Cardiac glycosides are used principally in the prophylactic management and treatment of heart failure and to control the ventricular rate in patients with atrial fibrillation.
Digoxin is the most commonly used cardiac glycoside, principally because it may be administered by various routes, has an intermediate duration of action, and has been extensively studied in patients with or without renal insufficiency. Some clinicians believe that digitoxin is the cardiac glycoside of choice in patients with renal failure because elimination half-life is unchanged in these patients; however, digitoxin is no longer commercially available in the US. Use of digoxin for maintenance therapy has replaced digitalis because the latter is standardized biologically and not by glycoside content.
Cardiac glycosides are used, usually in conjunction with other agents, in the management of symptomatic heart failure associated with left ventricular systolic dysfunction. Current guidelines for the management of heart failure in adults generally recommend inhibition of the renin-angiotensin-aldosterone system with a combination of drug therapies, including neurohormonal antagonists (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-adrenergic blocking agents (β-blockers), aldosterone receptor antagonists) to inhibit the detrimental compensatory mechanisms in heart failure and reduce morbidity and mortality. ( and .) Additional agents (e.g., cardiac glycosides, diuretics, sinoatrial modulators [i.e., ivabradine]) added to a heart failure treatment regimen in selected patients have been associated with symptomatic improvement of heart failure and/or reduction in heart failure-related hospitalizations. Cardiac glycoside therapy may be initiated in the early development of heart failure in patients who have started but not yet responded symptomatically to an ACE inhibitor or a β-blocker. Alternatively, cardiac glycosides may be withheld until the patient's symptomatic response to the ACE inhibitor or β-blocker has been defined and then used only in those patients who remain symptomatic while receiving ACE inhibitor or β-blocker therapy. In patients with heart failure who are receiving a cardiac glycoside without an ACE inhibitor or β-blocker, the cardiac glycoside should not be withdrawn, but appropriate therapy with an ACE inhibitor and/or a β-blocker should be added. The beneficial effects of cardiac glycosides have been shown to be additive with those of ACE inhibitors and/or diuretics; symptomatic and functional deterioration can occur when cardiac glycosides are withdrawn from patients whose failure was stabilized on a regimen of combined therapy. Use of cardiac glycosides is not recommended in patients with asymptomatic left ventricular systolic dysfunction (New York Heart Association [NYHA] heart failure functional class I) since such patients should only receive treatment to prevent progression of heart failure and cardiac glycosides have not been shown to have demonstrable effect on such progression when used in symptomatic patients.
In patients with heart failure, cardiac glycosides may alleviate symptoms and decrease heart failure-related hospitalizations. Although data demonstrating an overall survival benefit of cardiac glycosides are lacking, a large, controlled study (the Digitalis Investigation Group [DIG] study) showed reductions in hospitalization rates, both overall and for worsening heart failure, as well as a reduction in the combined incidence of death from worsening heart failure and hospitalization for such worsening, when a cardiac glycoside (digoxin) was added to a regimen of ACE inhibitors and/or diuretics in patients with normal sinus rhythm and chronic left ventricular heart failure (principally mild to moderate). The decision to use a cardiac glycoside in patients with symptomatic heart failure caused by systolic left ventricular dysfunction should be based not on an anticipated improvement in survival but on potential benefits of less deterioration of the condition and associated improvement in hospitalization rates as well as of improved symptomatic and functional status.
Cardiac glycosides increase cardiac output resulting in diuresis and relief of the symptoms of right-sided heart failure caused by systemic venous congestion (e.g., peripheral edema) and the symptoms of left-sided heart failure caused by pulmonary congestion (e.g., dyspnea, orthopnea, and paroxysmal nocturnal dyspnea). Cardiac glycosides increase left ventricular ejection fraction and improve symptoms of heart failure (as evidenced by exercise capacity, heart failure-related hospitalizations and emergency care), while having no apparent effect on overall mortality. The acute and sustained hemodynamic efficacy of cardiac glycosides is well established, at least in patients with symptomatic heart failure caused by predominant systolic ventricular dysfunction, and the drugs can provide symptomatic and functional improvement. However, some clinicians state that cardiac glycosides generally are not indicated for the stabilization of patients with acutely decompensated heart failure requiring IV inotropic therapy, unless they have rapid atrial fibrillation. Cardiac glycoside therapy may be initiated in these patients in an effort to establish a long-term treatment strategy.
Cardiac glycosides generally are most effective in the management of low-output failure secondary to hypertension, coronary artery or atherosclerotic heart disease, primary myocardial disease, nonobstructive cardiomyopathies, and valvular heart disease. The drugs are less effective in high-output failure caused by bronchopulmonary insufficiency, infection, hyperthyroidism, anemia, fever, arteriovenous fistula, thiamine deficiency, or Paget's disease and heart failure precipitated by complete AV block, cor pulmonale, acute glomerulonephritis, or toxic or infectious myocarditis (e.g., diphtheria, acute rheumatic fever). Heart failure resulting from hypermetabolic or hyperdynamic states (e.g., hyperthyroidism, hypoxia, arteriovenous shunt) is best treated by addressing the underlying condition rather than by using cardiac glycosides. Cardiac glycosides are of limited value in the management of heart failure caused by mechanical disturbances such as constrictive pericarditis, pericardial tamponade, mitral stenosis with normal sinus rhythm, and pure valvular aortic stenosis. Patients with idiopathic hypertrophic subaortic stenosis receiving cardiac glycosides may have a worsening of outflow obstruction as a result of the inotropic effects of the drugs. Cardiac glycosides should be used concomitantly with other drugs or measures to correct the underlying cause of the heart failure, if possible; the glycoside should be continued after failure is corrected unless the underlying cause has been corrected.
Digoxin is used for controlling rapid ventricular rate in patients with atrial fibrillation; however, the drug usually is not considered first-line therapy for this use, in part because of its slow onset of action. Experts recommend the use of β-blockers or nondihydropyridine calcium-channel blocking agents (e.g., diltiazem, verapamil) as the preferred drugs for ventricular rate control in patients with atrial fibrillation. Digoxin may be used in combination with one of these agents to improve heart rate control during exercise and also may be useful in patients with concomitant heart failure. Choice of therapy should be individualized based on the clinical situation and patient-related factors. Digoxin should not be used in patients with preexcited atrial fibrillation because the drug may increase ventricular response and result in ventricular fibrillation.
Other Supraventricular Tachycardias
Cardiac glycosides are used in the management of paroxysmal supraventricular tachycardia (PSVT) due to AV nodal reentry tachycardia (AVNRT) or AV reentry tachycardia (AVRT). Although cardiac glycosides (e.g., digoxin) are not as effective in the treatment of PSVT as they are in the treatment of chronic atrial fibrillation, some experts state that use of oral digoxin may be reasonable for ongoing management of PSVT in patients who are not candidates for, or prefer not to undergo, catheter ablation. Because of the potential for adverse effects, use of digoxin generally is reserved for patients who fail or cannot take preferred therapies (e.g., β-adrenergic blocking agents, nondihydropyridine calcium-channel blocking agents, flecainide, propafenone). If acute treatment of PSVT is necessary, however, measures to increase vagal tone (such as carotid sinus massage and Valsalva maneuver) or administration of adenosine are the treatments of choice. Cardiac glycosides should not be used for the management of chaotic (multifocal) atrial tachycardia.
Digoxin has been used in the management of regular supraventricular (reciprocating) tachycardia associated with Wolff-Parkinson-White (WPW) syndrome, but the drug may be potentially harmful if used in patients with preexcited atrial fibrillation because acceleration of the ventricular rate may occur. Digoxin should not be administered to patients with WPW syndrome and preexcited atrial fibrillation. The preferred treatment of choice in hemodynamically compromised patients with WPW syndrome usually is prompt direct-current cardioversion.
Use of cardiac glycosides in acute myocardial infarction is controversial.
(See Cautions: Precautions and Contraindications.)Most clinicians believe that mild left ventricular dysfunction after acute myocardial infarction should be treated with modest diuresis (e.g., with a parenteral loop diuretic) and afterload and preload reduction (e.g., with parenteral nitroglycerin); institution of ACE inhibitor therapy also may be appropriate. The precise role of cardiac glycosides is less clear. Empiric information from observational studies has shown equivocal results with cardiac glycosides in terms of mortality, and concern about increased mortality associated with long-term milrinone therapy has prompted reexamination of this empiric information. Although a recent large, controlled study (the Digitalis Investigation Group [DIG]) in patients with normal sinus rhythm and chronic heart failure (principally mild to moderate) showed no reduction in total mortality when a cardiac glycoside (digoxin) was added to a regimen of ACE inhibitors and/or diuretics, reductions in hospitalization rates both overall and for worsening heart failure, as well as in the combined incidence of death from worsening heart failure and hospitalization for such worsening, were observed in cardiac glycoside-treated patients. In addition, other recent studies have shown that cardiac glycoside therapy can improve symptomatic and functional status and favorably affect the neurohormonal system in patients with definite systolic left ventricular dysfunction and sinus rhythm who are receiving diuretics and/or ACE inhibitors. Therefore, because of this and other evidence of potential beneficial effects of cardiac glycosides on morbidity, the drugs can be used selectively in patients recovering from an acute myocardial infarction, generally reserving their use for patients with a supraventricular arrhythmia and for those with systolic left ventricular heart failure that is refractory to first-line agents.
Cardiac glycosides are effective in the treatment of persistent supraventricular tachyarrhythmias in patients with acute myocardial infarction. Rapid digitalization can be used to slow a rapid ventricular response and improve left ventricular function in patients with supraventricular tachyarrhythmias, especially in those with atrial fibrillation. Atrial fibrillation following acute myocardial infarction most often occurs within the initial 24 hours postinfarction and usually is transient but may recur. The incidence of atrial fibrillation and flutter appears to be decreased in patients receiving thrombolytic therapy for acute myocardial infarction. Cardiac glycosides may be particularly useful for slowing a rapid ventricular response in patients with coexisting left ventricular dysfunction. For patients without clinical evidence of left ventricular dysfunction and in whom there are no other risks of β-blockade (e.g., bronchospastic disease, AV block), an IV β-blocker (e.g., atenolol, metoprolol) can be used as an alternative to a cardiac glycoside to slow a rapid ventricular response.
Cardiac glycosides have been used in the treatment of cardiogenic shock; however, most clinicians consider these drugs to have little benefit in this situation because they have a positive inotropic effect only on the noninfarcted part of the ventricle and do not increase cardiac output. In patients with cardiogenic shock and atrial fibrillation or flutter with rapid ventricular rate, cardiac glycosides are used to improve left ventricular function.
Cardiac glycosides may be useful, especially in conjunction with a β-blocker, in the treatment of angina pectoris in patients with cardiomegaly and heart failure; however, cardiac glycosides alone are not beneficial in the treatment of angina pectoris in patients without cardiomegaly and heart failure.