Editors: Peacock, W. Frank
Title: Short Stay Management of Heart Failure, 1st Edition
Copyright ©2006 Lippincott Williams & Wilkins
> Table of Contents > 7 - Drugs that Should not be Used in the Observation Unit Management of Heart Failure: the Adverse Effects of Selected Drugs
Drugs that Should not be Used in the Observation Unit Management of Heart Failure: the Adverse Effects of Selected Drugs
Harischandra B. Karunaratne
Arti N. Bhavsar
It is estimated that approximately 1 million patients are discharged from the hospital annually with a diagnosis of chronic heart failure (HF). As the population ages, the prevalence of HF will increase significantly. The number of patients admitted to the hospital with HF continues to grow at an unprecedented rate. Eighty percent of men and 70% of women younger than 65 years diagnosed with HF will die within 8 years. Long-term survival following the diagnosis of HF has been found to be better in women than in men. However, less than 15% of women diagnosed with HF survive more than 8 to 12 years. The mortality rate in this cohort is high, with one in five patients dying within 1 year.1 Recognizing the devastating effects of various medications on the exacerbation of HF, this discussion focuses on best practices in the drug therapy management of patients with HF.
One third of all HF patients admitted to the hospital are readmitted for the same condition within 90 days. Analysis of the factors leading to this high readmission rate shows many preventable causes. Nearly 50% of readmissions are due to noncompliance either with a salt-restricted diet or with prescribed drug therapy. Sixteen percent of all hospital readmissions due to exacerbation of HF are associated with the use of inappropriate medications.2
These findings have led to the development of disease management programs based on clinical guidelines and standardized protocols designed to improve and optimize outcomes of both the in-patient and outpatient treatment of HF. These approaches use trained nurse clinicians and advanced nurse practitioners focusing on patient education during the in-patient stay. These programs also provide follow-up supervision
through telephone contact and outpatient monitoring. Close attention is paid to weight gain, adherence to a salt-free diet, appropriate adjustment of diuretic dosage, and potassium supplements. Moreover, the continuation of evidence-based care with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), and beta-blockers is maintained.
Many patients with HF are elderly with multiple comorbid conditions and require long-term follow-up. The concomitant use of medications that have the potential to precipitate or exacerbate HF or to produce life-threatening arrhythmias must be closely monitored. Often, these drugs may have been prescribed by another physician for the treatment of a comorbid chronic condition such as diabetes mellitus or may be inadvertently consumed by the patient for the temporary relief of some type of ailment, for example, an over-the-counter nonsteroidal anti-inflammatory drug (NSAID) for arthritic pain.
The “2005 Guidelines for Diagnosis and Management of Chronic Heart Failure in the Adult”3 lists three classes of drugs that can exacerbate HF and that should be avoided in these patients. These include antiarrhythmic agents, calcium channel blockers, and NSAIDs.
Table 7-1 is a comprehensive list of medications that have the potential to precipitate or worsen HF. An extensive review of the literature has been conducted. Two excellent reports, by Amabile and Spencer4 and Feenstra et al.,5 have eloquently addressed the issue of medications that exacerbate HF.
In this discussion, agents traditionally used in the treatment of acute or chronic HF that may have potentially serious side effects have been excluded. Consideration of certain other medications is beyond the scope of this discussion, including chemotherapeutic agents such as the anthracyclines, cyclophosphamide, trastuzumab (Herceptin), and paclitaxel and the immunomodulating agents interferon-alpha and -gamma and interleukin-2. In addition, the adverse cardiovascular effects of anesthetic agents and the effects of recreational drugs are not addressed.
Drug-induced exacerbation of HF may occur for varying reasons. It may take place in patients with impaired left ventricular (LV) function due to increased cardiac afterload, as a result of increased systemic vascular resistance from vasoconstriction. It may also result from a rise in preload due to fluid retention and volume expansion and the depression of cardiac contractility caused by negative inotropy of drugs. However, other factors may also play an important role in producing adverse outcomes in HF. Some of these mechanisms are summarized in Table 7-2.
Anti-inflammatory agents are the most widely used medications that exacerbate HF. These include corticosteroids, NSAIDs, and selective cyclo-oxygenase 2 inhibitors (coxibs).
TABLE 7-1 Drugs that Precipitate or Exacerbate Chronic Heart Failure
Corticosteroids are frequently used in clinical practice for the treatment of a broad array of common diseases such as asthma, chronic obstructive pulmonary disease (COPD), and multiple allergic conditions and as immunosuppressive agents in organ transplantation. Their use for these purposes in HF patients has not been specifically addressed. These drugs
often cause sodium and fluid retention, plasma volume expansion, and a loss of hypertensive control.
Elevation of blood pressure by corticosteroids appears to be mediated by a decrease in the nitric oxide–mediated vasodilatation and increased responsiveness to vasoconstrictors.6 Because of the likelihood of exacerbation of HF, patients using these drugs should be closely monitored for weight gain, diuresis, and blood pressure control. The dose and duration of a course of these drugs should be minimized, and the requirement for continuation of steroids should be frequently assessed. The use of drugs with minimal mineralocorticoid activity is also helpful.4
TABLE 7-2 Mechanisms by Which Drugs May Exacerbate Chronic Heart Failure
Nonsteroidal Anti-Inflammatory Drugs
NSAIDs act primarily through their ability to inhibit prostaglandin synthesis, by blocking cyclo-oxygenase. Renal prostaglandins play an important role in maintaining kidney perfusion in patients with HF. The use of NSAIDs, even in a single dose, may significantly reduce glomerular filtration rate, leading to sodium and water retention and plasma volume expansion.7 These agents also reduce the effectiveness of diuretics in HF.
Elderly patients who have New York Heart Association (NYHA) Class III and IV HF and have been stabilized with diuretics have an increased rate of hospitalization for worsening symptoms when given NSAIDs (other than aspirin).8 The multiple NSAIDs currently available do not appear to have any difference in their ability to exacerbate HF. Hospitalization rate for HF exacerbation appears to be highest early after the initiation of these agents.
The use of NSAIDs in patients with HF should always be avoided. Although elderly patients on large doses of loop diuretics are at greatest risk, younger individuals are likely to show exacerbation with these drugs. If the use of these agents cannot be avoided, close monitoring for the
deterioration of renal function, weight gain, dyspnea, and edema is of critical importance.
The use of acetylsalicylic acid (ASA) along with ACE inhibitors has been the focus of much research discussion.8 Results from retrospective studies appear to justify the use of ASA and ACE inhibitors when there is a clear indication for the use of ASA, as in patients with ischemic dilated cardiomyopathy. However, others have claimed that because ASA inhibits cyclo-oxygenase and prostaglandin synthesis, it may blunt the beneficial effects of ACE inhibitors. From the currently available data, the potential likelihood of reduced ACE inhibitor effectiveness does not appear to overcome the known beneficial effects of ASA, primarily in patients with ischemic heart disease.
Cyclo-Oxygenase II Inhibitors
Coxibs were originally developed to reduce an adverse effect profile in relation to reduced gastrointestinal bleeding.9 Coxibs selectively block cyclo-oxygenase 2, which accumulates at sites of inflammation. It was originally postulated that they would not interfere with prostaglandin production in the gastric mucosa or renal parenchyma or at sites of platelet aggregation. However, currently available data leave unresolved the issue that these drugs may be prothrombotic. Cox 2 appears to be present in the human kidney and its inhibition leads to fluid and sodium retention. Based on these findings, coxibs do not appear to have any advantage over the conventional NSAIDs with reference to fluid retention and the aggravation of HF.
Table 7-3 summarizes the influence of anti-inflammatory medications on the exacerbation of HF. The type of medication, mode of adverse reaction, and appropriate recommendations are presented.
Certain cardiovascular medications are known to have adverse effects in HF. These include antiarrhythmic drugs as well as some antihypertensive agents and are listed in Table 7-4.
The management of ventricular arrhythmias in patients with HF has evolved over the last decade. Empiric therapy with antiarrhythmic drugs has a limited role in the management of patients with ventricular arrhythmia and LV dysfunction. It is generally limited to the use of one agent, amiodarone, in asymptomatic patients with nonsustained ventricular tachycardia (VT) who are otherwise not candidates for electrophysiologic study and/or device therapy. Vaughn-Williams Class I and the Class III agents sotalol and ibutilide should not be used to treat ventricular arrhythmias in patients with LV dysfunction because of their proarrhythmic and negative inotropic activity. Electrophysiology (EP) study–guided
antiarrhythmic and/or device therapy is now the standard of care in this cohort of patients.3
TABLE 7-3 Anti-Inflammatory Medications That Exacerbate Chronic Heart Failure
Drug therapy in patients with atrial fibrillation (AF) complicating HF represents a more difficult problem. Approximately 20% to 30% of patients with AF also have a history of HF. The age-adjusted odds ratio for AF in patients with HF is 6:8. In the Stroke Prevention in Atrial Fibrillation (SPAF) study, a post hoc analysis showed an increased incidence of cardiac death in patients with HF and AF who were treated with antiarrhythmic agents.10 Although sometimes used for AF, Class I antiarrhythmic agents, including quinidine, procainamide, disopyramide, flecainide, and propafenone, are negatively inotropic to varying degrees and have proarrhythmic potential. They should not be used in the treatment of AF associated with HF and/or LV dysfunction.
TABLE 7-4 Cardiovascular Medications That May Exacerbate Chronic Heart Failure
The Class III agent sotalol, a mixture of the D and L isomers, is often used to maintain sinus rhythm once AF patients have been converted to normal sinus rhythm.11 Its use in patients with LV dysfunction and concomitant HF is not recommended because of reports of a higher likelihood of the occurrence of polymorphic VT (torsades de pointes). A clinical trial using only the D-isomer of sotalol (D-sotalol), a drug that has only Class III arrhythmic properties and no significant beta-blocking effect, showed an increased mortality risk in patients with ejection fraction less than 40%.12
Ibutilide, a Class III antiarrhythmic agent, is often used as an initial intravenous infusion over a 10-minute period for restoration of sinus rhythm
in patients with AF. In one placebo-controlled double-blind randomized clinical trial, Ellenbogen et al.13 reported that 6 of 197 patients (3.0%) developed VT. All 6 patients had LV systolic dysfunction. Based on these findings, ibutilide should not be used for arrhythmia conversion in patients presenting with both AF and HF. Two other Class III agents, amiodarone and dofetilide, are the only antiarrhythmic agents that can be administered safely to maintain sinus rhythm in patients with AF and LV systolic dysfunction.
The “2005 Guidelines for Diagnosis and Management of Chronic Heart Failure in the Adult”3 classifies HF into four stages: A, B, C, and D. Stage A HF comprises patients at high risk but without structural heart disease and symptoms. One of the most important subgroups in Stage A includes patients with hypertension (HTN). Antihypertensive therapy in these patients prevents worsening the progression of HF from Stage A to asymptomatic LV dysfunction.
Recent studies have suggested that certain drugs that are effective antihypertensive agents and can be safe in patients with Stage A HF may actually worsen or aggravate the condition when used in Stage B and beyond. The alpha-adrenergic blocking agent prazosin is an effective vasodilator and antihypertensive. However, it was found to be no better than placebo in the V-heft I study.14 In the ALLHAT study, the alpha-blocker doxazosin was associated with an increased risk of developing HF.15 As a result, this drug was withdrawn from the study prematurely.
In the recently published “2005 Guidelines for Diagnosis and Management of Chronic Heart Failure in the Adult”3 update, alpha-blockers, although not specifically contraindicated, are not among the antihypertensive medications listed as useful in the treatment of various stages of HF. They do still fill a role in the treatment of symptomatic benign prostatic hypertrophy. The use of alpha-blockers in patients with HF for such purposes should be discouraged and minimized, because adverse effects such as orthostatic hypotension may frequently occur in these patients.
Calcium Channel Blockers
The nondihydropyridine calcium channel blockers verapamil and diltiazem have both negative chronotropic and negative inotropic effects. They have been demonstrated to be associated with deteriorating HF when used in patients with LV dysfunction. Although diltiazem is less negatively inotropic and chronotropic than verapamil, the use of both of these agents as antihypertensive therapy in patients with LV dysfunction and HF is not recommended.
Diltiazem is often used in combination with beta-blockers and digoxin when a rate control strategy is used in patients with AF. When patients with LV dysfunction are managed by rate control, the use of beta-blockers and digoxin is preferred to diltiazem alone or in combination.
Admittedly, in certain patients the benefit of effective rate control with combination therapy (beta-blockers, digoxin) may be great enough to permit the use of diltiazem along with these drugs, even in patients with LV dysfunction. Limiting diltiazem to the smallest effective dose is recommended in such situations. Alternative rate control strategies such as atrioventricular nodal ablation and pacing should also be considered.
Dihydropyridine calcium channel blockers do not have significant negative chronotropy. The two long-acting dihydropyridine calcium channel blockers amlodipine and felodipine have not shown any adverse outcomes in patients with HF. In a study conducted with amlodipine, a group of patients with nonischemic dilated cardiomyopathy did show modest benefits.16
On the other hand, the calcium channel blockers nifedipine, nisoldipine, and isradipine have demonstrated clinical deterioration and increased hospitalization in HF and are therefore contraindicated in these patients. They appear to produce this effect by their negative inotropic activity and detrimental activation of the renin-angiotensin axis and sympathoadrenal system. Consequently, if calcium channel blockers must be used, the preferred choice is amlodipine or felodipine.
Minoxidil is a potent arterial vasodilator. It causes a significant drop in blood pressure for hypertensive patients through its reduction of systemic vascular resistance by direct smooth muscle relaxation. The drug causes extensive fluid retention and edema formation. Increasing doses of loop diuretics may be required in NYHA Class III or IV HF patients. It is best to avoid the use of this agent for this group of patients.
Cardiovascular Agents Used in the Treatment of Peripheral Vascular Disease
Cilastazol (Pletal) is an agent that is used for treatment of intermittent claudication in patients with peripheral vascular disease. It is a phosphodiesterase III inhibitor and has been shown to increase heart rate, the frequency of premature ventricular contractions, and nonsustained VT. Adverse outcomes have been reported in patients with HF who have been treated with other oral phosphodiesterase inhibitors, such as oral amrinone or milrinone. Therefore, the use of cilostazol in patients with HF is not recommended.
Metformin is a biguanide used in the treatment of type II diabetes, either alone or in combination with other oral agents. It acts by decreasing hepatic glucose production. It is most useful in the treatment of overweight diabetics. A small number of patients taking the drug, 0.03 cases per 1,000 patients, develop lactic acidosis, which increases the risk of mortality by
50%. Metformin is renally eliminated and hence the risk of lactic acidosis is highest in patients with renal insufficiency. In a study of 47 patients with metformin-related lactic acidosis, 38% had HF.17 Consequently, metformin should not be used in patients with NYHA Class III or IV HF and diabetes.
As many as 12% of patients with type II diabetes have HF. The thiazolidinediones (TZDs) rosiglitazone and pioglitazone are used alone or in combination to treat type II diabetes. An estimated 2% to 5% of patients on monotherapy with these drugs and 5% to 15% of patients receiving concomitant insulin therapy will develop peripheral edema and weight gain. A recent study showed that these agents increase intravascular volume by 6% to 7%.18 Development of HF and pulmonary edema as early as 3 days and as late as 13 months after initiating treatment with TZD has been described.19 The mechanism of fluid retention is currently unknown. However, it responds better to drug withdrawal than to diuretic therapy.
No direct adverse effect of TZD on cardiac function has been reported. Moreover, fluid retention appears to be independent of cardiac function. There is also a considerable body of knowledge that suggests that TZDs may have significant positive effects on cardiac function, including reduced vascular resistance, improved cardiac metabolism, and coronary vasodilation. If TZDs are used in patients with diabetes, careful monitoring for new or aggravated HF is essential. This group of drugs should be avoided in NYHA Class III or IV HF.
Table 7-5 summarizes the influence of diabetes medications on the exacerbation of HF. The type of medication, mode of adverse reaction, and appropriate recommendations are presented.
Neurologic and Psychiatric Medications
Amphetamines have been used to treat narcolepsy. However, more recently, they have been used in children and adults for the treatment of attention deficit hyperactivity disorder. These agents release norepinephrine, which stimulates both alpha and beta receptors, thereby increasing blood pressure and heart rate. Because sympathetic activation can promote arrhythmia in patients with HF, these drugs should be avoided in patients with HF.
Traditionally, these agents have been used to treat depression and insomnia. However, with the advent of selective serotonin reuptake inhibitors, they are now more frequently used to treat migraine and neuropathic pain. These
medications have a known proarrhythmic potential and have always been used with caution in patients with heart disease. Anecdotal case reports have also indicated a potential but rare risk of developing cardiomyopathy and HF.5 The use of these agents should be avoided in patients with HF.
TABLE 7-5 Diabetes Medications That Exacerbate Chronic Heart Failure
Table 7-6 summarizes the influence of neurologic and psychiatric medications on the exacerbation of HF. The type of medication, mode of adverse reaction, and appropriate recommendations are presented.
Herbal medications are widely used in this country. It is estimated that in the United States 3% of English-speaking adults and a much larger number of non–English-speaking adults take herbal medications. Despite the widespread use of herbal remedies, very little is known about the safety, quality control, or efficacy of these agents.
The use of digitalis preparations, derived from the foxglove plant to treat HF, date back more than 200 years. Adverse effects resulting from toxicity with this drug, including ventricular arrhythmias and heart block, are well recognized. However, owing to the lack of published data, little is known about the adverse effects of other herbal remedies on HF.
TABLE 7-6 Neurologic and Psychiatric Medications That Exacerbate Chronic Heart Failure
Ephedra or Ma Huang has been used in Chinese medicine for thousands of years. Ephedra contains several alkaloids, including ephedrine and pseudoephedrine, all of which are sympathomimetic and directly or indirectly increase heart rate, cardiac output, blood pressure, and peripheral vascular resistance.20 Ephedra has been used in the treatment of asthma and in narcolepsy to stimulate the central nervous system as well as for depressive states. Recently, ephedra has been marketed for weight loss and performance enhancement in a wide range of over-the-counter products. In February 2004, the U.S. Food and Drug Administration banned the use of ephedra-containing products citing, among others, its ability to increase mortality due to HF and sudden death in patients with chronic HF and coronary artery disease.21
Licorice is derived from the roots of a plant, Glycyrrhiza glabra, and is often used as a candy and in the treatment of dyspeptic symptoms. The active agent is similar to carbenoxalonesodium and causes fluid retention, hypokalemia, and HTN and exacerbates HF.10 It also appears to enhance aldosterone activity. It should not be used in patients with HF.
In patients with HF, attention must be directed to the high sodium content of some medications. For example, the excessive use of sodium-containing antacids may exacerbate HF. In conditions such as bacterial endocarditis, large doses of intravenous antibiotics with a high sodium content may also precipitate HF. Clearly, every effort must be made to treat HF patients with agents that have a reduced sodium content.
The medical management of patients presenting with HF represents a significant challenge. Hospitalizations are continuing to increase at an unprecedented rate in this cohort of patients. Many of these hospitalizations can be attributed to the exacerbation of preexisting HF. Dietary indiscretion, noncompliance with prescribed drug therapy, and the use of inappropriate medications are frequently found to be major factors responsible for HF patient cardiac decompensation.
Several drugs that exacerbate HF are often used in the treatment of comorbid conditions commonly found in an aging population. This includes arthritis, diabetes, HTN, and AF. An awareness of the possible adverse reactions of drugs used to treat these common comorbid conditions is essential in making rational therapeutic decisions for HF patients.
1. American Heart Association. Heart disease and stroke statistics—2005 update. Dallas, TX: American Heart Association, 2005.
2. Aghababian RV. Acutely decompensated heart failure: opportunities to improve care and outcomes in the emergency department. Rev Cardiovasc Med 2002;3[Suppl 4]: S3–9.
3. Hunt SA, American College of Cardiology, American Heart Association Task Force on Practice Guidelines (Writing Committee to update the 2001 Guidelines for the Evaluation and Management of Heart Failure). ACC/AHA 2005 Guideline update for the diagnosis 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 (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol 2005;46:e1–e82.
4. Amabile CM, Spencer AP. Keeping your patient with heart failure safe: a review of potentially dangerous medications. Arch Intern Med 2004;164:709–720.
5. Feenstra J, Grobbee DE, Remme WJ, Stricker BH. Drug-induced heart failure. J Am Coll Cardiol 1999;33:1152–1162.
6. Worth JA, Schyvens CG, Zhang Y, et al. The nitric oxide system in glucocorticoid-induced hypertension. J Hypertens 2002;20:1035–1043.
7. Feenstra J, Heerdingk ER, Grobbee DE, Stricker BHCh. Association of nonsteroidal anti-inflammatory drugs with first occurrence of heart failure: The Rotterdam Study. Arch Intern Med 2002;162:265–270.
8. Page J, Henry D. Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an underrecognized public health problem. Arch Intern Med 2000;160:777–784.
9. Whelton A, Fort JG, Puma JA, et al. Cyclooxygenase-2–specific inhibitors and cardiorenal function: a randomized, controlled trial of celecoxib and rofecoxib in older hypertensive osteoarthritis patients. Am J Ther 2001;8:85–95.
10. Flaker GC, Blackshear JL, McBride R, et al. Antiarrhythmic drug therapy and cardiac mortality in atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators. J Am Coll Cardiol 1992;20:527–532.
11. Antonaccio MJ, Gomoll A. Pharmacologic basis of the antiarrhythmic and hemodynamic effects of sotalol. Am J Cardiol 1993;72:27A–37A.
12. Waldo AL, Camm AJ, deRuyter H, et al. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction: The SWORD Investigators. Survival With Oral d-Sotalol. Lancet 1996;348:7–12.
13. Ellenbogen KA, Stambler BS, Wood MA, et al. Efficacy of intravenous ibutilide for rapid termination of atrial fibrillation and atrial flutter: a dose-response study. J Am Coll Cardiol 1996;28:130–136.
14. Cohn JN, Archibald DG, Ziesche S. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med 1986;314:1547–1552.
15. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2000;283:1967–1975.
16. Packer M, O'Connor CM, Ghali JK, et al. Effects of amlodipine on morbidity and mortality in severe chronic heart failure: Prospective Randomized Amlodipine Survival Evaluation Study Group. N Engl J Med 1996;335:1107–1114.
17. Misbin RI. The phantom of lactic acidosis due to metformin in patients with diabetes. Diabetes Care 2004;27:1791–1793.
18. Kennedy FP. Do thiazolidinediones cause congestive heart failure? Mayo Clin Proc 2003;78:1076–1077.
19. Kermani A, Garg A. Thiazolidinedione-associated congestive heart failure and pulmonary edema. Mayo Clin Proc 2003;78:1088–1091.
20. Dhar R, Stout CW, Link MS, et al. Cardiovascular toxicities of performance-enhancing substances in sports. Mayo Clin Proc 2005;80:1305–1315.
21. FDA News P04-17. (February 6, 2004). FDA issues regulation prohibiting sale of dietary supplements containing ephedrine alkaloids and reiterates its advice that consumers stop using these products. Available at http://www.fda.gov/bbs/topics/NEWS/2004/ NEW01021.html (accessed October 13, 2005).