Clinical Overview: Potentially Harmful Medications in Heart Failure

Heart disease is the leading cause of death in the United States, with heart failure (HF) being one of the most common types of heart disease.¹ The prevalence of HF is expected to increase from 6.5 million to >8 million Americans over the age of 20 by 2030.

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With this increased population, the total cost of care is expected to more than double, from $30.7 billion to $69.7 billion by 2030. An average patient with HF can take up to 6 medications for guideline-directed medical therapy; however, they may have other comorbidities that require pharmacologic management as well.

In fact, hypertension (63%), ischemic heart disease (44%), hyperlipidemia (48%), diabetes (33%), chronic kidney disease (25%), and atrial fibrillation (25%) were major comorbidities reported in some HF trials.² As such, it is increasingly important to not only be aware of guideline-directed care, but also medications that may potentially exacerbate HF.

Medications that may pose harm to a patient with HF work via several mechanisms.³ They may cause negative inotropic effects, sodium or water retention, direct myocardial toxicity, or increase the risk of fatal arrythmias. Although this is not an all-inclusive list, major drug classes that should prompt pharmacist intervention during medication therapy management will be discussed.

Negative Inotropes

Negative inotropic medications, such as non-dihydropyridine calcium channel blockers (e.g., diltiazem, verapamil), are potent vasodilators and afterload reducers.³ Over time, the response to vasodilation leads to activation of the renin angiotensin aldosterone system.

Continued activation of this pathway further increases left ventricular remodeling. They also act as myocardial depressants which further exacerbates underlying myocardial dysfunction.

An increase in symptom burden or hospitalization has been identified when used in patients with an ejection fraction <50%. Therefore, the 2022 ACC/AHA/HFSA heart failure guidelines do not recommend non-dihydropyridine calcium channel blockers in patients with a reduced ejection fraction and classify them as harmful.⁴

This becomes a factor to consider when managing patients with multiple comorbidities. In patients with atrial fibrillation, management with beta blocker or anti-arrhythmic therapy should be considered.³ In patients with uncontrolled hypertension, a dihydropyridine calcium channel blocker such as amlodipine may be used instead.

Antiarrhythmics

Class I and certain class III antiarrhythmic drugs also act like negative inotropes and are not recommended in HF.³ Class I antiarrhythmics, such as flecainide and disopyramide, are sodium channel blockers. These drugs bind to fast sodium channels and prolong depolarization, which in turn slows conduction.

A post hoc analysis of the Stroke Prevention in Atrial Fibrillation trial revealed that patients with HF who were receiving antiarrhythmic therapy with Class I agents had a greater risk of cardiac death than patients not receiving one.⁵ The 3 subclasses differ in their efficacy for prolonging depolarization, with Ic drugs having the greatest and Ib drugs having the smallest effect.⁶

Regardless, all class I agents are not recommended in patients with HF.^3,4 Other antiarrhythmic agents, beta blockers, or ICD placement should be considered.

Class III antiarrhythmics, such as sotalol and dronedarone, block potassium channels and delay repolarization.^3,7 It is thought to exacerbate underlying cardiac dysfunction through its negative inotropic and proarrhythmic properties.

In studies with sotalol, the incidence of new or worsened HF over 1 year was 3% in patients without previous HF and 10% in those with a history of HF. Although not contraindicated, its use as a first-line therapy for ventricular arrythmias is not supported by the ACC/AHA/HFSA practice guidelines.⁴

Dronedarone shares similar properties to amiodarone, however, it has greater negative inotropic activity. Multiple trials with dronedarone have ended prematurely for increased deaths in HF patients.⁸

As such, it carries a black box warning for increased mortality and is contraindicated in patients with symptomatic HF with recent decompensation requiring hospitalization or New York Heart Association (NYHA) Class IV HF.⁹ Pharmacists noting dronedarone during a medication reconciliation for a patient that is admitted for HF decompensation can play a significant role in disease management.

Additionally, amiodarone and dofetilide, although class III agents, may be suggested instead because they are known to have a neutral mortality risk. Both are equally recommended by ACC/AHA/HFSA guidelines.⁴

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Nonsteroidal anti-inflammatory drugs (NSAIDS) are commonly used by the general population because of their anti-inflammatory and analgesic properties. Through prostaglandin inhibition, they cause vasoconstriction of afferent renal arterioles.

This leads to an increase in sodium and fluid retention. NSAIDS may also blunt the response to diuretics. In a cohort study of patients well controlled on diuretics, concomitant NSAID and diuretic use doubled the risk of hospitalization for HF.¹⁰

This usually occurs within the first 30 days of NSAID use.With the exception of low-dose aspirin for cardio and cerebroprotection, non-selective and selective NSAIDs should be avoided in HF patients.³ If utilized, patients should be counseled to monitor for weight changes, edema, or dyspnea.

Anti-diabetics

Thiazolidinediones, such as pioglitazone and rosiglitazone, increase insulin sensitivity but may also increase sodium and water reabsorption through activation of the peroxisome proliferator activated receptor gamma. This receptor regulates glucose metabolism, as well as sodium reabsorption in the renal collecting ducts.

Several meta-analyses and randomized controlled trials have suggested that thiazolidinediones exacerbate existing HF and increase the risk for new-onset HF.^11-13 As a result, ACC/AHA/HFSA guidelines classify thiazolidinediones as a class that may cause harm in patients with HRrEF.⁴ The 2023 American Diabetes Association guidelines note fluid retention and HF as a concern.¹⁴ Management of diabetics with HFrEF should encompass other therapies.

Dipeptidyl peptidase-4 (DPP-4) inhibitors, specifically saxagliptin and alogliptin, have been shown to increase the risk of HF hospitalization in patients with type 2 diabetes and high cardiovascular risk.⁴ The mechanism for this effect remains unknown, therefore, the FDA has added warnings to their respective prescribing labels. As such, they should be avoided in patients with HF with a reduced ejection fraction. Sitagliptin and linagliptin have not demonstrated similar negative outcomes. If a DPP-4 inhibitor is warranted, either drug may be recommended instead.

Increased Risk of Mortality

Cilostazol, an antiplatelet and vasodilatory agent, is indicated in patients with intermittent claudication.¹⁵ Although not directly studied in patients with HF, it is thought to increase the risk of fatal arrythmias through selective inhibition of phosphodiesterase type 3.³

Additionally, cilostazol increases the heart rate by 5 to 7 BPM and causes a higher rate of ventricular premature beats and nonsustained ventricular tachycardia. Due to a potentially fatal outcome, cilostazol is contraindicated in all patients with HF. If an antiplatelet is needed for intermittent claudication management, pentoxifylline should be considered instead.³

Tumor Necrosis Factor Inhibitors (TNFi)

TNFi (e.g., infliximab, adalimumab) are commonly used therapies in the management of various autoimmune conditions. At one point, infliximab was evaluated for use in the management of moderate to severe HF.¹⁶ 

However, a failure to improve clinical status along with increased rates of death and HF hospitalization were observed in those trials. Additionally, an association with new onset or worsening HF has been identified in postmarketing data for approved indications.^17,18

Of the TNF inhibitors, only etanercept does not have specific language in its prescribing information regarding potential HF worsening.¹⁹ If used in a patient with HF, pharmacists should closely monitor for new or worsening symptoms of HF. Also, careful attention to infliximab dosing should be made as doses greater than 5 mg/kg are contraindicated in patients with moderate to severe HF.¹⁷

Antineoplastics

A wide range of antineoplastic agents have been known to cause direct myocardial toxicity. This toxicity can be categorized as type 1 (irreversible damage) or type 2 (reversible damage).²⁰

Although not an all-inclusive list, type 1 is most commonly observed with the anthracyclines (e.g., doxorubicin), alkylating agents (e.g., cyclophosphamide), and antimetabolites (e.g., florouracil). Type 2 damage is often observed with certain monoclonal antibodies (e.g., trastuzumab, bevacizumab).

Anthracycline-induced cardiotoxicity can occur early at the onset of treatment and even up to several years following completion of therapy.²¹ It is thought to cause myocardial toxicity through the generation of free radicals in the myocardium and subsequent oxidative stress.

Additionally, anthracyclines can interfere with the iron-handling system within the heart, further contributing to the oxidative damage. The risk of drug-induced cardiomyopathy increases significantly at cumulative doses.

As such, specific lifetime dose limits are in place for each anthracycline agent. Pharmacists should be aware of these limits and chart the cumulative doses received, with recommendations for appropriate follow-up (echocardiogram). Additionally, patients receiving type 1 or type 2 agents should have cardiac function (e.g., echocardiogram) monitoring at baseline, every 3 months during treatment, and 12 and 18 months after initiation of treatment.²²

Conclusion

As multiple comorbidities are common in HF patients, it is important for all health care providers to be aware of therapies that may potentially be harmful. As evidenced by the multitude of mechanisms, alternative therapies, and monitoring parameters mentioned in this review, there are many opportunities for pharmacists to advise prescribers and provide education to patients.

Thorough medication reconciliation along with identification and prevention of adverse drug events can improve overall outcomes and decrease the risk for HF exacerbation or rehospitalization.

References

1. Heart failure facts and information. Heart Failure Society of America. https://hfsa.org/patient-hub/heart-failure-facts-information. Accessed on: April 06, 2023.
2. Khan MS, Samman Tahhan A, Vaduganathan M, Greene SJ, Alrohaibani A, Anker SD, Vardeny O, Fonarow GC, Butler J. Trends in prevalence of comorbidities in heart failure clinical trials. Eur J Heart Fail. 2020 Jun;22(6):1032-1042.
3. Page RL, O'Bryant CL, Cheng D, Dow TJ, Ky B, Stein CM, Spencer AP, Trupp RJ, Lindenfeld J. Drugs that may cause or exacerbate heart failure: a scientific statement from the American Heart Association. Circulation. 2016; 134:e32–e69.
4. HF Writing Committee Members; ACC/AHA Joint Committee Members. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. J Card Fail. 2022 May;28(5):e1-e167.
5. Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, Arensberg D, Baker A, Friedman L, Greene HL, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991 Mar 21;324(12):781-8.
6. King GS, Goyal A, Grigorova Y, et al. Antiarrhythmic Medications. [Updated 2023 Feb 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482322/. Accessed July 7, 2023.
7. A.L. Waldo, A.J. Camm, H. deRuyter, P.L. Friedman, D.J. MacNeil, J.F.Pauls, B. Pitt, C.M. Pratt, P.J. Schwartz, E.P. Veltri. 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, 348 (9019) (1996), pp. 7-12.
8. Kober L, Torp-Pedersen C, McMurray JJ, et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med. 2008;358:2678– 2687.
9. Multaq (dronedarone) product information.Bridgewater, NJ: Sanofi;July 2009.
10. Heerdink E, Leufkens H, Herings R, Ottervanger J, Striker B, Bakker A. NSAIDs associated with in- creased risk of congestive heart failure in elderly patients taking diuretics. Arch Intern Med. 1998; 158:1108-1112
11. Singh S, Loke YK, Furberg CD. Thiazolidinediones and heart failure:ateleo-analysis.DiabetesCare.2007;30:2148–2153.
12. Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, et al.DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet. 2006 Sep 23;368(9541):1096-105.
13. HernandezAV,UsmaniA,RajamanickamA,MoheetA.Thiazolidinedionesandriskofheartfailureinpatientswithorathighriskoftype2diabetesmellitus:ameta-analysisandmeta-regressionanalysisofplacebo-controlledrandomizedclinical trials. Am J Cardiovasc Drugs. 2011;11:115–128.
14. ElSayed N, Aleppo G, Aroda VR, Bannuru RR, Brown FM, et al; on behalf of the American Diabetes Association, Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2023. Diabetes Care 1 January 2023; 46 (Supplement_1): S140–S157.
15. Pletal (cilostazol) product information.Otsuka: Rockville, MD.May 2017.
16. Chunge ES, Packer M, Lo KH, Fasanmade AA, Willerson JT; Anti-TNF Therapy Against Congestive Heart Failure Investigators. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation. 2003 Jul 1;107(25):3133-40.
17. Humira (adalimumab) product information.North Chicago, IL: Abbvie; February 2021.
18. Remicade (infliximab) product information.Horsham, PA: Janssen; October 2021.
19. Enbrel (etanercept) product information.Thousand Oaks, CA: Amgen; August 2020.
20. Morelli MB, Bongiovanni C, Da Pra S, Miano C, Sacchi F, et al. Cardiotoxicity of Anticancer Drugs: Molecular Mechanisms and Strategies for Cardioprotection. Front Cardiovasc Med. 2022 Apr 15;9:847012. doi: 10.3389/fcvm.2022.847012.
21. Cardinale D, Iacopo F, Cipolla CM. Cardiotoxicity of Anthracyclines. Front Cardiovasc Med. 2020 Mar 18;7:26.
22. Stone JR, Kanneganti R, Abbasi M, Akhtari M.Monitoring for Chemotherapy-Related Cardiotoxicity in the Form of Left Ventricular Systolic Dysfunction: A Review of Current Recommendations.JCO Oncology Practice 2021; 17:5, 228-236.