facilitate prompt echocardiographic and, when necessary, invasive evaluation of myocardial function. Bioimpedance monitoring also may be a useful adjunct. Because approximately 20% of patients with CS develop hypotension without pulmonary congestion, a small fluid challenge (100-250 ccs NS) may be appropriate. If pulmonary congestion is present, this intervention should be omitted. Almost all patients will require intubation and sedation to protect the airway and decrease oxygen demand associated with increased work of breathing. Therapy with agents that may lower BP (ACEIs, diuretics, nitrates, and b-blockers) should be withheld.
If there is no improvement in systemic perfusion after fluid challenge, and in the setting of hypotension with pulmonary congestion, inotropic agents should be considered. In particular, inotropic therapy will be required if there is no improvement in tissue perfusion after fluid bolus. These agents may stabilize the patient and preserve perfusion while other interventions aimed at restoring cardiac function (e.g., PTCA, intra-aortic balloon pump [IABP], CABG) are being considered and/or mobilized. Agents with pure inotropic activity, or inotropic and vasodilator properties (i.e., milrinone, dobutamine), are inadequate in the setting of shock. Optimal therapy requires agents with both vasopressor and inotropic activity (e.g., dopamine). However, combination therapy with a vasopressor (i.e., dopamine) and a pure inotrope (i.e., dobutamine) may be more effective than use of either agent alone.2
Patients with CS may require prompt revascularization by either percutaneous procedures or emergency CABG. The placement of an intra-aortic balloon pump can serve as a bridge until such therapies are available. In the case of acute MI complicated by a right ventricular (RV) infarction, hypotension is treated with vigorous IV fluids. However, cardiac output will not increase if fluid therapy causes RV distension (causing compromise of the LV cavity) or produces an unacceptably high increase in pulmonary capillary wedge pressure (PCWP). Dobutamine and/or therapy with IABP is the next line of therapy in such patients. Finally, because hypotension may result from preload reduction, the clinician should be cautious with medications that produce this hemodynamic effect (e.g., NTG, loop diuretics, etc.).
Acute Pulmonary Edema. The failing heart is sensitive to increases in afterload. In some HF patients, when systolic BP is elevated to the 150 mmHg systolic range, pulmonary edema will ensue. Prompt BP reduction often will break the downward spiral of pulmonary edema and avoid the need for intubation. Although diuretic therapy is important, it is critical to lower BP and cardiac filling pressures. These authors recommend that initial therapy consist of repeat doses of sublingual (SL) NTG, provided there is adequate BP. In APE, NTG is placed sublingually, at the rate of one per minute (each tab is 0.4 mg) until IV NTG can be started. Following this maneuver, IV NTG then is titrated rapidly upward until BP is controlled. If pressures remain elevated, or clinical improvement is not achieved, conversion to IV nitroprusside may be required.
IV furosemide or bumetanide are the preferred diuretics in the setting of APE. Ethacrynic acid is useful if the patient has a serious sulfa allergy. These agents are characterized by quick onset; diuresis can be expected 10-15 minutes after the use of IV furosemide. If urine output is inadequate after 20-30 minutes, the diuretic dose should be increased and repeated. Diuretics also may have an early effect as weak venodilators. IV morphine may be helpful to venodilate and to decrease respiratory distress and circulating catecholamine levels. (See Table 1.)
|Table 1. Initial Therapy for Acute Pulmonary Edema (APE)|
|1. Sit the patient upright with legs dependent (to reduce venous filling), if possible.
2. Administer 100% oxygen.
3. Administer nitrates if systolic BP > 100.
• Sublingual nitroglycerin 0.4 mg q 1-5 minutes (monitor BP closely)
• IV nitroglycerine or nitroprusside if needed.
4. Administer IV furosemide (or ethacrynic acid if sulfa allergy)
5. Administer IV morphine 2-6 mg (if no respiratory acidosis/depression)
6. Cardioversion to restore sinus rhythm
When hypertrophic obstructive cardiomyopathy (HOCM) occurs concurrently with APE, special attention is required. These patients have dynamic outflow obstruction that is exacerbated by increases in cardiac contractility or heart rate. Conditions of decreased preload or afterload also can worsen the obstructive gradient. Consequently, ideal therapy for HOCM in the setting of APE will decrease the outflow gradient by slowing the heart rate and myocardial contractility. This can be accomplished with IV b-blockers, a pharmacotherapeutic intervention best left to the cardiologist in the intensive care unit/critical care unit (ICU/CCU) environment. If shock is present, the pressor of choice is phenylephrine. Phenylephrine vasoconstricts the peripheral vascular tree without increasing cardiac contractility.
Decompensated HF. Patients in this group have stable vital signs, adequate oxygenation and ventilation, and organ function at or near baseline. The majority will require diuresis with an IV loop diuretic, supplemental oxygen, education about low-salt diet, and therapy aimed at lowering BP to acceptable levels. Some patients can be followed in a clinical decision unit, while others will require admission to the hospital or ICU.
Multiple large-scale clinical trials have provided clinicians with an evidence-based approach to managing stable, systolic dysfunction HF. The principal drugs from which the clinician should choose include b-blockers, ACEIs, angiotensin-receptor blockers (ARBs), hydralazine/nitrates, diuretics, digoxin, and spironolactone. In general, the hemodynamic management of chronic systolic HF focuses on maintaining the lowest possible BP to allow mentation, ambulation, and urination.3
One common misunderstanding about the management of HF pertains to the timing for initiating individual therapeutic agents. HF patients with clinically stable disease and mild symptoms may benefit most from the addition of a new drug to their medical regimen. All HF patients without contraindications should be on an ACEI and a b-blocker, even in the setting of stable disease and minimal symptoms. The neurohormonal antagonism requirements of HF therapy are different from other disease states, where the impetus to expand therapy is driven primarily by continuing symptoms.
Pump Failure Without Signs of Shock. If systemic congestion persists despite nitroprusside therapy and IV diuretics, IV inotropes may be required. Although several agents are available for treatment of acute HF, each drug has unique properties, hemodynamic effects, and potential side effects. The emergency physician should be familiar with the use of dobutamine and milrinone, although the ICU environment, where invasive monitoring is possible, is the optimal setting for monitoring such therapy. Typically, however, dopamine is reserved for patients with signs of shock.
Pharmacotherapeutic Strategies and Specific Agents for HF
Therapeutic options for HF have evolved dramatically during the past decade. Interestingly, some unexpected approaches have characterized some of these new clinical paradigms. For example, the place of b-blockers in the therapeutic arsenal has evolved from one of absolute contraindication to that of a central role as cornerstone agents. The use of ACEIs and powerful loop diuretics such as furosemide has decreased the morbidity of this debilitating disease, while ACEIs have decreased mortality rates as well. Many patients with HF now can enjoy a longer life, relatively free from daily congestive symptoms previously attributed to this syndrome.
ACE-Inhibitors. Vasodilators, which are used to "unload" the heart and improve pump function, have been studied extensively. However, it is clear that all vasodilators used in HF are not created equal. While powerful agents (e.g., amlodipine, flolan) have failed to benefit patients with HF, less potent vasodilators such as ACEIs have altered the natural history of this condition.
Put simply, ACEIs are the cornerstone of pharmacological therapy for HF. In the absence of contraindications, all patients with HF should be treated with an ACEI. There also is strong evidence that patients with asymptomatic LV dysfunction derive benefit from ACEIs.4 In placebo-controlled studies, ACEIs have been shown to decrease the overall mortality rate and combined end-point of death or hospitalization in HF.5 For example, use of enalapril leads to a 31% decrease in one-year mortality in class IV patients and a 16% mortality reduction in class II and III patients.6 ACEIs appear to be superior to both ARBs and the combination of hydralazine and isosorbide.7-9
It should be stressed that the salutary effects of ACEIs on HF are not explained fully by their vasodilating properties. These agents exert clinical effects primarily by suppressing levels of angiotensin II and augmenting levels of endothelium-protective bradykinins. The long-term effects of ACE-inhibition include prevention of ventricular remodeling, a benefit that persists despite failure chronically to suppress angiotensin II levels. All patients with systolic HF should receive ACEIs, except those who meet exclusionary criteria summarized in Table 2.
|Table 2. Contraindications to Angiotensin- Converting Enzyme Inhibitors (ACEIs)|
• Progressive azotemia (> 3 mg/dL, especially if progressively increasing)
• Bilateral renal artery stenosis
• Systemic hypotension (systolic blood pressure < 80, especially in ambulatory patients)
• Hemodynamic instability
• Intolerance secondary to severe cough
ACEI-induced angioedema occurs as a result of increased bradykinin production precipitated by ACE-inhibition. Treatment in the ED is similar to that of routine angioedema, and includes permanent cessation of ACEI use. The presence of cough during ACEI therapy should prompt a search for other causes (pulmonary congestion, infection, bronchospasm) before these symptoms are ascribed to drug-related side effects. If no other cause for cough is identified, then cessation of ACEIs should be considered, and if the symptoms are drug-related, they will disappear within 1-2 weeks. If the cough is not severe, patients should be educated about the significant benefits of these drugs and encouraged to continue therapy. In patients who are unable to take ACEIs, ARBs or a combination of hydralazine and isosorbide dinitrate, with or without spironolactone, should be considered strongly.
Diuretics. Diuresis may sensitize patients to the hypotensive effect of ACEIs, and therefore, ACEI therapy should be delayed during aggressive diuresis. Hyponatremia may be a sign of heightened renin-angiotensin-aldosterone system (RAAS) activation, and may predict ACEI-induced hypotension. In the absence of postural symptoms, hypotension is relatively well-tolerated. In patients who experience symptomatic hypotension with the first doses of ACEI, diuretic doses can be decreased and the ACEI continued. Additionally, the use of diuretics activates the RAAS, and concurrent use of ACEIs helps to blunt this effect. The development of mild azotemia during ACEI therapy should be tolerated as long as the patient does not have bilateral renal artery stenosis, oliguria, acute renal failure from other causes, or serum creatinine greater than 3 mg/dL.
Potassium balance and renal function should be followed carefully in patients who are started on ACEIs. In general, low doses should be started and titrated up to the same doses used in major trials. However, recent data suggest that even lower doses of ACEIs are effective in reducing mortality.10 These agents work by inhibiting neurohormonal pathways and, therefore, may take weeks to months to exert symptomatic benefit. Even in the absence of symptomatic improvement, ACEI therapy should be continued for the long-term effects on LV remodeling and overall mortality benefit. (See Table 3 for dosing guidelines.)
|Table 3. ACEIs/ARBs for Chronic Systolic Heart Failure Agents*|
|Drug||Start||Target Dose||Trial Data|
|6.25 mg tid||50 mg tid||SAVE|
|2.5 mg qd||40 mg qd||ATLAS|
|5 mg qd||20 mg qd||SOLVD|
|2.5 mg qd||10 mg bid||AIRE|
|50 mg qd||50 mg bid||ELITE|
|40 mg bid||160 mg bid||Val-HeFT|
|* Dosing data from major clinical trials|
Angiotensin Receptor Blockers. ARBs were developed to directly inhibit the adverse effects of angiotensin II. These agents also were developed with the hope that they would have fewer effects on bradykinin metabolism and produce a lower incidence of side effects than ACEIs. The therapeutic effects of ARBs are due to blockade of the angiotensin receptor subtype AT1. Stimulation of the AT1 receptor by angiotensin II promotes aldosterone release, LV remodeling (including apoptosis), arterial vasoconstriction, and renal damage.11 Because inhibition of these effects is associated with vasodilation, ARBs are effective and are among the most well-tolerated agents for treatment of hypertension. In addition, they are more effective than b-blockers (such as atenolol) at reducing LVH.12 ARBs also may decrease proteinuria and have a renoprotective effect in patients with diabetes.13 Cough and angioedema are reported less frequently with ARBs than with ACEIs.
Some authors have suggested that ACEIs may be superior to ARBs for reducing cardiac mortality due to their ability to inhibit bradykinin breakdown. Bradykinins are presumed to have a vascular protective and vasodilatory effect. Whether theory translates into clinical effect has been the subject of intensive recent study. It is notable that there are currently no prospective, randomized, placebo-controlled trials that have studied whether ARBs are associated with a mortality benefit compared to placebo in patients with HF.14 Clearly, more data is needed before ARBs are recommended for the treatment of HF in patients who are otherwise tolerant to ACEIs.
Beta-blockers. Once contraindicated in HF, b-blockers currently are advocated for management of patients with HF because of studies suggesting impressive mortality reduction data, as well as evidence for symptomatic relief that is comparable to, and in some cases eclipses, benefits observed with some ACEIs. One study found metoprolol led to a 34% reduction in one-year overall mortality for class II-III HF patients.15 In addition, there was a 41% decrease in sudden death compared to placebo. Other large-scale trials evaluating b-blockers have yielded similar results. Benefit has been shown for patients with NYHA class II, III, and IV HF.16 Norepinephrine levels are elevated in HF and contribute to myocardial hypertrophy, increased afterload, and coronary constriction. b-blockers are thought to exert their clinical effect via reductions in sympathetic nervous system activity. All of the major studies evaluating b-blockers in HF have included patients who already were taking ACEIs.
Although carvedilol (a combined a- and b-blocker) improves mortality rates in class IV patients, the use of b-blockers in these patients is best left to an HF specialist. Because therapy can be initiated only in the absence of fluid overload, and preferably in patients with stable disease, it may be problematic for the emergency physician to have all the data required to initiate these drugs in the acute setting. As with ACEIs, patients should be started on b-blockers even if they are clinically stable. The benefits of b-blockers lie in their ability to prevent sudden death and improve overall mortality. Upon initiation of b-blockers, patients may complain of increased fatigue. However, since benefits occur even in the absence of subjective improvement, patients should be encouraged to continue their b-blocker regimen.
All patients with HF should be considered for b-blocker therapy, except in those situations listed in Table 4. Therapy begins with low doses, and patients should be monitored closely for signs of deterioration. Daily weights are important. If weight increases, the dose of diuretic can be increased, or therapy with the b-blocker may be decreased or deferred. Doses should be titrated upward to the levels used in most clinical trials. b-blockers can take months to provide symptom improvement. (See Table 5 for dosage recommendations.)
|Table 4. Contraindications to Beta-Blockers|
| • Unstable hemodynamics, or congested and requiring IV diuresis (most ED patients)
• Severe bronchospastic airway disease
• Symptomatic bradycardia
• Advanced heart block
• Acute vascular insufficiency or worsening claudication/rest pain
• Class IV stable HF (therapy should be provided by HF specialist)
• Inotropic therapy/cardiogenic shock
• Severe conduction system disease (unless protected by a pacemaker)
|Table 5. Beta-Blockers for Chronic Systolic Heart Failure*|
|Drug||Starting Dose||Target Dose||Trial Data|
|Metoprolol xl/cr||12.5 mg qd||100 mg qd||MERIT-HF|
|Carvedilol||3.125 mg||bid 25-50 mg bid||US-TRIALS COPERNICUS|
|Bisoprolol||1.25 mg qd||10 mg qd||CIBIS II|
|* Dosing data from major clinical trials|
For patients who develop brochospasm and pulmonary symptoms, the clinician should be sure that congestion is not playing a role. Bradycardia can develop and should prompt dose reduction or withdrawal if it is symptomatic or of advanced degree (second or third degree). Other drugs that act on the conduction system (i.e., clonidine, calcium channel blockers, digoxin) may have to be discontinued to allow continuation of b-blocker therapy. Some patients may develop symptomatic hypotension on b-blockers, especially if they also are taking ACEIs. The clinician often can adjust the dosage of the ACEI or diuretic to ameliorate these symptoms. Additionally, dosing of the ACEI and b-blocker can be separated by a couple of hours. Agents with peripheral vasodilating effects (carvedilol) may have to be changed to agents without this effect (metoprolol) if hypotension is a problem.
The strategy for patients currently being treated with b-blockers who present with worsening HF symptoms should be considered on an individual basis. In the absence of tissue hypoperfusion or pulmonary edema, clinicians may consider continuation of b-blockers, although the dose may have to be reduced or diuretics may need to be increased. If b-blockers need to be withheld, they should be re-instituted at low doses as soon as the patient is hemodynamically stable and is back to his/her baseline weight.
The acutely decompensated patient who presents to the ED and already is receiving b-blocker therapy presents a difficult management problem. Termination of the b-blocker may cause clinical deterioration. However, higher doses of b-blockers may compromise tenuous hemodynamics. The optimal compromise may be a short course of an IV inotrope, such as milrinone, to provide hemodynamic support, while using other measures to stabilize hemodynamics (e.g., IV diuretics and vasodilators).
Digoxin. Recognized as beneficial for HF for more than 200 years, this foxglove alkaloid functions by inhibiting myocardial cellular membrane Na+/K+ ATPase. Digoxin generally is used for patients with HF and atrial fibrillation. However, b-blockers may be more effective than digoxin in controlling the ventricular response in patients with atrial fibrillation.9 Digoxin also can be used to improve clinical symptoms when therapy with ACEIs and b-blockers is initiated. This may be helpful, as the clinical effect of ACEIs and b-blockers may take some time to manifest. Digoxin also may be considered when therapy with ACEIs, b-blockers, and diuretics fails to control symptoms of HF.
In this regard, it should be emphasized that, although therapy with digitalis does not produce a mortality benefit, it may decrease symptoms and the incidence of hospitalization for symptoms associated with HF.17 Digoxin should not be discontinued in patients who are not receiving other HF therapies, and levels should be monitored closely if there is concomitant renal insufficiency. Physicians should be aware of important drug interactions between digoxin and such other agents as amiodarone, spironolactone, verapamil, or macrolides. Electrolyte levels must be monitored periodically because derangements increase the risk of digitalis toxicity. Typically, digoxin is started at a dose of 0.125 mg per day. There is a trend toward using lower doses of digoxin, and the practice of using the highest tolerable dose no longer is recommended.9 Elderly patients, as well as those with renal insufficiency, should be maintained at low doses and even considered for every-other-day dosing.
Digoxin toxicity may produce cardiac arrhythmia (e.g., heart block, ectopic, and re-entrant rhythms); gastrointestinal symptoms such as nausea or vomiting; and neurologic complaints, including visual disturbances (in only 10%), disorientation, and confusion. The arrythmogenic effect of digitalis toxicity is secondary to increased automaticity associated with cellular calcium overload in combination with AV conduction block. Typical arrythmias include paroxysmal atrial tachycardia with AV block and atrial fibrillation with slow ventricular response. Serum levels are helpful if they exceed 2 ng/mL, but toxicity can occur at lower levels, especially with hypokalemia or hypomagnesemia. Quinidine, verapamil, spironolactone, flecainide, propafenone, and amiodarone may increase digoxin levels; if one of these drugs is added to the regimen, the dose of digoxin should be decreased. For rate control of atrial fibrillation, doses in excess of 0.25 mg daily are not recommended.
Diuretics. Patients with systemic or pulmonary congestion should receive loop diuretics. Diuretics provide rapid symptomatic relief in HF. These agents also sensitize patients to the hemodynamic effects of ACEIs by decreasing intravascular volume. Note that diuretics are not indicated as monotherapy for HF.18,19 No study has documented a mortality benefit of diuretics (except spironolactone). Once signs and symptoms of congestion have resolved, a fixed maintenance dose should be continued to prevent recurrence of symptoms and to preserve the new "dry" body weight.
Loop diuretics promote water and sodium excretion, and are efficacious, except in cases of severe renal dysfunction (creatinine clearance less than 5 mL/min). This compares to distal tubule diuretics (thiazides, metalozone, and potassium-sparing agents), which are less effective and lose activity with moderate renal dysfunction (creatinine clearance less than 30 mL/min).18 Ethacrynic acid is the only loop diuretic that can be used in patients with sulfa allergy.
For dyspnea secondary to pulmonary congestion, furosemide is an inexpensive and efficacious loop diuretic. An equivalent dose equal to twice the patient’s daily usage, up to a maximum of 180 mg, can be administered intravenously. If the patient previously has not been on a loop diuretic, 40 mg is an adequate initial dose. If bumetadine is used, 1 mg of bumetadine equals 40 mg furosemide.20 Some patients require the addition of a thiazide diuretic, such as metalozone, to maintain effective diuresis. Metolazone can be given 20-30 minutes prior to furosemide. (See Table 6.) The physiological rationale for combined diuretic therapy—a loop and thiazide diuretic—may be explained by the action of these agents on different sites in the nephron.
|Table 6. Diuretics for Acute Heart Failure|
|Agent||Dosing (IV)||Effect||Side Effects|
No prior use: 40 mg IVP
If prior use: Double last
24-hour usage (max 180 mg)
If no effect by 20-30 min:
| • Diuresis starts within 15-20 min
• Duration of action is 4-6 hrs
| • Reduced K+ and Mg++;
• Hyperuricemia; ototoxicity
• Sulfa allergy; hypovolemia;
• Pre-renal azotemia;
1 mg ~ 40 mg furosemide
| • Diuresis starts within 10 min
• Peak action at 60 min
|Same as above|
|| • Diuresis starts within 10 min
• Duration of action is 6-8 hrs
• Better oral bioavailability than furosemide
|Same as above|
|50 mg||Similar to furosemide|| • Same as above
• Non-sulfa agent
• Increased ototoxicity
|5-10 mg po 20-30 min before IV furosemide||Additive to loop diuretic|| • Similar to furosemide except no ototoxicity
• Has liver disease caution
Hypokalemia can be quite severe in patients undergoing aggressive diuresis, and therefore, HF patients should be monitored carefully and/or switched to a loop diuretic plus a potassium-sparing agent. Electrolytes should be monitored closely in any patient on IV diuretics (especially if the patient is also on digoxin). A widening QT interval may suggest hypocalcemia, hypokalemia, or hypomagnesemia. Loop diuretics rarely have been associated with hyperuricemia and the precipitation of gout. Ototoxicity is rare, but may be seen when diuretics are used in conjunction with aminoglycoside antibiotics.
Urinary response to diuretics should be monitored. In more symptomatic patients who are unresponsive to initial IV diuretics, the dose may be doubled and administered again in 30-60 minutes. In stable patients, if urine output is inadequate 2-3 hours after IV bolus furosemide, the physician should consider doubling and repeating the diuretic. If urinary output still is limited, hospitalization is necessary. Adequate urinary output should exceed 500 ccs within two hours, unless the creatinine exceeds 2.5 mg/dL; in that case, two-hour urine output goals are halved. (See Table 6.) Diuretic response correlates with prognosis. Patients with poor diuresis in the setting of APE have a four-fold increased acute mortality.21 In a retrospective study, less than 1 liter of net fluid output was more common in HF patients who subsequently failed outpatient observation unit management.22
Outpatient diuretic use ideally is guided by daily measured body weight. Diuretic complications are common, and consist of electrolyte abnormalities, hypertension, azotemia, and neurohormonal activation. Resistance to diuretics occurs, but may be overcome by IV use or by combination of multiple diuretics.
All patients taking diuretics should limit their sodium intake to fewer than 3 g per day. In addition, they should be advised against taking agents that antagonize diuretic action, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors, especially rofecoxib.9 Those with severe systemic congestion will require IV diuretics, as bowel wall edema can preclude proper absorption of oral agents. The diuretic dose should be titrated dependent on symptoms and stabilization of body weight. The duration of action of oral loop diuretics is approximately six hours.
Proper use of diuretics can relieve patients of congestive symptoms that would otherwise limit them from tolerating therapy with b-blockers. In this way, diuretics are key drugs in HF, as they pave the way for the efficacious and tolerant use of ACEIs and b-blockers. (See Table 6 for a summary of diuretic characteristics.)
Spironolactone. The RALES study demonstrated a significant mortality benefit with the aldosterone antagonist spironolactone in patients with class III and IV HF.23 Because there was a 30% decrease in all-cause mortality, the trial was terminated early. Most patients were on ACEIs and a diuretic. Patients who also were taking b-blockers and digoxin had a significant mortality reduction. The major side effects in the trial were hyperkalemia and gynecomastia. Current recommendations for spironolactone are limited to patients who remain symptomatic, despite ACEI, b-blocker, digoxin, and diuretics. Patients with creatinine greater than 2.5 mg/dL, or potassium greater than 5 mmol/L, should not receive spironolactone. Lastly, the use of spironolactone in patients with mild HF (stage I-II) is not recommended.
Vasodilators. Selecting optimal treatment for HF requires determining perfusion status and estimating the degree of pulmonary congestion. Patients who are vasoconstricted will benefit from vasodilators; those with congestion require diuretics.24 The most common presentation of HF in the ED is the vasoconstricted/congested patient for whom treatment with vasodilators and diuretics will generate the best outcomes. This strategy, because it decreases PCWP and increases cardiac output, is likely to produce the best clinical results in chronic HF, in which mortality rates are linked predictably to the PCWP.25 (See Table 7 for a summary of commonly used vasodilators.)
|Table 7. Vasodilators for Acute Heart Failure|
SL q 1-5 min
|Blood pressure symptoms|| • Hypotension
|Blood pressure symptoms|| • Hypotension
|Blood pressure symptoms|| • Hypotension
• Possibility of coronary steal
• Cyanide toxicity
|2 mcg/kg bolus then
infusion of 0.01 mcg/kg/min
|Titration usually unnecessary||• Hypotension|
Prior to aggressive treatment with vasodilators, the physician should ascultate for and inquire about murmurs of HOCM or aortic stenosis, since these patients may become hypotensive after administration of arterial or venous vasodilators. In any patient who becomes acutely hypotensive after the administration of nitrates, the physician should consider the differential diagnosis listed in Table 8.
Table 8. Possible Causes of Hypotension after
|• Right ventricular infarction
• Aortic stenosis
• Hypertrophic obstructive cardiomyopathy
• Cardiogenic shock
• Intravascular volume depletion
Nitroglycerin. NTG has benefits in HF, provided there is adequate systolic BP, and especially if there is hypertension. A fast-acting, systemic arterial and venous dilator, NTG decreases mean arterial pressure by reducing afterload, and diminishes preload. The coronary vasodilation effects of NTG also may decrease myocardial ischemia, and thereby, improve cardiac function.
NTG can be administered through the IV, SL, or transdermal route. NTG paste may be used for less critical presentations. One inch is placed on the chest wall with a non-absorbent backing material. IV NTG is initiated at 10-20 mcg/min and rapidly is increased by 5-10 mcg/min, titrated to BP and symptomatic improvement. High doses may be required in the acute setting (usually greater than 100 mcg/min).
The most important complication, hypotension, is more likely to occur with volume depletion and RV infarct. It usually resolves after cessation of NTG. If this fails to improve BP, a small fluid bolus (e.g., 250 ccs) may be required. Headache is frequent, but acetaminophen usually is adequate for relief. Meth-hemoglobinemia has been reported with use of high doses of NTG.
Nitroprusside. When further afterload reduction is required (i.e., continued high systemic BP), IV nitroprusside usually is indicated and effective. It is a more potent arterial vasodilator than NTG. Hemodynamic effects include decreased BP, decreased LV filling pressure, and increased cardiac output. Some have suggested that nitroprusside may promote a vasodilation that results in blood being shunted away from the coronary arteries (the so-called "coronary steal"). The clinical relevance of this coronary steal has not been studied formally, but some clinicians recommend simultaneous use of a low dose of IV NTG if recent ischemia or severe CAD is suspected.
The starting dose is usually 0.1-0.2 mcg/kg/min, then titrated up every 5-10 minutes based on BP and clinical response. It also is used to decrease systemic vascular resistance (SVR), as guided by hemodynamic data. The major complication is hypotension. Long-term use (for more than several days at high dose) is associated with thiocyanate toxicity, especially in patients with renal failure. Cyanide toxicity has been reported with high doses (greater than 10 mcg/kg/min) of nitroprusside.
Nesiritide—A New Advance in HF Therapy
Nesiritide is the first medication approved for HF by the U.S. Food and Drug Administration in more than a decade. Pharmacologically, it consists of the recombinant DNA manufactured form of endogenously synthesized B-type natriuretic polypeptide (BNP). Consequently, when given as a therapy, its use represents an amplification of the natural compensatory mechanism for neurohormonal and hemodynamic derangements that occur in HF. As a neurohormonal antagonist,26 nesiritide serves as a counterpoint to the RAAS; it antagonizes the sympathetic nervous system and causes decreases in aldosterone and endothelin levels.
Background. Understanding the clinical importance of neurohormonal antagonism in HF therapy represents a major shift in the management of HF patients. Historically, relief of congestion with diuretics has represented the main thrust of HF therapy in the ED. While diuretics still are important for acute relief of congestion, they provide symptomatic relief, but without improvements in the mortality rate. Studies with a combined population of more than 20,000 patients—evaluating the role of ACEIs, b-blockers, and other agents—have demonstrated that neurohormonal antagonism is required for mortality improvement. Direct neurohormonal antagonism represents one significant and specific advantage of nesiritide over currently available inotropes and vasodilators used for ED-based therapy of HF.
As a rule, ED patients who present with HF are dyspneic and congested and require prompt IV diuresis. There is theoretical support for the use of a neurohormonal antagonist in combination with diuretics for HF. First, the pathophysiological consequences of successful diuresis are intravascular volume loss and sodium depletion. Ultimately, the patient is decongested, but the consequence is a maximally stimulated neurohormonal axis. Unchecked, this compensatory neurohormonal activation attempts to restore the patient to his pre-diuresis state by vasoconstriction and retention of sodium and water. The use of a neurohormonal antagonist, such as nesiritide, at the time of diuresis, blunts the degree of compensatory neurohormonal activation.
In addition to being an effective neurohormonal antagonist, nesiritide also has direct effects on fluid homeostasis. It is both a weak diuretic and a natriuretic. After an IV infusion, both urinary sodium and volumes increase, but without a statistically significant increase in urinary potassium or creatinine clearance. It is important to note that although nesiritide has diuretic effects, it still is necessary to combine this agent with a loop diuretic to ensure adequate diuresis for treatment of decompensated HF.
Finally, of special clinical significance to the emergency physician are the acute hemodynamic effects of nesiritide, which causes vasodilation of both the systemic veins and arteries. This leads to a rapid and predictable decrease in right atrial pressure (RAP), pulmonary artery pressure (PAP), PCWP, SVR, and mean arterial pressure (MAP), with subsequent increases in the stroke volume index (SVI) and the cardiac index (CI).27,28 These effects are beneficial in the decompensated HF patient, and the resulting hemodynamic improvements translate into a synergistic augmentation of other therapeutic components of standard HF treatment, i.e., diuretics, NTG, etc. (See Table 9.)
|Table 9. Nesiritide Effect Summary|
|• Decreases afterload
• Decreases preload
• Vasodilator (including corornary arteries)
|• Promotes free water loss
• Promotes sodium loss
• Minimal kaliuretic effect
• Global clinical status
|Important lack of effect|
|• Not inotropic
• Not arrhythmogenic
• Sympathetic nervous system
• Renin angiotensin system
Clinical Effects. Several prospective studies have evaluated the clinical effects of nesiritide. The PRECEDENT trial evaluated the effects of varying doses of nesiritide or dobutamine on cardiac ectopy.29 Dobutamine-treated patients had ectopy rates as high as 13%, whereas the nesiritide group had ectopy rates of only 6%. Although 5% of the dobutamine group suffered cardiac arrest, no nesiritide patients did. The rate of ventricular tachycardia was 22% with dobutamine, compared to 7% with nesiritide. Another study, evaluating six-month survival following short-term nesiritide therapy, showed a marked decrease in death rates compared to dobutamine.30 Similar favorable trends were observed for nesiritide as far as readmission rates and total cost of care.
Studies suggest nesiritide is superior to the most commonly used inotropes for HF. Compared to NTG, the most commonly used vasodilator for HF, nesiritide had a better decrease in PCWP, superior dyspnea score at three hours, and lower rates of headache and hypotension. At 24 hours, the nesiritide group had less dyspnea, and the global clinical evaluation was better than with NTG. Adverse event rates were similar in regard to myocardial infarction, ventricular tachycardia, and symptomatic hypotension.31
Safety in ACS
In the United States, underlying CAD is one of the most common causes of HF. Therefore, in patients presenting to the ED with signs and symptoms of decompensated HF, underlying ACS must be considered in the differential diagnosis. In a retrospective review30, the Cleveland Clinic found that 14% of decompensated HF patients in the ED ultimately "rule in" for ACS with a positive troponin. Whether the elevated cardiac markers were a precipitant or a consequence of the decompensated HF was unclear. However, any medication for use in ED patients with decompensated HF should be safe in the occurrence of concurrent ACS.
There is little published data specifically evaluating the safety of nesiritide in ACS. However, its physiologic profile would suggest it is safe when used in the HF patient who ultimately is found to have an underlying ACS. An important management strategy in the treatment ACS is to minimize myocardial oxygen demand (MVO2), thus limiting the size of a potential infarction. This is accomplished by controlling the major determinates of (MVO2), i.e., heart rate and afterload (MAP), with b-blockers. b-blockers are contraindicated in the acutely congested HF patient requiring IV diuresis. Nesiritide, with neither inotropic (tension-inducing)32 nor chronotropic (HR-increasing) effects, should not increase MVO2. The lack of inotropic and chronotropic activity suggests there may be an increased margin of safety using this agent if there is coincident underlying ACS in an HF patient. Prospective studies will be required to evaluate this hypothesis.
Other characteristics of nesiritide also suggest safety in HF patients with a concurrent acute coronary ischemic syndrome. Nesiritide functions to decrease systolic BP (decreasing MAP), the other major determinant of MVO2. As a result, it should provide benefit as long as hypotension is avoided. Finally, nesiritide is an epicardial coronary artery vasodilator.33 While nesiritide is not indicated for the primary treatment of ACS, the characteristic of coronary vasodilation increases safety for use in decompensated HF. In summary, the early use of nesiritide in ED patients with suspected decompensated HF is not dependent upon the return of negative cardiac enzymes. Nesiritide may be initiated early in the course of the ED visit, based on congestive HF symptoms, and before the results of lab investigation are known. If the patient ultimately is diagnosed with acute MI, the clinician has the option of discontinuing nesiritide therapy and replacing this agent with standard ACS therapy (e.g., NTG, heparin, or low molecular weight heparin [LMWH], etc.).
Finally, nesiritide may be used in acute decompensated HF without CS. It should be used concurrently with ACEIs, b-blockers, and diuretics. Recommended dosing is to administer an initial bolus of 2 mcg/kg followed by a fixed dose of 0.01 mcg/kg/min IV. The most common complication is hypotension, with an overall rate of 4%.
Vasodilators and Inotropic Agents
Hydralazine/Isosorbide Dinitrate (ISDN). The combination of hydralazine and ISDN has the advantage of producing preload and afterload reduction, while at the same time achieving protective effects against ventricular remodeling.9 The V-HeFT trial demonstrated that in HF, the combination of hydralazine plus ISDN resulted in significant mortality reduction compared with placebo. However, the V-HeFT-II study showed that enalapril-treated patients had better long-term outcomes than patients treated with the combination of hydralazine and ISDN.7 Because of this, the use of hydralazine and ISDN should be considered only in patients who have proven to be intolerant to ACEIs. Moreover, therapy with the combination of hydralazine/ISDN can be cumbersome and can result in significant side effects (i.e., drug-induced lupus, hypotension, gastrointestinal complaints, and headache). As a result, some clinicians prefer to use ARBs prior to hydralazine/ISDN in patients who are unable to take ACEIs. There is no data to support the use of hydralazine or ISDN as single agents in the management of stable, compensated HF.
The dose of hydralazine typically is started at 10-25 mg TID and titrated up to a maximum of 300 mg per day. ISDN is started at 10 mg TID and titrated to a maximum dose of 240 mg per day. If once-a-day nitrate dosing is desired, isosorbide mononitrate can be used starting at 30 mg, with a maximum daily dose of 240 mg.
Morphine Sulfate. Morphine can be used in APE, provided there is adequate BP. It is used to reduce overall anxiety, decrease adrenergic responsiveness of vascular beds, as a venodilator, and to treat pain associated with myocardial infarction. Dosing is 2-5 mg IV, initially, titrated to clinical effect. Since it is a respiratory and central nervous system (CNS) depressant, morphine use should be avoided if there is significant respiratory depression (e.g., respiratory acidosis) or altered sensorium. Naloxone should be available if needed. Complications include hypotension, hypoventilation, sedation, nausea, and vomiting. Hypotension is particularly likely if there is a concurrent RV infarct.
Inotropic therapy. Since inotropic therapy improves cardiac performance, it would appear that it would be of value in patients with HF. As a class, these drugs augment myocardial function by improving contractility, and some agents decrease SVR through vasodilation. In the short term, these effects improve cardiac output. Inotropes are used most appropriately as a bridge to definitive therapy. Unfortunately, despite the short-term hemodynamic effects, no lasting improvement in symptoms or clinical outcomes has been documented with these agents.18,34 In fact, long-term IV therapy with inotropes has produced increased mortality rates.18,33,35,36 Consequently, chronic use cannot be recommended.
Nevertheless, there are appropriate uses for inotropic therapy. In patients on chronic b-blocker therapy who present with congestive findings as a result of dietary or non-compliance issues, inotropes may be used as temporizing therapy. In this population, for whom it may not be prudent to stop b-blockers, inotropes may serve as a bridge to hemodynamic stability. Inotropes can be used while awaiting the placement of an LV assist device or heart transplant. (See Table 10.)
|Table 10. Inotrope Characteristics|
|ß-1 > ß-2 > A-1
||0.5-20 mcg/kg/min IV||• Primarily ß-1 stimulation
• Less vasodilation than milrinone
• Less effective if ß-receptor downregulation
• Quicker onset than milrinone
(increases cellular cAMP)
|Load 50 mcg/kg IV over 10 min
Maintenance: 0.375-0.75 mcg/kg/min IV
|• Risk of hypotension especially when use loading dose
• Needs adjustment for renal insufficiency
• Effective in states of ß-receptor downregulation
• Possibly less ischemic potential than dobutamine
|Low Dose 1-2 mcg/kg/min
Medium Dose 2-10 mcg/kg/min IV
ß-1 > A-1 > ß-2
High Dose 10 mcg/kg/min IV
A-1 > ß-1 > ß-2
|See Mechanism||• Agent of choice when shock or unacceptable hypotension
• Prefer a central line to prevent skin extravasation
• Lower doses promote renal blood flow
• Can increase PCWP
• Goal is to bring systolic blood pressure to acceptable range
PCWP = Pulmonary capillary wedge pressure
CI = Cardiac index
D-1 = Dopamine receptor
cAMP = Cyclic adenosine-monophosphate
The use of intermittent (so-called "holiday") inotropic therapy for chronic HF is not recommended.9 Studies have been sparse, but appear to show a trend toward increased mortality in patients treated with intermittent therapy with either IV or oral inotropes.9 A distinction between intermittent inotropic therapy for stable end-stage HF must be distinguished from long-term, home inotropic therapy for end-stage HF. The latter group of patients is often inotrope-dependent, in that they could not be weaned from inotropes during their hospitalization. Even though long-term inotropic therapy likely will not provide clinical benefit (and even may lead to harm), withdrawal of the inotrope would result in prompt decompensation.
Dopamine. A first-line agent for CS, dopamine has dose-dependent effects. At doses less than 2.5 mcg/kg/min, dopaminergic stimulation dilates renal, cardiac, and splanchnic vessels. In the range of 2.5-5 mcg/kg/min, b1 effects predominate. When doses exceed 5-10 mcg/kg/min, both a and b1 effects occur. Finally, as dosing increases above 10 mcg/kg/min, a tone progressively increases. Dosing usually begins at 3-5 mcg/kg/min and is titrated up to 20-50 mcg/kg/min, to maintain BP. Complications include arrhythmia, extremity gangrene, and tachycardia at high doses (which increases myocardial oxygen demand and may extend ischemia).
Dobutamine. Dobutamine usually is used for acute HF with signs of poor perfusion, but systolic BP greater than 90 mHg. It is primarily a b1-agonist, with weak b2 stimulation. The net effect increases cardiac output and lowers systemic vascular resistance, with little change in BP. Started at 3-10 mcg/kg/min, dobutamine is titrated to 20-40 mcg/kg/min. Complications include arrhythmia, nausea, and headache. If there is an inadequate response to this agent alone, dopamine may be added to support BP. Dobutamine is used in the hemodynamic management of acute HF to improve myocardial contractility. It also is used in the setting of right-sided myocardial infarction when volume infusion fails to improve cardiac output.
Overall, dobutamine has the hemodynamic effects of reducing PCWP, increasing CI, producing a small dose-dependent increase in heart rate, and decreasing SVR. Dobutamine is fairly neutral in its effect on BP, and can be expected to increase only minimally the mean arterial pressures. Therefore, it may be preferred in the HF patient with borderline hypotension.
Chronic HF can result in a state of b-receptor downregulation.37 As a result, dobutamine may not exert the desired inotropic response in some patients. These patients may require the addition of milrinone (which can be used with dobutamine). In addition, patients with hypotension may require the addition of dopamine to preserve tissue perfusion.
Dobutamine is initiated at 0.5 mcg/kg/min and titrated up to the usual dosage of 2.5 to 20 mcg/kg/min. Hemodynamic monitoring during titration is required to observe the desired effect of increased CI and decreased PCWP.
Milrinone. Milrinone is a phosphodiesterase inhibitor. Inhibition of the phosphodiesterase enzyme results in an increase in intracellular levels of cyclic adenosine-monophosphate (cAMP) and calcium. Increased levels of intracellular cAMP enhances myocardial contractility and promotes peripheral vascular smooth muscle relaxation, resulting in arterial and venous vasodilation. In this regard, milrinone is considered to function as both an ionotrope and a vasodilator. Milrinone especially is effective in patients with chronic severe HF who may not respond well to dobutamine because of b-receptor downregulation.
Milrinone has a longer half-life than dobutamine and must be given as a loading dose to facilitate prompt hemodynamic effect. The typical loading dose is 50 mcg/kg given over 10 minutes, followed by a maintenance infusion at 0.375-0.750 mcg/kg/min. The loading dose can cause excessive hypotension. Milrinone is extensively renally cleared and the dose must be reduced in renal insufficiency. There is some suggestion that milrinone may have a more favorable effect on myocardial oxygen demand than dobutamine.38 Therefore, it may be preferred over dobutamine when patients require inotropic support in the setting of suspected ischemia or known severe CAD.
Patients must be monitored closely for hypotension and arrythmias. Long-term use of milrinone has been associated with an increase in mortality. Thus, the main use of milrinone is short-term treatment (usually fewer than 72 hours) of severe acute HF that has persisted despite diuretics and nitroprusside. Milrinone also is used for hemodynamic support after cardiac surgery.
Outpatient Therapy. The risk of thromboembolism in the clinically stable outpatient with HF is low, and is estimated to be 1-3% per year. It is greatest in patients with low ejection fractions.39,40 While many physicians use warfarin in HF, there is insufficient data to suggest an optimal or precise approach.18,41 However, in the absence of contraindications, patients with atrial fibrillation should be anticoagulated and should receive sufficient warfarin to maintain an international normalized ratio (INR) between 2.0 and 3.0.41 Other patient subgroups, especially those with low ejection fractions, LV dysfunction, and previous history of AMI, may be considered for long-term oral anticoagulation therapy.
There is evidence to suggest the syndrome of HF may predispose to a hypercoaguable state. Several large-scale trials are underway to determine if the use of antiplatelet and/or anticoagulant (i.e., warfarin) drugs is warranted in patients with LV dysfunction in the absence of atrial fibrillation. Most authors would give warfarin if there is significant LV dysfunction in the presence of atrial fibrillation, LV thrombus, or prior embolic event.41
Inpatient Therapy. While the majority of literature regarding deep venous thrombosis (DVT) and pulmonary embolism prophylaxis is derived from post-surgical patients, recent publications have identified specific subgroups of medical patients who also are at moderate- to high-risk for thrombotic complications.42-44 These include HF, mobile intensive care unit (MICU) admissions, and those with acute coronary syndromes. In the MEDENOX trial comparing the LMWH enoxaparin to placebo in hospitalized medical patients, administration of enoxaparin 40 mg subcutaneously once daily was shown to decrease the rate of venographically documented DVT in patients with HF by as much as 63%. In particular, restricted patients with HF are at greater risk for sustaining the morbid sequelae and complications associated with DVT. Accordingly, the threshold for empirical prevention of DVT in this patient population must be balanced against the relatively low risk of serious complications associated with anticoagulant-mediated prophylaxis. The supplement to Part I of this series discussed in detail the mandate to prevent VTED. The screening and risk-stratification algorithm is presented in this section to help clinicians identify patients who should be prophylaxed with enoxaparin. (See Insert.)
Therapeutic Approaches to Be Avoided in HF
Calcium Channel Blockers (CCBs). CCBs are not recommended routinely in HF.18,41 Short-term use may result in pulmonary edema and CS, while long-term use may increase the risk of worsening HF and death.45-48 These adverse effects have been attributed to the negative inotropic effects of CCBs. If necessary, amlodipine, which has no clear adverse effect on mortality, may be used preferentially for compelling clinical reasons (e.g., as an antianginal agent despite maximal therapy with nitrates and b-blockers).
Non-Steroidal Anti-Inflammatory Drugs. As a rule, NSAIDs should be avoided in HF.18,41 They inhibit the effects of diuretics and ACEIs, and can worsen cardiac and renal function.18 The routine use of aspirin for CAD, with concurrent ACEI treatment, is controversial. In a retrospective subset analysis of 464 HF and CAD patients on ACEIs and/or ASA, 5-year mortality was 24% with both agents. This compared to a 34% 5-year death rate if ACEIs were used alone (p=0.001).49 Further data is needed for comprehensive treatment recommendations.
Antiarrhythmics. Since patients with HF are particularly sensitive to the pro-arrhythmic and cardiodepressant effects of the commonly used antiarrhythmics, suppression of asymptomatic ventricular arrhythmias usually is unnecessary. Furthermore, their use does not prevent sudden cardiac death. If there has been resuscitation from sudden death, ventricular fibrillation, or sustained ventricular tachycardia, electrophysiologic stimulation testing, and consideration for an implantable device is warranted.18
Class I antiarrhythmics (quinidine, procainamide, flecanide, encainide) should not be used in HF, except for immediate treatment of life-threatening ventricular arrhythmias.18,41,50,51 Some class III agents (e.g., amiodarone) do not increase the risk of sudden death.52,53 Therefore, class III agents are preferred for atrial arrhythmias.18 However, due to toxicity, amiodarone is not recommended for routine use to prevent sudden death in patients already treated with mortality reducing drugs (ACEIs, b-blockers).18
Sudden Death/Ventricular Arrhythmias.
The diagnosis of HF is an important risk factor for sudden death. Ventricular arrhythmias are common in these patients, and PVCs are seen in 95% of patients with dilated cardiomyopathy. Non-sustained ventricular tachycardia occurs in 30-40%. Sudden death risk increases proportionally to ejection fraction deterioration and the severity of HF,54 and occurs in 10-40%54-56 of HF patients. Progressive pump failure is the fatal event in approximately 50%.
Since arrhythmia is common in HF, neither Holter monitoring nor electrophysiologic studies predict individuals at risk for sudden death,56 so therapy is guided by symptoms. Syncope, resuscitation after cardiac arrest, sustained ventricular tachycardia, symptomatic non-sustained ventricular tachycardia, and ventricular fibrillation suggest aggressive management. Prophylactic administration of antiarrhythmics is not effective, and may increase mortality.50
Cardiogenic Shock. Patients presenting with CS have high short-term mortality, require aggressive circulatory support, and may benefit from pulmonary artery catheterization. Hence, they require ICU admission. Furthermore, patients with CS should be evaluated for emergency revascularization to correct any potential cardiac ischemia.
Acute Pulmonary Edema. APE frequently requires ICU admission. A small subset of patients will improve greatly while still in the ED. In these, admission to a non-ICU monitored bed may be feasible, but only if nursing staffing ratios are adequate to ensure that hemodynamic monitoring is vigilant and other precipitants of APE are excluded (e.g., myocardial infarction). Because transient hypertension can result in precipitous hemodynamic instability, close monitoring is needed. (See Table 11 for ICU admission indications.)
11. Indications for Admission to Cardiac ICU
in Patients with HF
Decompensated HF. Decompensated HF patients usually require hospital admission, IV diuresis, vasodilator therapy, titration of medicines, and correction of any potentially reversible causes of their decompensation. All patients with new onset HF, evidence of myocardial ischemia, poor social support, hypoxemia, hypercarbia, concurrent infection, respiratory distress, syncope, or symptomatic hypotension should be admitted to the hospital. Patients who have mild symptoms that resolve with therapy; normal lab, x-ray, and ECG evaluation; and a strong social situation, and who are likely to comply with outpatient follow up, may be discharged from the ED. More significant symptoms, inadequate response to therapy, or a poor social situation suggest hospital admission is required.
Stable fluid-overloaded patients with a prior HF diagnosis may be admitted to a non-monitored setting or an ED observation unit. Intensive short-stay therapy has beneficial effects in the prevention of repeat visits. To realize the benefit of fewer revisits, it is important for the ED observation unit to have an HF protocol established. It should address specific therapy, as well as education and social issues.57
1. Arroliga AC. Noninvasive positive pressure ventilation in acute respiratory failure: Does it improve outcomes? Cleve Clin J Med 2001; 68:677-802.
2. Richard C, Ricome JL, Rimallho A, et al. Combined hemodynamic effects of dopamine and dobutamine in cardiogenic shock. Circulation 1983;67:620-626.
3. Mills RM, Young JB. Heart failure therapy: Not as complicated as it looks. Clin Cardiol 1999;22:339.
4. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992;327:685-691.
5. Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials. JAMA 1995;273:1445-1456.
6. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced ventricular ejection fraction and congestive heart failure. N Engl J Med 1991;325:293-302.
7. Cohn J, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:303-310.
8. The ELITE II Investigators. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: Randomized trial—The Losartan Heart Failure Study ELITE II. Lancet 2000;355:1582-1587.
9. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2001 American College of Cardiology Web site: Available at http://www.acc.org/clinical/guidelines/failure/hf_index.htm. (Accessed 3/28/2002.)
10. The NETWORK Investigators. Clinical outcome with enalapril in symptomatic chronic heart failure: A dose comparison. Eur Heart J 1998;19:481-489.
11. Ramahi TM. Expanded role for ARBs in cardiovascular and renal disease? Recent observations have far-reaching implications. Postgrad Med 2001;109:115-122.
12. Thurmann PA, Kenedi P, Schmidt A, et al. Influence of the angio-tensin II antagonist valsartan on left ventricular hypertrophy in patients with essential hypertension. Circulation 1998;98:2037-2042.
13. Opie LH, Yusuf S, Poole-Wilson PA, et al. Angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, and aldosterone antagonism. In: Opie LH (Ed). Drugs for the Heart (5th edition). Philadelphia: WB Saunders; 2001:107-153.
14. McMurray JJV. Angiotensin receptor blockers for chronic heart failure and acute myocardial infarction. Heart 2001;86:97-103.
15. The MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomized intervention trial in congestive heart failure. Lancet 1999;353:2001-2007.
16. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651-1658.
17. The Digoxin Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997; 336:525-533.
18. Packer M, Cohn JN. Consensus recommendations for the management of chronic heart failure. Am J Cardiol 1999;83:1A-38A.
19. Clinical Practice Guideline, Number 11. Heart Failure: Evaluation and care of patients with left-ventricular systolic dysfunction. U.S. Department of Health and Human Services. AHCPR publication No. 94-0612;June 1994
20. Medical Economics Staff (eds.). Bumetadine. In: Physician’s Desk Reference. Montvale, NJ: Medical Economics Co.;1998:2441-2443.
21. Le Conte P, Coutant V, N’Guyen JM, et al. Prognostic factors in acute cardiogenic pulmonary edema. Am J Emerg Med 1999;17: 329-332.
22. Peacock W, Aponte J, Craig M, et al. Predictors of unsuccessful treatment for congestive heart failure in the emergency department observation unit. Acad Emerg Med 1997;4:494.
23. The RALES Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341;709-719.
24. Stevenson LW. Tailored therapy to hemodynamic goals for advanced heart failure. Eur J Heart Fail 1999;1:251-257.
25. Fonarow GC, Stevenson LW, Steimle AE, et al. Persistently high LV filling pressures predict mortality despite angiotensin converting enzyme inhibition in advanced heart failure. Circulation 1994; 90: 1-488.
26. Colucci WS, Elkayam U, Horton DP, et al. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. Nesiritide Study Group. N Engl J Med 2000;343:246-253.
27. Marcus LS, Hart D, Packer M, et al. Hemodynamic and renal excretory effects of human brain natriuretic peptide infusion in patients with congestive heart failure. A double-blind, placebo-controlled, randomized crossover trial. Circulation 1996;94:3184-3189.
28. Abraham WT, Lowes BD, Ferguson DA, et al. Systemic hemodynamic, neurohormonal, and renal effects of a steady-state infusion of human brain natriuretic peptide in patients with hemodynamically decompensated heart failure. J Cardiac Fail 1998;4:37-44.
29. Elkayam U. Effect of short-term therapy with nesiritide. J Card Fail 2000;6(Supp.):169.
30. Peacock WF, Emerman CL, Doleh M, et al. The incidence of elevated cardiac enzymes in decompensated heart failure. Acad Emerg Med 2001;5:552.
31. Scios, Inc. Natrecor (nesiritide) package insert. Sunnyvale, CA. September 2001.
32. Roden RL, Asano K, Wichman S, et al. Inotropic effect of human B-type natriuretic peptide in the failing human heart. J Card Fail 1998;4:19.
33. Zellner C, Protter AA, Ko E, et al. Coronary vasodilator effects of BNP: Mechanisms of action in coronary conductance and resistance arteries. Am J Physiol 1999;276(3 Pt 2):H1049-H1057.
34. Packer M, Carver JR, Rodeheffer RJ, et al. For the PROMISE Study Research Group. Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med 1991;325:1468-1475.
35. Lubsen J, Just H, Hjalmarsson AC, et al. Effect of pimobendan on exercise capacity in patients with heart failure: Main results for the pimobendan in congestive heart failure (PICO) trial. Heart 1996;76: 223-231.
36. Cohn JN, Goldstein SO, Greenberg BH, et al. A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. N Engl J Med 1998;338:1810-1816.
37. Management of acute and decompensated heart failure. In: Hosenpud JD, Greenberg BH (Eds). Congestive Heart Failure (2nd edition). Philadelphia: Lippencott Williams & Wilkins; 2000:553-568.
38. Monrad ES, Baim DS, Smith HS, et al. Milrinone, dobutamine, and nitroprusside: Comparative effects on hemodynamics and myocardial energetics in patients with severe congestive heart failure. Circulation 1986;73:S168-S174.
39. Cioffi G, Pozzoli M, Forni G, et al. Systemic thromboembolism in chronic heart failure. A prospective study in 406 patients. Eur Heart J 1996;17:1381-1389.
40. Baker DW, Wright RF. Management of heart failure. IV Anticoagulation for patients with heart failure due to left ventricular systolic dysfunction. JAMA 1994;272:1614-1618.
41. Guidelines for the evaluation and management of heart failure: Report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee of Evaluation and Management of Heart Failure). Circulation 1995; 92: 2764-2784.
42. Mismetti P, Laporte-Simitsidis S, Tardy B, et al. Prevention of venous thromboembolism in internal medicine with unfractionated or low-molecular-weight heparins: A meta-analysis of randomisedclinical trials. Thromb Haemost 2000;83:14-19.
43. Shively BK. Deep venous thrombosis prophylaxis in patients with heart disease. Curr Cardiol Rep 2001;3:56-62.
44. Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest 2001;119:132S-175S.
45. Elkayam U, Weber L, McKay C, et al. Spectrum of acute hemodynamic effects of nifedipine in severe congestive heart failure. Am J Cardiol 1985;56:560-566.
46. Barjon JN, Rouleau JL, Bichet D, et al. Chronic renal and neurohumoral effects of the calcium entry blocker nisoldipine in patients with congestive heart failure. J Am Coll Cardiol 1987;9:622-630.
47. Elkayam U, Amin J, Mehra A, et al. A prospective, randomized, double-blind, crossover study to compare the efficacy and safety of chronic nifedipine therapy with that of isosorbide dinitrate and their combination in the treatment of chronic congestive heart failure. Circulation 1990;82:1954-1961.
48. Goldstein RE, Boccuzzi SJ, Cruess D, et al. Diltiazem increase late-onset congestive heart failure in post-infarction patients with early reduction in ejection fraction. The Adverse Experience Committee and the Multicenter Diltiazem Post-infarction Research Group. Circulation 1991;83:52-60.
49. Loer J, Reicher-Reiss H, Goldbourt U, et al. Aspirin and mortality in patients treated with angiotensin-converting enzyme inhibitors: A cohort study of 11,575 patients with coronary artery disease. J Am Coll Cardiol 1999;33:1920-1925.
50. The Cardiac Arrhythmia Suppression Trail (CAST) Investigators. Preliminary report: Effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989;321:406-412.
51. The Cardiac Arrhythmia Suppression Trail II Investigators. Effect of antiarrhythmic agent moricizine on survival after myocardial infarction. N Engl J Med 1992;327:227-233.
52. Doval HC, Nul DR, Grancelli HO, et al, for Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA). Randomised trial of low-dose amiodarone in severe congestive heart failure. Lancet 1994;344:493-498.
53. Singh SN, Fletcher RD, Fisher SG, et al, for the Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmias. N Engl J Med 1995;333:77-82.
54. Batsford WP, Mickleborough LL, Elefteriades JA. Ventricular arrhythmias in heart failure. Cardiol Clin 1995;13:87-91.
55. Stevenson WG, Stevenson LW, Middlekauff HR, et al. Sudden death prevention in patients with advanced ventricular dysfunction. Circulation 1993;88:2953-2961.
56. Hobbs RE, Czerska MD. Congestive heart failure. Current and future strategies to decrease mortality. Postgrad Med 1994;96: 167-172.
57. Peacock WF 4th, Albert NM. Observation unit management of heart failure. Emerg Med Clin North Am 2001;19:209-232.