Drugs that should be avoided or used with caution in patients with heart failure

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".)

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.

●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/valsartan 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/valsartan should never be taken with an ACE inhibitor. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction" and "Secondary pharmacologic therapy for heart failure with reduced ejection fraction".)

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 "Essential thrombocythemia: Treatment and prognosis" and "Polycythemia vera and secondary polycythemia: Treatment and prognosis".)

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 "Essential thrombocythemia: Treatment and prognosis", 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 therapies 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, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity" and "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines" 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. Available data are insufficient to recommend androgen therapy in patients with HF. (See "Predictors of survival in heart failure with reduced ejection fraction".)

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 "Management of refractory chronic obstructive pulmonary disease", section on 'Theophylline, monitored by drug levels'.)

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.)