Drugs That Should Be Avoided or Used With Caution in Patients With Heart Failure - UpToDate

Drugs that should be avoided or used with caution in patients with heart failure - UpToDate 05/08/20 16.
34
Official reprint from UpToDate®

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Drugs that should be avoided or used with caution in

patients with heart failure
Author: Wilson S Colucci, MD
Section Editor: Stephen S Gottlieb, MD
Deputy Editor: Susan B Yeon, MD, JD, FACC
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2020. | This topic last updated: Oct 09, 2019.
INTRODUCTION
A number of medications that are in common clinical use are relatively or absolutely
contraindicated in patients with heart failure (HF), either because they can cause exacerbations
of HF or because there is a higher risk of adverse reactions in such patients (table 1) [1]. Drug-
induced exacerbation or decompensation of established HF is a relatively common occurrence.
Its prevention requires frequent reassessment and meticulous management of often complex
medication regimens.
Utilization of drugs that can exacerbate HF is common in patients with HF. In a study from
Denmark, 34 percent of patients received at least one nonsteroid anti-inflammatory agent or
cyclooxygenase-2 inhibitor after discharge for first hospitalization for HF [2]. Use of some of
these drugs may be increasing. As an example, a review of Medicare beneficiaries hospitalized
with the diagnoses of HF and diabetes mellitus found that the proportion using metformin and/or
a thiazolidinedione increased from 13.5 percent in 1998 to 1999 to 24.4 percent in 2000 to 2001
[3].
Management of patients with HF is discussed separately. (See "Treatment and prognosis of

heart failure with preserved ejection fraction".)
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Drugs that should be avoided or used with caution in patients with heart failure - UpToDate 05/08/20 16.34
GENERAL PRINCIPLES
General principles for avoiding drug-induced worsening of HF include the following:
● Recognition of the basic mechanisms by which drugs can exacerbate HF including:
• Sodium retention
• Negative inotropic effect
• Direct cardiotoxicity
● Identification of significant drug interactions among medications used to treat HF and

concomitant diseases. A complete and updated list of medications including prescription or
nonprescription vitamins, supplements, and remedies should be obtained at each
encounter. Common HF drugs often affected by pharmacokinetic drug interactions include:
digoxin, amiodarone, warfarin, and beta-blockers (via CYP 2D6 metabolism).
Examples of significant pharmacodynamic interactions that may occur in patients with HF

include: combinations of drugs increasing the risk of hyperkalemia (eg, angiotensin
converting enzyme inhibitor plus potassium supplement), digoxin with hypokalemia
increasing the risk of digoxin-induced arrhythmias, QTc-prolonging drugs and electrolyte
disturbances increasing the risk of torsades de pointes, and the combination of drugs
prescribed for HF (eg, angiotensin converting enzyme inhibitor and beta blocker) with other
drugs with blood pressure-lowering effects (eg, alpha-1-blockers) increasing the risk of
hypotension. (See 'Drugs that may cause hyperkalemia' below.)
● Awareness that drug absorption, distribution, and clearance can be significantly altered
during acute overload state which may cause gut edema, hepatic congestion, and/or renal
insufficiency.
For example, warfarin dose requirement is generally much lower in an acute exacerbation
versus chronic stable HF. Digoxin clearance may decrease, and a trough should be
checked during acute HF exacerbation to monitor for risk of toxicity.
● Surveillance for drug effects that are altered as chronic HF progresses. For example, the
volume of distribution tends to decrease for certain HF drugs (eg, digoxin) as HF advances
as well as with aging or renal failure. Lower load and maintenance dosing may be required
to avoid an increase in risk of drug toxicity.
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● Monitoring HF management involving frequent assessment and adjustment of several

drugs with similar pharmacodynamic effects.
● Patients should receive education about the drugs they are prescribed. They should also
receive information about drugs that should be avoided including nonprescription
medications, alternative treatments, and dietary supplements.
Consultation with a clinical pharmacist with cardiovascular expertise may be valuable in some
instances.
DRUGS
Some drugs and classes of drugs that may cause or exacerbate HF are discussed here. A 2016
American Heart Association Scientific Statement on drugs that may cause or exacerbate HF
provides an extensive tabulation of drugs of concern [4].
Nonsteroidal anti-inflammatory drugs — Nonsteroidal anti-inflammatory drug (NSAID) use

(nonselective or cyclooxygenase [COX]-2 selective [coxibs]) is associated with increased risk of
first occurrence or exacerbation of HF. NSAID use is also associated with increased risk of renal
dysfunction and hyperkalemia and impairment of responses to angiotensin converting enzyme
(ACE) inhibitors and diuretics. Observational data in patients with HF indicated an association
between NSAID (nonselective or coxibs) use and increased mortality. These issues are
discussed in detail separately. (See "NSAIDs: Adverse cardiovascular effects", section on
'NSAIDs and heart failure'.)
Aspirin — While patients with HF and vascular disease (including coronary disease) and/or
cardiovascular risk factors may have indications for aspirin use, the risks and benefits of aspirin
in patients with HF but without other indications are not well established. Aspirin use in patients
with HF is discussed separately. (See "Antithrombotic therapy in patients with heart failure".)
Calcium channel blockers — Some initial studies suggested a possible deleterious effect of
calcium channel blockers in patients with HF with reduced ejection fraction (HFrEF), while later
trials with the vasoselective calcium channel blocker amlodipine showed a neutral effect on
morbidity and mortality [5,6]. Thus, although there is NO direct role for calcium channel blockers
in the management of HFrEF, amlodipine appears to be safe in patients with HF and can be
used if treatment with a calcium channel blocker is necessary for another indication, such as
angina or hypertension. (See "Calcium channel blockers in heart failure with reduced ejection
fraction".)
Drugs that may cause hyperkalemia — Patients with HFrEF are treated with drugs that raise
serum potassium levels (eg, inhibitors of the renin-angiotensin-aldosterone system such as
ACE inhibitor, angiotensin II receptor blocker [ARB], or sacubitril/neprilysin and
mineralocorticoid receptor antagonist [MRA]). Monitoring of serum potassium levels is
recommended for patients taking one or more of these inhibitors of the renin-angiotensin-
aldosterone system, and additional monitoring is recommended after an MRA is added to an
ACE inhibitor or an ARB. Routine use of the combination of an ACE inhibitor and an ARB is
potentially harmful and should be avoided. Likewise, sacubitril/neprilysin should never be taken
with and ACE inhibitor. (See "Initial pharmacologic therapy of heart failure with reduced ejection
fraction in adults" and "Secondary pharmacologic therapy in heart failure with reduced ejection
fraction (HFrEF) in adults".)
For patients taking an ACE inhibitor or ARB and/or MRA, potassium supplements should be
used only as needed (eg, if required to offset potassium wasting caused by loop diuretic
therapy), and potassium sparing diuretics such as amiloride and triamterene should generally
be avoided.
Trimethoprim-sulfamethoxazole — In patients taking an ACE inhibitor, ARB, or MRA,

trimethoprim-sulfamethoxazole (TMP-SMX) should be avoided or used with caution with careful
monitoring. An elevated risk of hyperkalemia and acute kidney injury has been observed in
patients treated with ACE inhibitor plus TMP-SMX [7], and an elevated risk of hyperkalemia has
been observed in patients treated with MRA plus TMP-SMX [8,9]. In addition, an increased risk
of sudden death has been observed in patients treated with ACE inhibitor or ARB plus TMP-
SMX [10] or spironolactone plus TMP-SMX [11], although a causal relationship has not been
established.
Antidepressants — Depression is common in patients with HF and is associated with worse

outcomes, including increased mortality rates. While concern has been raised that certain
antidepressants, particularly tricyclic antidepressants (TCAs), may cause adverse
cardiovascular effects, an analysis found that depression rather than antidepressant use was
independently associated with worse outcomes. (See "Predictors of survival in heart failure with
reduced ejection fraction".)
Limited data are available on the safety and efficacy of antidepressants in patients with HF. A
review of randomized controlled trials found that TCAs and selective serotonin reuptake
inhibitors were associated with similar rates of major adverse cardiovascular events (such as
HF, myocardial infarction, stroke, or cardiovascular death) [12]. However, other cardiovascular
side effects (particularly palpitations) were more common among patients taking TCAs.
Oral hypoglycemic agents — The oral hypoglycemic agents thiazolidinediones and metformin
pose particular risks in patients with HF.
Thiazolidinediones — Thiazolidinediones cause fluid retention, which may precipitate HF.

This issue is discussed in detail separately. (See "Thiazolidinediones in the treatment of type 2
diabetes mellitus", section on 'Cardiovascular effects'.)
Metformin — Patients with HF who take metformin are at increased risk of potentially lethal
lactic acidosis as discussed separately. (See "Metformin in the treatment of adults with type 2
diabetes mellitus", section on 'Lactic acidosis'.)
Phosphodiesterase inhibitors — Concerns have been raised about the safety of

phosphodiesterase-3 (PDE-3), and phosphodiesterase-5 (PDE-5) inhibitors in patients with HF.
Cilostazol and anagrelide should be avoided in patients with HF.
PDE-3 inhibitors — In patients with HFrEF, the chronic use of oral PDE-3 inhibitors for
inotropic therapy was associated with increased mortality compared with placebo [13]. (See
"Inotropic agents in heart failure with reduced ejection fraction", section on 'Intravenous
phosphodiesterase-3 inhibitors'.)
Cilostazol is a PDE-3 inhibitor approved by the United States Food and Drug Administration
(FDA) for the treatment of intermittent claudication. While it is not established that cilostazol
impacts mortality in patients with HF, the FDA regards HF of any severity as a contraindication
to the use of cilostazol [14]. (See "Inotropic agents in heart failure with reduced ejection
fraction", section on 'Intravenous phosphodiesterase-3 inhibitors' and "Management of
claudication due to peripheral artery disease", section on 'Cilostazol'.)
Anagrelide is a PDE-3 inhibitor used in the treatment of proliferative hematologic disorders such
as essential thrombocythemia and polycythemia vera. (See "Prognosis and treatment of
essential thrombocythemia" and "Prognosis and treatment of polycythemia vera".)
Anagrelide has positive inotropic and vasodilatory effects. The development of fluid retention,
and less commonly HF with or without development of cardiomyopathy, has been reported with
its use, although controlled data are lacking. It may also cause high-output HF. Anagrelide use
should be avoided in patients with HF. (See "Prognosis and treatment of essential
thrombocythemia", section on 'Anagrelide'.)
PDE-5 inhibitors — PDE-5 inhibitors, such as sildenafil, vardenafil, and tadalafil, are widely
used in the treatment of erectile dysfunction in men. These drugs are vasodilators that can
lower pulmonary and systemic arterial pressure.
The use of PDE-5 inhibitors with any form of nitrate therapy (regular or intermittent) is
contraindicated. Nitroglycerin is contraindicated after the use of sildenafil within the previous 24
hours or tadalafil within 48 hours and may have an augmented hypotensive effect beyond these
time windows. An American College of Cardiology/American Heart Association expert
consensus document concluded that the PDE-5 inhibitors are potentially hazardous in patients
with HF who have borderline low blood pressure and/or low volume status. (See "Sexual activity
in patients with cardiovascular disease".)
Clinical data on use of these agents in patients with HF are limited. In a randomized comparison
of sildenafil to placebo in 35 patients with New York Heart Association class II to III HF who
were not taking nitrates, a single 50 mg dose of sildenafil caused an asymptomatic 6 mmHg
decrease in mean systemic blood pressure at two hours that had resolved by four hours [15].
Over a six-week course of therapy, no patient developed symptoms of hypotension or
worsening of HF while taking sildenafil. In another trial of 34 HF patients randomly assigned to
receive either sildenafil or placebo, no significant difference in incidence of symptomatic
hypotension was observed [16].
The potential role of sildenafil in selected patients with HF complicated by pulmonary

hypertension is discussed separately. (See "Investigational and emerging strategies for
management of heart failure" and "Pulmonary hypertension due to left heart disease (group 2
pulmonary hypertension) in adults" and "Pulmonary hypertension due to left heart disease
(group 2 pulmonary hypertension) in adults", section on 'Targeted therapy for pulmonary
hypertension'.)
Antiarrhythmic agents — Most antiarrhythmic drugs have some negative inotropic activity
and, in patients with reduced left ventricular function, can precipitate HF [1]. The further
reduction in left ventricular function can also impair the elimination of these drugs, resulting in
drug toxicity. In addition, some antiarrhythmic drugs exert a possible proarrhythmic effect,
particularly class I agents and the class III agents ibutilide and sotalol. HF is a risk factor for
torsades de pointes in patients receiving the class III agents ibutilide, sotalol, and dofetilide.
Amiodarone is generally considered to be less proarrhythmic than other antiarrhythmic agents

and is generally the preferred drug for treatment of arrhythmias in HF. Amiodarone side effects
and drugs interactions are discussed separately. (See "The management of atrial fibrillation in
patients with heart failure" and "Primary prevention of sudden cardiac death in patients with
cardiomyopathy and heart failure with reduced LVEF", section on 'Antiarrhythmic drugs' and
"Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".)
Chemotherapy agents — Cardiotoxic chemotherapeutic agents should be avoided in patients

with HF. Cardiotoxic agents include anthracyclines, high-dose cyclophosphamide, trastuzumab,
and bevacizumab. (See "Clinical manifestations, monitoring, and diagnosis of anthracycline-
induced cardiotoxicity" and "Prevention and management of anthracycline cardiotoxicity" and
"Cardiotoxicity of non-anthracycline cancer chemotherapy agents" and "Cardiotoxicity of
trastuzumab and other HER2-targeted agents".)
Androgens — Limited data are available on the impact of androgen therapy on cardiovascular
function. Although disorders including sudden death, hypertension, and left ventricular
hypertrophy have been reported in individuals taking androgens, a causal relationship has not
been established. FDA-approved labeling for the testosterone patch includes a warning that
edema, with or without HF, may be a complication of androgen treatment in patients with pre-
existing cardiac, renal, or hepatic disease [17]. (See "Use of androgens and other hormones by
athletes".)
The 2010 Endocrine Society guidelines on testosterone therapy for men with androgen
deficiency recommended against testosterone therapy in patients with uncontrolled or poorly
controlled HF [18].
In men with HF, deficiency in anabolic hormones, including androgens (testosterone,

dehydroepiandrosterone), is common and is an independent marker of poor prognosis.
However, the nature of the relationship between androgen deficiency and HF severity is not
known. (See "Predictors of survival in heart failure with reduced ejection fraction".)
Available data are insufficient to recommend androgen therapy in patients with HF as discussed
separately. (See "Investigational and emerging strategies for management of heart failure",
section on 'Testosterone'.)
Sodium-containing preparations — Some drug preparations contain clinically significant
quantities of sodium. For example, sodium bicarbonate and Fleet PhosPho soda include one
and two grams of sodium, respectively, per dose. An additional concern with sodium phosphate
preparations is that ACE inhibitors (used to treat HFrEF) may enhance the risk of acute
phosphate nephropathy [19].
Antihistamines — Long QT syndrome has been reported with some second generation
antihistamines (terfenadine and astemizole) but not others (eg, fexofenadine, cetirizine).
Theophylline — There is a narrow therapeutic index for methylxanthines such as theophylline

in treating chronic airway disease. During acute decompensation of HF, theophylline serum
levels may increase, causing toxicity. Tachycardia and atrial arrhythmias may occur at serum
concentrations considered therapeutic, particularly among patients with heart disease. If this
drug cannot be avoided in HF, dose reduction with monitoring of levels or discontinuation of
medication may be required. (See "Theophylline use in asthma" and "Role of methylxanthines
in the treatment of COPD".)
TNF-alpha inhibitors — Tumor necrosis factor-alpha inhibitors may be associated with new
onset or worsening of pre-existing HF. United States product information includes HF as a
warning for these agents as a class and a specific contraindication for infliximab dosed over 5
mg/kg. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on
'Heart failure'.)
"Natural" remedies and supplements — Naturoceutical products or dietary supplements may

be construed by some patients as benign, although they are not of proven benefit and some
may pose health risks. For example, ephedra (also called Ma huang) is a plant source of
ephedrine that is contained in some products promoted for athletic performance enhancement
or weight loss. Case reports suggest that ephedra may cause HF and left ventricular systolic
dysfunction [20]. The FDA has banned dietary supplements containing ephedra since 2004.
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Heart failure in adults".)
SUMMARY AND RECOMMENDATIONS
● A number of medications that are in common clinical use are relatively or absolutely
contraindicated in patients with heart failure (HF), either because they can cause
exacerbations of HF or because there is a higher risk of adverse reactions in such patients
(table 1). (See 'Introduction' above.)
● General principles for avoiding drug-induced exacerbation of HF include recognition of the

basic mechanisms by which drugs can exacerbate HF, identification of significant drug
interactions, awareness of potential alterations in pharmacokinetics in the setting of HF,
surveillance for changes in drug effects with changes in HF status, and monitoring the
pharmacodynamic effects of HF management. (See 'General principles' above.)
● Nonsteroid anti-inflammatory agent use in HF patients is associated with increased risk of

HF exacerbation, increased renal dysfunction, and impairment of responses to angiotensin
converting enzyme inhibitors and diuretics. (See 'Nonsteroidal anti-inflammatory drugs'
above.)
● The oral hypoglycemic agents thiazolidinediones and metformin pose particular risks in
patients with HF. Thiazolidinediones cause fluid retention and may precipitate HF. Patients
with HF who take metformin are at increased risk of potentially lethal lactic acidosis. (See
'Oral hypoglycemic agents' above.)
● Concerns have been raised about the safety of phosphodiesterase-3 (PDE-3) inhibitors in
patients with HF. PDE-5 inhibitors may be used in carefully-selected patients with HF, but
are potentially hazardous in patients with low blood pressure and/or volume depletion, and
are contraindicated in any patient taking nitrate therapy. (See 'Phosphodiesterase
inhibitors' above.)
● Most antiarrhythmic agents have some negative inotropic activity and some have
proarrhythmic effects. Amiodarone is generally considered less proarrhythmic than other
antiarrhythmic agents and is generally the preferred drug for treatment of arrhythmias in
HF. (See 'Antiarrhythmic agents' above.)
● Drug list review should include any naturoceutical products or dietary supplements.
Although these may be construed by some patients as benign, some may pose health
risks. (See '"Natural" remedies and supplements' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES
1. Amabile CM, Spencer AP. Keeping your patient with heart failure safe: a review of
potentially dangerous medications. Arch Intern Med 2004; 164:709.
2. Gislason GH, Rasmussen JN, Abildstrom SZ, et al. Increased mortality and
cardiovascular morbidity associated with use of nonsteroidal anti-inflammatory drugs in
chronic heart failure. Arch Intern Med 2009; 169:141.
3. Masoudi FA, Wang Y, Inzucchi SE, et al. Metformin and thiazolidinedione use in Medicare
patients with heart failure. JAMA 2003; 290:81.
4. Page RL 2nd, O'Bryant CL, Cheng D, et al. Drugs That May Cause or Exacerbate Heart
Failure: A Scientific Statement From the American Heart Association. Circulation 2016;
134:e32.
5. WRITING COMMITTEE MEMBERS, Yancy CW, Jessup M, et al. 2013 ACCF/AHA

guideline for the management of heart failure: a report of the American College of
Cardiology Foundation/American Heart Association Task Force on practice guidelines.
Circulation 2013; 128:e240.
6. http://circ.ahajournals.org/content/suppl/2013/06/04/CIR.0b013e31829e8776.DC1/Online_
Data_Supplement.pdf.
7. Gentry CA, Nguyen AT. An evaluation of hyperkalemia and serum creatinine elevation
associated with different dosage levels of outpatient trimethoprim-sulfamethoxazole with
and without concomitant medications. Ann Pharmacother 2013; 47:1618.
8. Michel A, Martín-Pérez M, Ruigómez A, García Rodríguez LA. Risk factors for

hyperkalaemia in a cohort of patients with newly diagnosed heart failure: a nested case-
control study in UK general practice. Eur J Heart Fail 2015; 17:205.
9. Antoniou T, Gomes T, Mamdani MM, et al. Trimethoprim-sulfamethoxazole induced

hyperkalaemia in elderly patients receiving spironolactone: nested case-control study.
BMJ 2011; 343:d5228.
10. Fralick M, Macdonald EM, Gomes T, et al. Co-trimoxazole and sudden death in patients
receiving inhibitors of renin-angiotensin system: population based study. BMJ 2014;
349:g6196.
11. Antoniou T, Hollands S, Macdonald EM, et al. Trimethoprim-sulfamethoxazole and risk of

sudden death among patients taking spironolactone. CMAJ 2015; 187:E138.
12. Swenson JR, Doucette S, Fergusson D. Adverse cardiovascular events in antidepressant

trials involving high-risk patients: a systematic review of randomized trials. Can J
Psychiatry 2006; 51:923.
13. Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinone on mortality in severe
chronic heart failure. The PROMISE Study Research Group. N Engl J Med 1991;
325:1468.
14. www.fda.gov/cder/news/cilostazol/default.htm (Accessed on February 18, 2004).
15. Webster LJ, Michelakis ED, Davis T, Archer SL. Use of sildenafil for safe improvement of
erectile function and quality of life in men with New York Heart Association classes II and
III congestive heart failure: a prospective, placebo-controlled, double-blind crossover trial.
Arch Intern Med 2004; 164:514.
16. Lewis GD, Shah R, Shahzad K, et al. Sildenafil improves exercise capacity and quality of
life in patients with systolic heart failure and secondary pulmonary hypertension.
Circulation 2007; 116:1555.
17. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ac40e05b-6e67-4ff9-a0e8-2e897
e71b282 (Accessed on September 30, 2014).
18. Bhasin S, Brito JP, Cunningham GR, et al. Testosterone Therapy in Men With
Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab
2018; 103:1715.
19. Markowitz GS, Stokes MB, Radhakrishnan J, D'Agati VD. Acute phosphate nephropathy
following oral sodium phosphate bowel purgative: an underrecognized cause of chronic
renal failure. J Am Soc Nephrol 2005; 16:3389.
20. Peters CM, O'Neill JO, Young JB, Bott-Silverman C. Is there an association between
ephedra and heart failure? a case series. J Card Fail 2005; 11:9.
Topic 3499 Version 33.0
GRAPHICS
Drugs associated with increased risk of adverse effects in patients with heart
failure
Drug/drug class Adverse effect(s)
Anti-inflammatory medications
Glucocorticoids Sodium retention (particularly with fludrocortisone,

hydrocortisone)
NSAIDs ¶ Sodium retention and peripheral vasocontriction;

blunted response to diuretics and angiotensin
converting enzyme inhibitors
Cardiovascular medications
Class I antiarrhythmic agents* ¶ Negative inotropy; proarrhythmia; increased mortality

with IA and IC agents in post-MI trials
Class III antiarrhythmic agents (included sotalol Proarrhythmia

and ibutalide)* ¶
Calcium channel blockers (other than amlodipine or Negative inotropy; neurohumoral activation
felodipine)* ¶
Minoxidil* ¶ Sodium retention; neurohumoral activation
Diabetes medications
Metformin Lactic acidosis
Thiazolidinediones ¶ Sodium retention
Phosphdiesterase inhibitors
Anagrelide Palpitations; tachycardia; sodium retention; induction

or exacerbation of HF
Cilostazol Ventricular tachyarrhythmias
Neurologic and psychiatric medications
Amphetamines* ¶ Sympathetic agonist activity; hypertension;

tachycardia; tachyarrhythmias
Carbamazepine Negative inotropic effect; bradyarrhythmias
Clozapine Development of myocarditis and cardiomyopathy
Ergot alkaloids (ergotamine, dihydroergotamine) Sympathetic agonist activity; valve fibrosis
Pergolide (not available in the US) Valve fibrosis
Tricyclic antidepressants Negative inotropic effect; proarrhythmia
Miscellaneous
Beta-2 agonists Sympathetic agonist activity; tachyarrhythmias;

hypokalemia
Trimethoprim-sulfamethoxazole Risk of hyperkalemia or acute kidney injury when

taken with ACE inhibitor or ARB
Risk of hyperkalemia when taken with MRA
Itraconazole Negative inotropic effect; also can increase serum

digoxin concentrations
Licorice Mineralocorticoid excess: sodium retention and

hypokalemia
Sodium-containing preparations (eg, Fleet PhosPho

soda)
Sodium load QT-prolonging drugs (eg, haloperidol, Proarrhythmia

erythromycin)
NSAIDs: nonsteroidal anti-inflammatory drugs; MI: myocardial infarction; HF: heart failure; ACE: angiotensin-
converting enzyme; ARB: angiotension II receptor blockers; MRA: mineralocorticoid receptor antagonist.
* Evidence from randomized placebo controlled trials.
¶ Increased risk noted in American College of Cardiology/American Heart Association heart failure guidelines (Hunt
SA, et al. Circulation 2005; 112:e154.).
Data modified from Amabile CM, Spencer AP. Arch Intern Med 2004; 164:709.
Graphic 68838 Version 6.0
Contributor Disclosures
Wilson S Colucci, MD Grant/Research/Clinical Trial Support: Merck [Heart failure (Enalapril)].
Consultant/Advisory Boards: Novartis [Heart failure (Valsartan, sacubitril/valsartan)], Merck [Heart failure
(Enalapril)]. Stephen S Gottlieb, MD Grant/Research/Clinical Trial Support: Pfizer [Amyloidosis, Heart
failure]; Cytokinetics [Heart failure]; Bristol-Myers Squibb [Heart failure]; BTG International [Renal].
Consultant/Advisory Boards: Cytokinetics [Heart failure]. Susan B Yeon, MD, JD, FACC Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy

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Official reprint from UpToDate®

Drugs that should be avoided or used with caution in

Management of patients with HF is discussed separately. (See "Treatment and prognosis of

General principles for avoiding drug-induced worsening of HF include the following:

● Recognition of the basic mechanisms by which drugs can exacerbate HF including:

● Identification of significant drug interactions among medications used to treat HF and

Examples of significant pharmacodynamic interactions that may occur in patients with HF

● Monitoring HF management involving frequent assessment and adjustment of several

Nonsteroidal anti-inflammatory drugs — Nonsteroidal anti-inflammatory drug (NSAID) use

Trimethoprim-sulfamethoxazole — In patients taking an ACE inhibitor, ARB, or MRA,

Antidepressants — Depression is common in patients with HF and is associated with worse

Thiazolidinediones — Thiazolidinediones cause fluid retention, which may precipitate HF.

Phosphodiesterase inhibitors — Concerns have been raised about the safety of

The potential role of sildenafil in selected patients with HF complicated by pulmonary

Amiodarone is generally considered to be less proarrhythmic than other antiarrhythmic agents

Chemotherapy agents — Cardiotoxic chemotherapeutic agents should be avoided in patients

In men with HF, deficiency in anabolic hormones, including androgens (testosterone,

Sodium-containing preparations — Some drug preparations contain clinically significant

Theophylline — There is a narrow therapeutic index for methylxanthines such as theophylline

"Natural" remedies and supplements — Naturoceutical products or dietary supplements may

SOCIETY GUIDELINE LINKS

SUMMARY AND RECOMMENDATIONS

● General principles for avoiding drug-induced exacerbation of HF include recognition of the

● Nonsteroid anti-inflammatory agent use in HF patients is associated with increased risk of

Use of UpToDate is subject to the Subscription and License Agreement.

5. WRITING COMMITTEE MEMBERS, Yancy CW, Jessup M, et al. 2013 ACCF/AHA

8. Michel A, Martín-Pérez M, Ruigómez A, García Rodríguez LA. Risk factors for

9. Antoniou T, Gomes T, Mamdani MM, et al. Trimethoprim-sulfamethoxazole induced

11. Antoniou T, Hollands S, Macdonald EM, et al. Trimethoprim-sulfamethoxazole and risk of

12. Swenson JR, Doucette S, Fergusson D. Adverse cardiovascular events in antidepressant

14. www.fda.gov/cder/news/cilostazol/default.htm (Accessed on February 18, 2004).

Topic 3499 Version 33.0

Drug/drug class Adverse effect(s)

Glucocorticoids Sodium retention (particularly with fludrocortisone,

NSAIDs ¶ Sodium retention and peripheral vasocontriction;

Class I antiarrhythmic agents* ¶ Negative inotropy; proarrhythmia; increased mortality

Class III antiarrhythmic agents (included sotalol Proarrhythmia

Minoxidil* ¶ Sodium retention; neurohumoral activation

Metformin Lactic acidosis

Thiazolidinediones ¶ Sodium retention

Anagrelide Palpitations; tachycardia; sodium retention; induction

Cilostazol Ventricular tachyarrhythmias

Neurologic and psychiatric medications

Amphetamines* ¶ Sympathetic agonist activity; hypertension;

Carbamazepine Negative inotropic effect; bradyarrhythmias

Clozapine Development of myocarditis and cardiomyopathy

Ergot alkaloids (ergotamine, dihydroergotamine) Sympathetic agonist activity; valve fibrosis

Pergolide (not available in the US) Valve fibrosis

Tricyclic antidepressants Negative inotropic effect; proarrhythmia

Beta-2 agonists Sympathetic agonist activity; tachyarrhythmias;

Trimethoprim-sulfamethoxazole Risk of hyperkalemia or acute kidney injury when

Itraconazole Negative inotropic effect; also can increase serum

Licorice Mineralocorticoid excess: sodium retention and

Sodium-containing preparations (eg, Fleet PhosPho

Sodium load QT-prolonging drugs (eg, haloperidol, Proarrhythmia

Graphic 68838 Version 6.0

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