Considerations for Certain Concomitant Medications in Patients With COVID-19
Last Updated: August 4, 2021
|Rating of Recommendations: A = Strong; B = Moderate; C = Optional |
Rating of Evidence: I = One or more randomized trials without major limitations; IIa = Other randomized trials or subgroup analyses of randomized trials; IIb = Nonrandomized trials or observational cohort studies; III = Expert opinion
Individuals with underlying medical conditions, such as cardiovascular disease, pulmonary disease, diabetes, and malignancy, are at higher risk of severe illness with COVID-19. These patients are often prescribed medications to treat their underlying medical conditions. It is unclear whether these concomitant medications have a positive or negative impact on the treatment and outcomes of COVID-19.
The following section reviews the available data on the use of certain concomitant medications for comorbid conditions in patients with COVID-19 and discusses the considerations clinicians should be aware of when evaluating a patient’s concomitant therapy. When prescribing medications for the treatment of COVID-19, clinicians should always assess the patient’s current medications for potential drug interactions and adverse effects. The decision to continue or change a patient’s medications should be individualized based on their condition.
Patients with COVID-19 who are treated with concomitant medications for an underlying medical condition should not discontinue these medications during acute management of COVID-19 unless discontinuation is otherwise warranted by their clinical condition (AIII). Some of these medications have been evaluated as potential treatments for COVID-19; this section will discuss the available data and any additional considerations that clinicians should be aware of when using these medications.
Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers
- Patients with COVID-19 who are receiving angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) for cardiovascular disease (or other non-COVID-19 indications) should not discontinue these medications unless discontinuation is otherwise warranted by their clinical condition (AIIa).
- The COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of ACE inhibitors or ARBs for the treatment of COVID-19, except in a clinical trial (AIII).
These recommendations are in accord with a joint statement of the American Heart Association, the Heart Failure Society of America, and the American College of Cardiology.1
ACE2 is the cell surface receptor for SARS-CoV-2. It has been hypothesized that using ACE inhibitors or ARBs to modulate ACE2 could suppress or enhance SARS-CoV-2 replication.2,3 Meta-analyses and an ongoing systematic review have not found an association between the use of ACE inhibitors or ARBs and the likelihood of a positive result on a SARS-CoV-2 test or the severity of COVID-19.4,5
In a multicenter, open-label randomized trial, hospitalized patients with COVID-19 (n = 659) who were receiving chronic ACE inhibitor therapy or ARB therapy were randomized to continue or discontinue their therapy for 30 days. Treatment of COVID-19 followed local standards of care, and the use of alternative therapies to replace the discontinued medications was at the discretion of the treating physician. The study did not enroll any patients who required invasive mechanical ventilation or who had hemodynamic instability or multiple organ failure.
Overall, there was no difference between the arms in the primary endpoint of days alive and out of the hospital; the mean number of days alive and out of the hospital was 21.9 days in the discontinuation arm and 22.9 days in the continuation arm (mean ratio 0.95; 95% CI, 0.90–1.01). No differences were observed in the secondary endpoints of the percentages of patients who experienced death, cardiovascular events, or COVID-19 progression. Subgroup analyses identified an interaction between the treatment effect and the subgroup of patients who had more severe COVID-19 (those with oxygen saturation <94%, pulmonary infiltrates >50%, or a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen [PaO2/FiO2] <300 mm Hg). There may be a clinical benefit to continuing ACE inhibitor therapy or ARB therapy in these patients. Because of limitations in the available data, it is difficult to interpret these findings in patients with certain comorbid conditions, severe or critical illness, and pre-existing diagnoses of heart failure.6
Additional investigations into the role of ACE inhibitors, ARBs, and recombinant human ACE2 in the management of COVID-19 are underway.1 Please see ClinicalTrials.gov for the latest information.
- Patients with COVID-19 who are receiving inhaled or systemic corticosteroids for an underlying condition should not discontinue these medications unless discontinuation is otherwise warranted by their clinical condition (AIII).
- There is insufficient evidence for the Panel to recommend either for or against the use of inhaled budesonide for the treatment of COVID-19.
- Systemic treatment with dexamethasone or other corticosteroids is recommended for certain populations of patients with COVID-19. See Therapeutic Management of Hospitalized Adults With COVID-19, Corticosteroids, and Special Considerations in Pregnancy for specific recommendations.
Oral corticosteroid therapy prescribed for an underlying medical condition (e.g., primary or secondary adrenal insufficiency, rheumatological diseases) should be continued in patients after the diagnosis of COVID-19.7 Supplemental or stress-dose steroids may be indicated in individual cases.
Inhaled corticosteroids that are used daily by patients with asthma and chronic obstructive pulmonary disease to control airway inflammation should not be discontinued in patients with COVID-19. A large, retrospective study of adult patients with chronic obstructive pulmonary disease and asthma found that those who were prescribed high doses of inhaled corticosteroids had a higher risk of mortality than those who received other inhaled medications without corticosteroids; however, the study had limitations.8 In fact, the authors suggested that this association may have been due to differences between the groups in the severity of the underlying disease rather than a harmful effect of the inhaled corticosteroids. For patients with COVID-19 who require nebulized corticosteroids, precautions should be taken to minimize the potential for transmission of SARS-CoV-2 in the home and in health care settings.9,10 Please see Corticosteroids for a summary of the clinical data on using inhaled corticosteroids to manage COVID-19 in outpatients.
The use of corticosteroids has been associated with delayed viral clearance and/or worse clinical outcomes in patients with other viral respiratory infections.11-13 Some studies have suggested that systemic corticosteroids slow SARS-CoV-2 clearance, especially when they are administered earlier in the course of infection.14-18 There is insufficient evidence to identify a relationship between inhaled corticosteroid use and the speed of viral clearance.
HMG-CoA Reductase Inhibitors (Statins)
- Patients with COVID-19 who are receiving statin therapy for an underlying condition should not discontinue these medications unless discontinuation is otherwise warranted by their clinical condition (AIII).
- The Panel recommends against the use of statins for the treatment of COVID-19, except in a clinical trial (AIII).
HMG-CoA reductase inhibitors, or statins, affect ACE2 as part of their function in reducing endothelial dysfunction. It has been proposed that these agents may have a potential role in managing patients with severe COVID-19.19
A large observational study in China found that hospitalized patients with COVID-19 who received statins had a lower risk of all-cause mortality than patients who did not receive statins (aHR 0.63; 95% CI, 0.48–0.84; P = 0.001).20 In contrast, a retrospective, multicenter study of critically ill patients with COVID-19 in Italy found no association between the long-term use of statins and mortality (aHR 0.98; 95% CI, 0.81–1.20; P = 0.87).21 Similarly, recent receipt of statin therapy was not associated with a higher mortality risk (aHR 0.96; 95% CI, 0.78–1.18) or the severity of disease (aHR 1.16; 95% CI, 0.95–1.41) in a national cohort study of 4,842 patients with COVID-19 in Denmark.22
More data are needed to clarify the impact of statin therapy on COVID-19. Clinical trials that are evaluating the therapeutic impact of statins as an adjunctive therapy for COVID-19 are currently underway. Please see ClinicalTrials.gov for the latest information.
Nonsteroidal Anti-Inflammatory Drugs
- Patients with COVID-19 who are receiving nonsteroidal anti-inflammatory drugs (NSAIDs) for an underlying medical condition should not discontinue therapy unless discontinuation is otherwise warranted by their clinical condition (AIII).
- Strategies for using antipyretic therapy (e.g., acetaminophen, NSAIDs) in patients with COVID-19 should remain similar to the approaches used in other patients (AIII).
In March 2020, news agencies promoted reports that anti-inflammatory drugs may worsen COVID-19. It has been proposed that NSAIDs can increase the expression of ACE22 and inhibit antibody production.23 Shortly after these reports, the Food and Drug Administration stated that there is no evidence linking the use of NSAIDs with worsening of COVID-19 and advised patients to use NSAIDs as directed.24
In a national cohort study of patients who tested positive for SARS-CoV-2 infection in Denmark, no association was found between a history of NSAID use and the need for hospitalization, the risk of mortality, or the severity of illness.25
- Patients with COVID-19 who are receiving acid-suppressive therapy for an underlying condition should not discontinue these medications unless discontinuation is otherwise warranted by their clinical condition (AIII).
- The Panel recommends against the use of famotidine for the treatment of COVID-19, except in a clinical trial (AIII).
Acid-suppressive therapies, such as proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs), increase gastric pH. Low gastric pH is proposed to be a protective mechanism against infection with viruses that can enter the body through the gastrointestinal tract (e.g., enteric viruses, SARS-CoV).26 Observational studies that have evaluated the relationship between the use of acid-suppressive therapy and the acquisition of SARS-CoV-2 or COVID-19 disease severity have produced mixed results.
A propensity-matched cohort study in South Korea observed that current PPI use was not associated with a higher risk of testing positive for SARS-CoV-2, but it was associated with a higher risk of severe illness.27 An online survey conducted in the United States identified no association between the use of H2RAs and the risk of SARS-CoV-2 infection, while PPI therapy was associated with higher odds of receiving a diagnosis of SARS-CoV-2 infection, especially in those who received twice-daily doses of PPIs.26 However, these studies had the inherent limitations of observational studies and studies that rely on surveys, and they likely had multiple confounding factors.
The impact of the H2RA famotidine on COVID-19 outcomes has been evaluated in observational studies. In a retrospective study of 878 hospitalized patients with COVID-19, the patients who received famotidine (n = 83) had lower odds of death than those who did not.28 In another retrospective study of 84 patients who received famotidine and a matched comparator group of 420 patients who did not, the use of famotidine was associated with a reduction in the composite outcome of death or intubation.29 Only a small proportion of the patients enrolled in these studies received famotidine, and it is unclear what the indications for famotidine therapy were or whether there were other confounding factors. These limitations make it difficult to draw conclusions about the efficacy of using famotidine to treat patients with COVID-19.
Results from ongoing clinical trials will provide more insights into the role of famotidine in the treatment of COVID-19. Please see ClinicalTrials.gov for the latest information.
In patients with COVID-19 who require PPI therapy, the American College of Gastroenterology suggests using the lowest effective dose of the PPI.30
- Bozkurt B, Kovacs R, Harrington B. Joint HFSA/ACC/AHA statement addresses concerns re: using RAAS antagonists in COVID-19. J Card Fail. 2020;26(5):370. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32439095.
- Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020;8(4):e21. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32171062.
- Patel AB, Verma A. COVID-19 and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: what is the evidence? JAMA. 2020;323(18):1769-1770. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32208485.
- Mackey K, Kansagara D, Vela K. Update alert 3: risks and impact of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers on SARS-CoV-2 infection in adults. Ann Intern Med. 2020;173(7):130-131. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32845705.
- Flacco ME, Acuti Martellucci C, Bravi F, et al. Treatment with ACE inhibitors or ARBs and risk of severe/lethal COVID-19: a meta-analysis. Heart. 2020;106(19):1519-1524. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32611676.
- Lopes RD, Macedo AVS, de Barros E Silva PGM, et al. Effect of discontinuing vs continuing angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on days alive and out of the hospital in patients admitted With COVID-19: a randomized clinical trial. JAMA. 2021;325(3):254-264. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33464336.
- Kaiser UB, Mirmira RG, Stewart PM. Our response to COVID-19 as endocrinologists and diabetologists. J Clin Endocrinol Metab. 2020;105(5). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32232480.
- Schultze A, Walker AJ, MacKenna B, et al. Risk of COVID-19-related death among patients with chronic obstructive pulmonary disease or asthma prescribed inhaled corticosteroids: an observational cohort study using the OpenSAFELY platform. Lancet Respir Med. 2020;8(11):1106-1120. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32979987.
- Cazzola M, Ora J, Bianco A, Rogliani P, Matera MG. Guidance on nebulization during the current COVID-19 pandemic. Respir Med. 2021;176:106236. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33248363.
- Sethi S, Barjaktarevic IZ, Tashkin DP. The use of nebulized pharmacotherapies during the COVID-19 pandemic. Ther Adv Respir Dis. 2020;14:1753466620954366. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33167796.
- Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Med. 2006;3(9):e343. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16968120.
- Rodrigo C, Leonardi-Bee J, Nguyen-Van-Tam J, Lim WS. Corticosteroids as adjunctive therapy in the treatment of influenza. Cochrane Database Syst Rev. 2016;3:CD010406. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26950335.
- Arabi YM, Mandourah Y, Al-Hameed F, et al. Corticosteroid therapy for critically ill patients with Middle East respiratory syndrome. Am J Respir Crit Care Med. 2018;197(6):757-767. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29161116.
- Chen Y, Li L. Influence of corticosteroid dose on viral shedding duration in patients with COVID-19. Clin Infect Dis. 2021;72(7):1298-1300. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454365/.
- Li S, Hu Z, Song X. High-dose but not low-dose corticosteroids potentially delay viral shedding of patients with COVID-19. Clin Infect Dis. 2021;72(7):1297-1298. Available at: https://pubmed.ncbi.nlm.nih.gov/32588877/.
- Ding C, Feng X, Chen Y, et al. Effect of corticosteroid therapy on the duration of SARS-CoV-2 clearance in patients with mild COVID-19: a retrospective cohort study. Infect Dis Ther. 2020;9(4):943-952. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32986226.
- Liu J, Zhang S, Dong X, et al. Corticosteroid treatment in severe COVID-19 patients with acute respiratory distress syndrome. J Clin Invest. 2020;130(12):6417-6428. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33141117.
- Spagnuolo V, Guffanti M, Galli L, et al. Viral clearance after early corticosteroid treatment in patients with moderate or severe covid-19. Sci Rep. 2020;10(1):21291. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33277573.
- Fedson DS, Opal SM, Rordam OM. Hiding in plain sight: an approach to treating patients with severe COVID-19 infection. mBio. 2020;11(2). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32198163.
- Zhang XJ, Qin JJ, Cheng X, et al. In-hospital use of statins is associated with a reduced risk of mortality among individuals with COVID-19. Cell Metab. 2020;32(2):176-187 e174. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32592657.
- Grasselli G, Greco M, Zanella A, et al. Risk factors associated with mortality among patients with COVID-19 in intensive care units in Lombardy, Italy. JAMA Intern Med. 2020;180(10):1345-1355. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32667669.
- Butt JH, Gerds TA, Schou M, et al. Association between statin use and outcomes in patients with coronavirus disease 2019 (COVID-19): a nationwide cohort study. BMJ Open. 2020;10(12):e044421. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33277291.
- Bancos S, Bernard MP, Topham DJ, Phipps RP. Ibuprofen and other widely used non-steroidal anti-inflammatory drugs inhibit antibody production in human cells. Cell Immunol. 2009;258(1):18-28. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19345936.
- Food and Drug Administration. FDA advises patients on use of non-steroidal anti-inflammatory drugs (NSAIDs) for COVID-19. 2020. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-advises-patients-use-non-steroidal-anti-inflammatory-drugs-nsaids-covid-19. Accessed July 28, 2021.
- Lund LC, Kristensen KB, Reilev M, et al. Adverse outcomes and mortality in users of non-steroidal anti-inflammatory drugs who tested positive for SARS-CoV-2: a Danish nationwide cohort study. PLoS Med. 2020;17(9):e1003308. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32898149.
- Almario CV, Chey WD, Spiegel BMR. Increased risk of COVID-19 among users of proton pump inhibitors. Am J Gastroenterol. 2020;115(10):1707-1715. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32852340.
- Lee SW, Ha EK, Yeniova AO, et al. Severe clinical outcomes of COVID-19 associated with proton pump inhibitors: a nationwide cohort study with propensity score matching. Gut. 2021;70(1):76-84. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32732368.
- Mather JF, Seip RL, McKay RG. Impact of famotidine use on clinical outcomes of hospitalized patients with COVID-19. Am J Gastroenterol. 2020;115(10):1617-1623. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32852338.
- Freedberg DE, Conigliaro J, Wang TC, et al. Famotidine use is associated with improved clinical outcomes in hospitalized COVID-19 patients: a propensity score matched retrospective cohort study. Gastroenterology. 2020;159(3):1129-1131 e1123. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32446698.
- American College of Gastroenterology. Information sheet and FAQs about proton pump inhibitors (PPIs) and risk of COVID-19. 2020. Available at: https://webfiles.gi.org/links/media/ACG_Almario_et_al_Info_Sheet_and_FAQs_About_PPIs_COVID19_07072020_FINAL.pdf.