{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T10:26:50Z","timestamp":1760956010930,"version":"build-2065373602"},"reference-count":41,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2020,6,15]],"date-time":"2020-06-15T00:00:00Z","timestamp":1592179200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL133290","R01HL143074"],"award-info":[{"award-number":["R01HL133290","R01HL143074"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["19POST34460025"],"award-info":[{"award-number":["19POST34460025"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>In light of the favorable outcomes of few small, non-randomized clinical studies, the Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) to Hydroxychloroquine (HCQ) for hospitalized coronavirus disease 2019 (COVID-19) patients. In fact, subsequent clinical studies with COVID-19 and HCQ have reported limited efficacy and poor clinical benefits. Unfortunately, a robust clinical trial for its effectiveness is not feasible at this emergency. Additionally, HCQ was suspected of causing cardiovascular adverse reactions (CV-AEs), but it has never been directly investigated. The objective of this pharmacovigilance analysis was to determine and characterize HCQ-associated cardiovascular adverse events (CV-AEs). We performed a disproportionality analysis of HCQ-associated CV-AEs using the FDA adverse event reporting system (FAERS) database. The FAERS database, comprising more than 11,901,836 datasets and 10,668,655 patient records with drug-adverse reactions, was analyzed. The disproportionality analysis was used to calculate the reporting odds ratios (ROR) with 95% confidence intervals (CI) to predict HCQ-associated CV-AEs. HCQ was associated with higher reporting of right ventricular hypertrophy (ROR: 6.68; 95% CI: 4.02 to 11.17), left ventricular hypertrophy (ROR: 3.81; 95% CI: 2.57 to 5.66), diastolic dysfunction (ROR: 3.54; 95% CI: 2.19 to 5.71), pericarditis (ROR: 3.09; 95% CI: 2.27 to 4.23), torsades de pointes (TdP) (ROR: 3.05; 95% CI: 2.30 to 4.10), congestive cardiomyopathy (ROR: 2.98; 95% CI: 2.01 to 4.42), ejection fraction decreased (ROR: 2.41; 95% CI: 1.80 to 3.22), right ventricular failure (ROR: 2.40; 95% CI: 1.64 to 3.50), atrioventricular block complete (ROR: 2.30; 95% CI: 1.55 to 3.41) and QT prolongation (ROR: 2.09; 95% CI: 1.74 to 2.52). QT prolongation and TdP are most relevant to the COVID-19 treatment regimen of high doses for a comparatively short period and represent the most common HCQ-associated AEs. The patients receiving HCQ are at higher risk of various cardiac AEs, including QT prolongation and TdP. These findings highlight the urgent need for prospective, randomized, controlled studies to assess the risk\/benefit ratio of HCQ in the COVID-19 setting before its widespread adoption as therapy.<\/jats:p>","DOI":"10.3390\/jcm9061867","type":"journal-article","created":{"date-parts":[[2020,6,16]],"date-time":"2020-06-16T00:50:49Z","timestamp":1592268649000},"page":"1867","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["A Pharmacovigilance Study of Hydroxychloroquine Cardiac Safety Profile: Potential Implication in COVID-19 Mitigation"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9409-1366","authenticated-orcid":false,"given":"Anand Prakash","family":"Singh","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Disease, The University of Alabama at Birmingham (UAB), Birmingham, AL 35294-1913, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6174-6541","authenticated-orcid":false,"given":"Sultan","family":"Tousif","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Disease, The University of Alabama at Birmingham (UAB), Birmingham, AL 35294-1913, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Prachi","family":"Umbarkar","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Disease, The University of Alabama at Birmingham (UAB), Birmingham, AL 35294-1913, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8980-9874","authenticated-orcid":false,"given":"Hind","family":"Lal","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Disease, The University of Alabama at Birmingham (UAB), Birmingham, AL 35294-1913, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,15]]},"reference":[{"unstructured":"World Health Organization (2020, March 12). Who Director-General\u2019s Opening Remarks at the Media Briefing on Covid-19\u201311 March 2020. Available online: https:\/\/www.who.int\/dg\/speeches\/detail\/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020.","key":"ref_1"},{"unstructured":"World Health Organization (2020). Coronavirus Disease (Covid-2019) Situation Reports, World Health Organization.","key":"ref_2"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1001\/jama.2020.2648","article-title":"Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72314 cases from the chinese center for disease control and prevention","volume":"323","author":"Wu","year":"2020","journal-title":"JAMA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.4269\/ajtmh.20-0290","article-title":"Chloroquine and hydroxychloroquine for the prevention or treatment of novel coronavirus disease (COVID-19) in Africa: Caution for inappropriate off-label use in healthcare settings","volume":"102","author":"Abena","year":"2020","journal-title":"Am. J. Trop. Med. Hyg."},{"doi-asserted-by":"crossref","unstructured":"Chen, Z., Hu, J., Zhang, Z., Jiang, S., Han, S., Yan, D., Zhuang, R., Hu, B., and Zhang, Z. (2020). Efficacy of hydroxychloroquine in patients with COVID-19: Results of a randomized clinical trial. medRxiv.","key":"ref_5","DOI":"10.1101\/2020.03.22.20040758"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1038\/s41421-020-0156-0","article-title":"Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro","volume":"6","author":"Liu","year":"2020","journal-title":"Cell Discov."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/0002-9343(83)91265-2","article-title":"Animal toxicity and pharmacokinetics of hydroxychloroquine sulfate","volume":"75","author":"McChesney","year":"1983","journal-title":"Am. J. Med."},{"unstructured":"Drugs.com (2020, May 18). Hydroxychloroquine Sulfate Monograph for Professionals. Available online: https:\/\/www.drugs.com\/monograph\/hydroxychloroquine-sulfate.html.","key":"ref_8"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6027","DOI":"10.1096\/fj.202000919","article-title":"Rethinking the role of hydroxychloroquine in the treatment of COVID-19","volume":"34","author":"Meyerowitz","year":"2020","journal-title":"FASEB J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"R155","DOI":"10.1186\/ar3895","article-title":"Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus","volume":"14","author":"Sacre","year":"2012","journal-title":"Arthritis Res."},{"doi-asserted-by":"crossref","unstructured":"Gautret, P., Lagier, J.C., Parola, P., Hoang, V.T., Meddeb, L., Mailhe, M., Doudier, B., Courjon, J., Giordanengo, V., and Vieira, V.E. (2020). Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial. Int. J. Antimicrob. Agents, 105949.","key":"ref_11","DOI":"10.1101\/2020.03.16.20037135"},{"doi-asserted-by":"crossref","unstructured":"Magagnoli, J., Narendran, S., Pereira, F., Cummings, T., Hardin, J.W., Sutton, S.S., and Ambati, J. (2020). Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. medRxiv.","key":"ref_12","DOI":"10.1101\/2020.04.16.20065920"},{"doi-asserted-by":"crossref","unstructured":"Molina, J.M., Delaugerre, C., Le Goff, J., Mela-Lima, B., Ponscarme, D., Goldwirt, L., and de Castro, N. (2020). No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Med. Mal. Infect.","key":"ref_13","DOI":"10.1016\/j.medmal.2020.03.006"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e208857","DOI":"10.1001\/jamanetworkopen.2020.8857","article-title":"Effect of high vs. low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: A randomized clinical trial","volume":"3","author":"Borba","year":"2020","journal-title":"JAMA Netw. Open"},{"unstructured":"U.S. Food & Drug Administration (2020, April 25). FDA Cautions against Use of Hydroxychloroquine or Chloroquine for Covid-19 Outside of the Hospital Setting or a Clinical Trial due to Risk of Heart Rhythm Problems, Available online: https:\/\/www.fda.gov\/media\/137250\/download.","key":"ref_15"},{"unstructured":"Mayo Clinic (2020, April 25). Guidance on Patients at Risk of Drug-Induced Sudden Cardiac Death from Off-Label Covid-19 Treatments. Available online: https:\/\/newsnetwork.mayoclinic.org\/discussion\/mayo-clinic-provides-urgent-guidance-approach-to-identify-patients-at-risk-of-drug-induced-sudden-cardiac-death-from-use-of-off-label-covid-19-treatments\/.","key":"ref_16"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1080\/15563650500514558","article-title":"Chronic hydroxychloroquine use associated with QT prolongation and refractory ventricular arrhythmia","volume":"44","author":"Chen","year":"2006","journal-title":"Clin. Toxicol. (Phila)"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.ipej.2020.04.003","article-title":"Cardiovascular risks of hydroxychloroquine in treatment and prophylaxis of COVID-19 patients: A scientific statement from the Indian Heart Rhythm Society","volume":"20","author":"Kapoor","year":"2020","journal-title":"Indian Pacing Electrophysiol. J."},{"doi-asserted-by":"crossref","unstructured":"Shi, S., Qin, M., Shen, B., Cai, Y., Liu, T., Yang, F., Gong, W., Liu, X., Liang, J., and Zhao, Q. (2020). Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol.","key":"ref_19","DOI":"10.1001\/jamacardio.2020.0950"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.thromres.2020.04.013","article-title":"Incidence of thrombotic complications in critically ill ICU patients with COVID-19","volume":"191","author":"Klok","year":"2020","journal-title":"Thromb. Res."},{"unstructured":"U.S. Food & Drug Administration (2020, April 25). Hydroxychloroquine Sulfate Drugs@FDA: FDA-Approved Drugs, Available online: https:\/\/www.accessdata.fda.gov\/scripts\/cder\/daf\/index.cfm?event=overview.process&ApplNo=040274.","key":"ref_21"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e13331","DOI":"10.1111\/ijcp.13331","article-title":"Assessing fluoroquinolone-associated aortic aneurysm and dissection: Data mining of the public version of the FDA adverse event reporting system","volume":"73","author":"Meng","year":"2019","journal-title":"Int. J. Clin. Pract."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4803","DOI":"10.1038\/s41598-020-61571-5","article-title":"Safety profile of epidermal growth factor receptor tyrosine kinase inhibitors: A disproportionality analysis of FDA adverse event reporting system","volume":"10","author":"Huang","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.jaccao.2019.10.006","article-title":"Osimertinib-induced cardiotoxicity: A retrospective review of the FDA Adverse Events Reporting System (FAERS)","volume":"1","author":"Anand","year":"2019","journal-title":"JACC Cardiooncol."},{"doi-asserted-by":"crossref","unstructured":"Bohm, R., von Hehn, L., Herdegen, T., Klein, H.J., Bruhn, O., Petri, H., and Hocker, J. (2016). OpenVigil FDA\u2014Inspection of U.S. American adverse drug events pharmacovigilance data and novel clinical applications. PLoS ONE, 11.","key":"ref_25","DOI":"10.1371\/journal.pone.0157753"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/nbt.2113","article-title":"OpenVigil\u2014Free eyeballs on AERS pharmacovigilance data","volume":"30","author":"Bohm","year":"2012","journal-title":"Nat. Biotechnol."},{"key":"ref_27","first-page":"427","article-title":"Quantitative signal detection using spontaneous ADR reporting","volume":"18","author":"Bate","year":"2009","journal-title":"Pharm. Drug Saf."},{"key":"ref_28","first-page":"483","article-title":"Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports","volume":"10","author":"Evans","year":"2001","journal-title":"Pharm. Drug Saf."},{"doi-asserted-by":"crossref","unstructured":"Inciardi, R.M., Lupi, L., Zaccone, G., Italia, L., Raffo, M., Tomasoni, D., Cani, D.S., Cerini, M., Farina, D., and Gavazzi, E. (2020). Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19). JAMA Cardiol.","key":"ref_29","DOI":"10.1001\/jamacardio.2020.1096"},{"doi-asserted-by":"crossref","unstructured":"Guo, T., Fan, Y., Chen, M., Wu, X., Zhang, L., He, T., Wang, H., Wan, J., Wang, X., and Lu, Z. (2020). Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol.","key":"ref_30","DOI":"10.1001\/jamacardio.2020.1017"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1007\/s40264-018-0689-4","article-title":"Cardiac complications attributed to chloroquine and hydroxychloroquine: A systematic review of the literature","volume":"41","author":"Chatre","year":"2018","journal-title":"Drug Saf."},{"unstructured":"U.S. Food & Drug Administration (2020, May 01). EUA Hydroxychloroquine Sulfate Health Care Provider Fact Sheet, Available online: https:\/\/www.fda.gov\/media\/136537\/download.","key":"ref_32"},{"unstructured":"OHDSI\u2014Observational Health Data Sciences and Informatics (2020, May 22). Hydroxychloroquine Safety and Potential Efficacy as an Antiviral Prophylaxis in Light of Potential Wide-Spread Use in Covid-19: A Multinational, Large-Scale Network Cohort and Self-Controlled Case Series Study. Available online: http:\/\/www.encepp.eu\/encepp\/viewResource.htm%3Fid=34498.","key":"ref_33"},{"doi-asserted-by":"crossref","unstructured":"Chorin, E., Wadhwani, L., Magnani, S., Dai, M., Shulman, E., Nadeau-Routhier, C., Knotts, R., Bar-Cohen, R., Kogan, E., and Barbhaiya, C. (2020). QT interval prolongation and torsade de pointes in patients with COVID-19 treated with hydroxychloroquine\/azithromycin. Heart Rhythm.","key":"ref_34","DOI":"10.1101\/2020.04.27.20074583"},{"doi-asserted-by":"crossref","unstructured":"Sarayani, A., Cicali, B., Henriksen, C.H., and Brown, J.D. (2020). Safety signals for QT prolongation or torsades de pointes associated with azithromycin with or without chloroquine or hydroxychloroquine. Res. Soc. Adm. Pharm.","key":"ref_35","DOI":"10.1016\/j.sapharm.2020.04.016"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2352","DOI":"10.1016\/j.jacc.2020.03.031","article-title":"Cardiovascular considerations for patients, health care workers, and health systems during the coronavirus disease 2019 (COVID-19) pandemic","volume":"75","author":"Driggin","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1001\/jama.2020.1585","article-title":"Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China","volume":"323","author":"Wang","year":"2020","journal-title":"JAMA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e32","DOI":"10.1161\/CIR.0000000000000426","article-title":"Drugs that may cause or exacerbate heart failure: A scientific statement from the American heart association","volume":"134","author":"Page","year":"2016","journal-title":"Circulation"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/S0733-8651(05)70164-8","article-title":"Diastolic dysfunction in the elderly. Genesis and diagnostic and therapeutic implications","volume":"18","author":"Kitzman","year":"2000","journal-title":"Cardiol. Clin."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"ehaa253","DOI":"10.1093\/eurheartj\/ehaa253","article-title":"Life-threatening cardiac tamponade complicating myo-pericarditis in COVID-19","volume":"41","author":"Hua","year":"2020","journal-title":"Eur. Heart J."},{"doi-asserted-by":"crossref","unstructured":"Mahevas, M., Tran, V.-T., Roumier, M., Chabrol, A., Paule, R., Guillaud, C., Gallien, S., Lepeule, R., Szwebel, T.-A., and Lescure, X. (2020). No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for COVID-19 infection with oxygen requirement: Results of a study using routinely collected data to emulate a target trial. medRxiv.","key":"ref_41","DOI":"10.1136\/bmj.m1844"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/6\/1867\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:39:10Z","timestamp":1760175550000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/6\/1867"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,15]]},"references-count":41,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["jcm9061867"],"URL":"https:\/\/doi.org\/10.3390\/jcm9061867","relation":{},"ISSN":["2077-0383"],"issn-type":[{"type":"electronic","value":"2077-0383"}],"subject":[],"published":{"date-parts":[[2020,6,15]]}}}