Cardiovascular disease (CVD) ranks as the leading cause of death across the globe, and nearly 18 million people died from CVDs in 2019. In the US alone, one of every four deaths is attributed to cardiovascular disease, and one person dies of CVD approximately every 26 seconds. Heart failure consistently remains the number one discharge diagnosis for patients 65 years of age or older, with the estimated cost of treatment for Medicare recipients expected to reach $53 billion by 2030. Although CVDs such as coronary heart disease are the predominant cause of heart failure, the risk of experiencing heart failure can be significantly heightened by using specific prescription medications.
Increased Risk of Serious Cardiovascular Problems With Medications
Extensive evidence shows that the more drugs a patient takes, the higher the likelihood of experiencing an adverse drug-drug interaction that can put their heart at risk for serious cardiovascular disease. A recent study found that patients taking a minimum of two different medications have a 13% risk for such a reaction. This risk reaches 38% for four medications, then rises to 82% for seven or more medications. Patients diagnosed with heart failure take an average of 6.8 prescription medications per day, not counting over-the-counter medications or complementary or alternative medications.
Medicare beneficiaries with heart failure visit an average of 15 to 23 different health care providers each year, further increasing the number of medications prescribed. Among these patients, 40% have five or more cardiovascular or non-cardiovascular chronic health conditions. The most common morbidities include osteoarthritis, obesity, chronic kidney disease, diabetes mellitus, chronic obstructive pulmonary disease, ocular disorders, and thyroid disorders. As the number of comorbidities increases, so too does the number of medications required to alleviate the symptoms of these conditions.
Medications can precipitate or exacerbate heart failure in many ways, by:
Causing myocardial toxicity, which prevents proper heart functioning
Weakening the force of the heart muscle’s contractions (negative inotropic effect)
Hindering myocardial relaxation after contraction (negative lusitropic effect)
The American Heart Association (AHA) lists the following prescription drugs as causing or intensifying the risk of heart failure:
Traditional non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, indomethacin, diclofenac, and ketorolac inhibit the COX-1 isoenzyme, creating an adverse effect on platelet aggregation (how well platelets clump together to form blood clots), maintenance of the body’s gastric mucosal barrier (allowing the stomach to safely contain gastric acid), and renal function. This can trigger heart failure by causing the retention of excess sodium and water, increasing systemic vascular resistance (the amount of force exerted on blood as it circulates through the body), and blunting the efficacy of diuretics.
Patients with prevalent heart failure who use NSAIDs are more likely to experience heart failure and are more often hospitalized for heart failure or myocardial infarction. They also have 10 times the risk of recurrence compared to heart failure patients who do not take NSAIDs and an increased risk of all-cause mortality.
Metformin, a biguanide insulin sensitizer, was traditionally not recommended for patients with heart failure or severe pulmonary disease because it increased the risk of lactic acidosis or accumulated lactic acid in the bloodstream. However, the FDA recently removed heart failure as a contraindication for metformin after observational studies found a minimal risk of lactic acidosis similar to other anti-diabetic medications. In addition, researchers have determined that metformin administration is linked to a reduction in mortality among patients with heart failure.
Thiazolidinediones (rosiglitazone and pioglitazone) are used to treat insulin resistance among patients with type 2 diabetes. Recent meta-analyses strongly indicate that these medications can exacerbate existing heart failure and increase the risk of developing new-onset heart failure. A recent trial found that patients who receive rosiglitazone experience an earlier onset of heart failure, a higher risk of cardiovascular mortality, and a higher risk of hospitalization than patients in the control group who received glyburide. The American Diabetes Association recommends that patients with symptomatic heart failure avoid both these medications.
Dipeptidyl peptidase-4 inhibitors comprise a newer class of anti-diabetic medications that bind to the dipeptidyl peptidase-4 enzyme to increase insulin release and decrease glucagon, the hormone formed in the pancreas that prevents blood glucose levels from dropping too low. This category includes alogliptin, linagliptin, sitagliptin, and saxagliptin; a meta-analysis of random trials found that patients treated with these medications experience an elevated overall risk of hospitalization due to heart failure, while other researchers have found this trend in increased hospital admission to be nonsignificant.
Class I antiarrhythmic medications such as disopyramide and flecainide are sodium channel blockers that show an increased risk of heart failure. Among patients prescribed with disopyramide to treat ventricular arrhythmia, some of them develop heart failure within the first 48 hours of beginning this therapy. Flecainide has been found to significantly depress left ventricle function in patients with preexisting dysfunction in this area and is associated with increased mortality in patients with heart failure or structural heart disease.
Class III antiarrhythmic medications containing sotalol are associated with a heightened risk of heart failure by depressing myocardial contractility and reducing left ventricular function. A study assessing the outcomes of patients who survived a myocardial infarction and were treated with d-sotalol had to be prematurely terminated due to the significant increase in mortality among patients. In addition, as the severity of the patients’ baseline heart failure increased, so did their risk of experiencing exacerbating heart failure.
Dronedarone is an α-and a β-adrenergic receptor antagonist that inhibits calcium, potassium, and sodium channels, similar to amiodarone. One study of dronedarone therapy found that this medication reduced cardiovascular hospitalizations and death, but a later study was terminated due to increased hospitalization for heart failure, stroke, and mortality. This medication has a black box warning that patients with symptomatic heart failure that require decompensation via hospitalization have double the risk of mortality when taking this medication.
Antihypertensive medications include α-blockers, calcium channel blockers, centrally acting α2-adrenergic agonists, and minoxidil. Patients taking α-blockers such as prazosin and doxazosin have an increased risk of heart failure. One study found this risk was doubled in patients who receive doxazosin compared to the control group receiving chlorthalidone. Dihydropyridine calcium channel blockers such as nifedipine show a significant worsening of heart failure. At the same time, amlodipine has an increased risk of peripheral edema and pulmonary edema, uncontrolled hypertension, and chest pain. Diltiazem and verapamil tend to worsen heart failure more than dihydropyridine.
Heart failure is associated with increased sympathetic adrenergic activity, and this increase directly impacts mortality. Centrally acting α2-adrenergic agonists clonidine and moxonidine show varied results among patients with heart failure. Patients treated with clonidine report bradycardia and atrioventricular dissociation, while patients treated with moxonidine have increased mortality compared to patients receiving a placebo. Minoxidil is a vasodilator that improves hemodynamics (blood flow and behavior within blood vessels) for heart failure but increases the need for diuretics and heightens the chances of death.
Antifungal medication itraconazole is associated with reports of cardiotoxicity, hypertension, ventricular fibrillation, ventricular contractions, worsening of existing heart failure, and increasing the risk for new-onset heart failure. Therefore, the FDA recommends that patients with ventricular dysfunction or heart failure should only prescribe this medication in cases of life-threatening fungal infections, not as a treatment for onychomycosis. Another antifungal medication, amphotericin B, shows a heightened risk for new-onset dilated cardiomyopathy and subsequent heart failure, but these symptoms can be reversed by discontinuing this medication.
Anticancer medications that may cause heart damage include anthracyclines, alkylating agents, antimetabolites, taxanes, and other medications.
Administration of anthracyclines results in acute, early-onset, and delayed-onset cardiotoxicity, and the risk of developing heart failure increases as the cumulative doses increase, but in some cases, it can occur more than two decades after medication therapy has been completed. In addition, patients can experience enhanced cardiotoxicity when they take this medication in combination with alkylating agents, taxanes, or other agents that may cause further cardiac damage.
Alkylating agents such as cyclophosphamide and ifosfamide cause the formation of free radicals in cardiac tissue that lead to cell damage, and autopsies of patients with fatal cyclophosphamide-induced heart failure show evidence of hemorrhagic myocarditis. Mitomycin C also leads to cardiac damage, and the prevalence of heart failure increases when used along with anthracyclines.
The antimetabolite fluorouracil is associated with cardiotoxic effects, particularly in patients with high-dose infusions.
Taxanes such as paclitaxel and docetaxel may result in heart arrhythmias, and paclitaxel specifically has been shown to increase the incidence of cardiac dysfunction, especially when administered with anthracyclines.
Other anticancer medications that can lead to heart failure include thalidomide, lenalidomide, and high-dose interleukin-2. Thalidomide is associated with edema, sinus bradycardia, venous thromboembolism, and lenalidomide is associated with hypersensitivity myocarditis, and high-dose interleukin-2 is associated with fulminant myocarditis.
Anagrelide is used for decreasing platelet count and reducing the risk of thrombosis. It can induce high-output heart failure, and this effect seems to be dose-related but can occur days to years after therapy. Common effects include edema, tachycardia, and palpitations, and some patients experienced sudden death after taking this medication. Cilostazol is a vasodilatory agent used to increase the mobility of patients with intermittent claudication (cramping typically caused by peripheral arterial disease). This medication causes a dose-related heart rate increase and a higher rate of ventricular premature beats and nonsustained ventricular tachycardia, independent of the dose received. Therefore, it is contraindicated in patients with heart failure of any kind.
Topical β-blockers, mainly timolol, have been known to cause significant issues in patients with heart failure, such as inducing bradycardia, hypertension, myocardial ischemia, and pulmonary edema, but discontinuation or reduction of the dose can rapidly resolve these side effects. Cholinergic agonists such as cholinesterase inhibitors are associated with heart rate changes, but little research has been conducted on this class of medications.
Patients who receive β2-agonists show a dose-related increase in the risk of hospitalization due to deteriorating heart failure. This effect is more robust in systemic formulations than in inhaled formulations. It is proposed that regular exposure to these agents causes decreased responsiveness in receptors and that this is what leads to heart failure deterioration.
Patients with pulmonary hypertension may be treated with epoprostenol, an intravenous prostaglandin, and bosentan, an oral endothelin-1 antagonist. Epoprostenol is associated with increased hospitalization in patients with heart failure due to weight gain, leg edema, and increased mortality risk. Bosentan demonstrates an increased risk of exacerbating heart failure or causing death during the first month of therapy, primarily due to fluid retention, but this risk decreases as treatment continues.
Tumor necrosis factor-α (TNF-α) inhibitors such as infliximab, etanercept, and adalimumab are used to manage symptoms of rheumatoid arthritis and Crohn’s disease, but they are sometimes associated with worsening or new-onset heart failure. In addition, patients aged 64 years old or older with rheumatoid arthritis and heart failure show an increased risk of hospitalization due to heart failure, so this medication is only recommended for patients with compensated heart failure if there are no other reasonable treatment options.
Antimalarial agents are commonly used for the treatment of rheumatoid arthritis, as well as systemic lupus erythematosus. However, chloroquine is shown to result in cardiotoxicity, often in the form of restricted or dilated cardiomyopathy or conduction system abnormalities. This has led to the more frequent use of hydroxychloroquine, which is similar in structure but less toxic.
The α1-blockers such as doxazosin, prazosin, tamsulosin, and terazosin may exacerbate existing heart failure by stimulating β1 receptors, which increases the levels of the enzyme renin and the hormone aldosterone. Aldosterone is crucial for maintaining sodium and potassium concentrations in the blood and managing blood volume and blood pressure, while renin controls the production of aldosterone.
Patients with heart failure are also prone to experiencing erectile dysfunction, particularly when they have coronary artery disease or myocardial infarction. However, erectile dysfunction medications such as Viagra, Cialis, and Levitra can cause arteries throughout the body to widen, leading to a drop in blood pressure even among healthy users. The FDA urges caution when prescribing such medications for patients with a history of heart failure, low blood pressure, or uncontrolled high blood pressure. Patients who already take nitrates cannot take erectile dysfunction medications because both drugs impact nitric oxide and can rapidly drop blood pressure to a dangerous level.
Albuterol is considered a short-acting bronchodilator and provides relief from symptoms of an asthma attack by relaxing the muscles within the airways. However, it is intended as a rescue medication, not a long-term asthma treatment, and excessive use can lead to tachycardia or heart palpitations. Doctors recommend preventing these side effects by reducing the dosage, changing to a different delivery method, and better managing asthma beyond Albuterol. Patients can reduce side effects by switching from a pill or liquid to an inhaler, from a nebulizer to a metered-dose inhaler, or from a metered-dose inhaler to a spacer or chamber device.
What Are the Common Symptoms of Cardiovascular Problems?
Cardiovascular diseases refer to the group of medical disorders that impact the functioning of the heart and blood vessels. The symptoms of cardiovascular disease depend on the specific type of disease you have. Some of the most common cardiovascular problems are listed below, with descriptions of their symptoms.
Coronary Artery Disease
Coronary artery disease is the disease of blood vessels supplying blood to the heart muscle in which arteries narrow or become blocked due to the accumulation of fatty plaques (atherosclerosis). In most cases, patients are not diagnosed with this disease until they experience a heart attack, stroke, or heart failure. Symptoms of coronary artery disease can differ between men and women, but they usually include:
Pain, tightness, pressure, or discomfort in the chest (angina)
Shortness of breath
Pain, weakness, numbness, or coldness in the arms or legs
Pain in the jaw, throat, neck, back, or upper abdomen
Peripheral Arterial Disease
Peripheral arterial disease is a form of cardiovascular disease in which your limbs do not receive sufficient blood flow, often due to atherosclerosis. The location of the pain is dependent on the location of the narrowed or clogged artery, and it is most common in the legs but can also occur in the arms. Symptoms of peripheral arterial disease include:
Painful cramping in the hips, thighs, or calf muscles (triggered by physical activity, such as climbing stairs) that disappears after resting a few minutes
Numbness or weakness in the leg
Coldness in the lower leg or foot when compared to the other leg
Sores on the leg, feet, or toes that do not heal
The skin of the leg changes color or becomes shiny
The reduced hair growth or hair loss on the legs
Reduced toenail growth
No pulse or a weak pulse in the legs or feet
Erectile dysfunction among male patients
Painful cramping or aching in the arms triggered by tasks such as writing or knitting that disappears after a few minutes of rest
Heart arrhythmia refers to an abnormal heartbeat. Arrhythmias are most common in patients with diseased or deformed hearts, often due to congenital heart defects, and they are unlikely to develop in patients with healthy hearts unless they are triggered by an outside factor, such as electrical shock or illicit drug use. They can also be caused by coronary heart disease or valvular heart disease. Symptoms of heart arrhythmia include:
Fluttering in your chest
Abnormally fast heartbeat (tachycardia)
Abnormally slow heartbeat (bradycardia)
Pain or discomfort in the chest
Shortness of breath
Dizziness, lightheadedness, or fainting
Cardiomyopathy is the disease of the heart muscle that reduces the ability of the heart to pump blood throughout the rest of the body. This can occur due to the enlargement of the left ventricle (dilated cardiomyopathy), abnormal thickening of the heart muscle (hypertrophic cardiomyopathy), or stiffening of the heart muscle that prevents it from adequately expanding and filling with blood (restrictive cardiomyopathy). Symptoms of cardiomyopathy include:
Rapid, pounding, or fluttering heartbeats
Pressure or discomfort in the chest
Breathlessness following activity or while at rest
Swelling in the legs, ankles, and feet
Coughing while lying down
Difficulty laying in a flat position to sleep
Dizziness, lightheadedness, or fainting
Endocarditis is a life-threatening infection of the inner lining of the heart chambers and valves (endocardium), typically caused by bacteria, viruses, fungi, or parasites that spread to the heart from other areas of the body. It can develop slowly or suddenly depending on the specific nature of the infection and the presence of other underlying heart problems. Symptoms of endocarditis include:
Chest pain while breathing
Shortness of breath
Dry or persistent cough
A new or changed heart murmur (the sound made by the blood moving through your heart)
Flu-like symptoms, such as chills and fever
Aching joints and muscles
Weakness or fatigue
Swelling in the feet, legs, or abdomen
Unexplainable weight loss
Blood in urine
Tenderness in the spleen
Red spots on the palms of the hands or soles of the feet (Janeway lesions)
Red, tender spots under the skin of the fingers or toes (Osler’s nodes)
Tiny red or purple spots on the skin, inside the mouth, or in the whites of the eyes (petechiae)
Heart Valve Disease
Heart valve disease refers to the improper functioning of one or more of the four valves within the heart that open and close to control blood flow, meaning it disrupts blood flow through your heart to the rest of your body. Damage to the heart valves can take many forms, primarily narrowing (stenosis), leaking (regurgitation or insufficiency), or improper closing (prolapse). The exact symptoms can differ based on which valve is affected, but they generally include:
Abnormal heart murmur
Shortness of breath, especially when lying down or after physical activity
Dizziness or fainting
Swollen feet or ankles
Preventing Cardiovascular Complications From Medication
Patients with cardiovascular issues often take multiple medications, sometimes prescribed by several different clinicians, without considering the potential for drug interactions and filled by different pharmacists. Physicians should always conduct a comprehensive medication review during every office visit and admission, carefully consider the risks of each medication before prescribing it, only prescribe drugs as needed, and discontinue medications that prove ineffective or are contraindicated for patients with heart conditions. It may also be valuable to discuss combination medications that treat multiple conditions to reduce the need for several medications. Because physicians are often under time constraints, please do your own careful research before your next doctor visit and come prepared with information such as we have provided in this comprehensive article. In this way, you and your prescriber can work together as a well-informed and efficiently coordinated team.
This content has been reviewed and approved by a licensed physician.
Dr. Michael Loes, M.D.
Dr. Michael Loes is board-certified in Internal Medicine, Pain Management and Addiction Medicine. He holds a dual license in Homeopathic and Integrative Medicine. He obtained his medical doctorate at the University of Minnesota, Minneapolis, MN, 1978. Dr. Loes performed an externship at the National Institute of Health for Psychopharmacology. Additionally, he is a well-published author including Arthritis: The Doctor’s Cure, The Aspirin Alternative, The Healing Response, and Spirit Driven Health: The Psalmist’s Guide for Recovery. He has been awarded the Minnesota Medical Foundation’s “Excellence in Research” Award.
Lyle Murphy is the founder of the Alternative to Meds Center, a licensed residential program that helps people overcome dependence on psychiatric medication and addiction issues using holistic and psychotherapeutic methods.
Medical Disclaimer: Nothing on this Website is intended to be taken as medical advice. The information provided on the website is intended to encourage, not replace, direct patient-health professional relationships. Always consult with your doctor before altering your medications. Adding nutritional supplements may alter the effect of medication. Any medication changes should be done only after proper evaluation and under medical supervision.