key: cord-0692950-z22g03v4 authors: Prodromos, Chadwick C. title: Hydroxychloroquine is protective to the heart, not Harmful: A systematic review date: 2020-08-20 journal: New Microbes New Infect DOI: 10.1016/j.nmni.2020.100747 sha: c7d3d15feb5d7aff251f836038ad4d194b3379ff doc_id: 692950 cord_uid: z22g03v4 Abstract Background Hydroxychloroquine (HCQ) has been shown to be at least somewhat effective in treating COVID 19 patients. Recently FDA and CDC warnings of fatal cardiac toxicity from Torsade de Pointes (TDP) arrhythmia from HCQ use have been made, notwithstanding the long safe HCQ use for lupus and rheumatoid arthritis. This has resulted in restricted access of HCQ for COVID 19 treatment. We hypothesized that HCQ and azithromycin have not been reported to cause significant acute cardiac arrhythmic mortality. Methods We performed a literature search for the effects of HCQ and azithromycin on the heart. Results No Torsade de Pointes or related deaths were found to have been reported as a result of HCQ and azithromycin use in the peer reviewed literature. To the contrary HCQ/azithromycin were uniformly found to substantially reduce cardiac mortality and also to decrease thrombosis, arrhythmia and cholesterol in treated patients in recent peer reviewed studies and meeting presentations. Conclusions HCQ and azithromycin do not cause TDP cardiac mortality. HCQ decreases cardiac events. HCQ should not be restricted in use for COVID 19 patients because of fear of cardiac mortality. Several clinical studies, now numbering thousands of patients, [1] [2] [3] [4] have shown 26 apparent substantial clinical benefit from the use of hydroxychloroquine (HCQ) in COVID 19 27 patients and have not reported adverse cardiac events. A number of meta-analyses [5] [6] [7] have 28 also shown overall good results although with limited quality studies. Usage of HCQ would 29 therefore be warranted for COVID 19 by physicians who were so inclined unless there were 30 significant clinical risks to offset the apparent benefits. 31 However, recently numerous warnings have been issued from the FDA [8], CDC [9] , the 32 American Heart Association [10] and elsewhere about potential fatal cardiac toxicity from 33 Torsade de Pointes or other ventricular arrhythmias from HCQ use. These warnings state that 34 such fatalities could occur secondary to the increase in QTc that is sometimes seen with the use 35 of HCQ as well as azithromycin, which is often used in combination with HCQ. The FDA warning 36 on reseased June 15 th along with the revoking of it's prior emergency use authorization states 37 that "Additionally, in light of ongoing serious cardiac adverse events and other potential serious 38 side effects, the known and potential benefits of chloroquine and hydroxychloroquine no 39 referenced by agencies that warn of HCQ cardiotoxicity, which rather refers to QTc 68 prolongation and the risk of Torsade de Pointes. 69 We conducted a search of the Pubmed, Medline, Cochrane, Embase, and Google Scholar 70 databases. Search terms included hydroxychloroquine and azithromycin and the following co-71 CAD was applicable across a range of ages, different genders, and multiple co-morbidities in a 120 2013 paper entitled "Chloroquine and hydroxychloroquine are associated with reduced 121 cardiovascular risk: a systematic review and meta-analysis" found a lower risk of CVD in 122 patients with rheumatic diseases who were using with HCQ or Chloroquine. Rempenault Izmirly [21] in 2013 showed the recurrence rate of cardiac-Neonatal Lupus in fetuses 138 exposed to HCQ was 7.5% (3/40) compared to 21.2% (46/217) in the unexposed group 139 (p=0.050). While there were no deaths in the exposed group, the overall case fatality rate of the 140 cardiac-NL fetuses in the unexposed group was 22%. The most important finding of this review is that evidence shows HCQ to be overall 176 significantly cardioprotective, and apparently not cardiotoxic in short term use. This supports 177 Pointes or related cardiac causes. This finding of cardioprotection, which was surprising to us, 179 goes well beyond our hypothesis. Perhaps because many of the studies showing 180 cardioprotection are relatively recent, the cardioprotective effect seems to be generally 181 unknown to both the general population and the medical community. The cardio-protection 182 includes a decrease in cardiac events, in thrombosis in general, in arrhythmia, in lipid profile 183 and even in fetal disease. With HCQ generally beneficial to the heart in patients with rheumatic 184 disease, there would be no reason to think that it would be cardiotoxic in COVID 19 patients, 185 unless these patients were late in the disease course with established viral cardiac damage. 186 Even then this would be only a theoretical risk because it is also possible that HCQ might be 187 protective of further damage in this circumstance. 188 The second major finding of this study is that we were unable to find any reports of TDP 189 Limitations of this study include the possibility that cardiac deaths have occurred but 210 not been reported. However, even if a small number of TDP deaths have occurred, it would not 211 change the finding that HCQ is overall safe and generally beneficial for the heart. 212 In fact, the finding of an anti-thrombotic effect, an anti-arrhythmic effect, and a 213 reduction in CVD events raises the possibility that HCQ should be considered in well controlled 214 clinical trials as a treatment for COVID 19 patients who have sustained cardiac damage as a 215 possible mitigant of these effects.. 216 Conclusions 218 HCQ is apparently not dangerous to the heart and indeed is cardioprotective. It results 219 in a lower incidence of cardiac events as well as lower levels of arrhythmia, cholesterol, and 220 thrombosis. No TDP deaths from HCQ have apparently been reported in the peer reviewed 221 literature. The potential risk of fatal arrhythmia, e.g. TDP, from HCQ, appears to be essentially a 222 theoretical risk only. It appears to occur very rarely if ever in clinical practice if HCQ is used 223 according to standard treatment protocols. Azithromycin used in combination with HCQ also 224 appears to be safe, does not appear to cause TDP mortality, and is also apparently 225 cardioprotective. Due to its ability to decrease CVD events, decrease arrhythmia, decrease 226 thrombosis and decrease cholesterol, HCQ should be considered as an agent for study to 227 potentially treat patients who have developed cardiac damage from COVID 19. A pilot study of hydroxychloroquine in treatment of patients with moderate 247 COVID-19], Zhejiang Da Xue Xue Bao Yi Xue Ban Early treatment of 253 COVID-19 patients with hydroxychloroquine and azithromycin: A retrospective analysis of 1061 254 cases Low dose of 256 hydroxychloroquine reduces fatality of critically ill patients with COVID-19 Controversial Doc in Trump's Ear Calls Malaria Drug "Garbage Does hydroxychloroquine combat COVID-19? A timeline of evidence, 261 A Rapid Systematic Review of Utilizing Chloroquine and Hydroxychloroquine as a Treatment for COVID-19 Review: Hydroxychloroquine and Chloroquine for Treatment of SARS-268 CoV-2 (COVID-19) FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside 270 of t he hospitalsetting or a clinical trial due to risk of heart rhythm problems 2020 Chloroquine Phosphate to Prevent and Treat Coronavirus Disease Association, Caution recommended on COVID-19 treatment with hydroxychloroquine 274 and azithromycin for patients with cardiovascular disease COVID-19) Update: FDA Revokes Emergency Use Authorization 276 for Chloroquine and Hydroxychloroquine, Food & Drug Administration update of the EULAR recommendations for the management 279 of systemic lupus erythematosus Ohio pharmacy board restricts prescriptions for experimental coronavirus 281 treatment drugs Gultekin Sh Fau -Hata Fatal antimalarial-induced cardiomyopathy: report of 2 cases Hydroxychloroquine cardiotoxicity in 288 systemic lupus erythematosus: a report of 2 cases and review of the literature, Semin Arthritis 289 Rheum Suspected hydroxychloroquine-associated QT-interval 291 prolongation in a patient with systemic lupus erythematosus Life Threatening Severe QTc Prolongation in Patient 294 with Systemic Lupus Erythematosus due to Hydroxychloroquine Chronic hydroxychloroquine use associated with QT 297 prolongation and refractory ventricular arrhythmia 299 Right Bundle Brunch Block and QTc Prolongation in a Patient with Novel Coronavirus Disease 300 (COVID-19) Treated with Hydroxychloroquine A cross-sectional study 302 of clinical thrombotic risk factors and preventive treatments in antiphospholipid syndrome Maternal use of hydroxychloroquine is associated 306 with a reduced risk of recurrent anti-SSA/Ro-antibody-associated cardiac manifestations of 307 neonatal lupus Effect of prednisone and hydroxychloroquine 309 on coronary artery disease risk factors in systemic lupus erythematosus: a longitudinal data 310 analysis Hydroxychloroquine may be 312 associated with reduced risk of coronary artery diseases in patients with rheumatoid arthritis: A 313 nationwide population-based cohort study Hydroxychloroquine Blood Levels and Risk of Thrombotic Events American College of Rhematology Annual MeetingAtlanta, GA Effect of antimalarials on thrombosis and survival in patients with 319 systemic lupus erythematosus Drugs Used in the Treatment of 321 Rheumatoid Arthritis: Relationship between Current Use and Cardiovascular Risk Factors QT interval prolongation under hydroxychloroquine/azithromycin 325 association for inpatients with SARS-CoV-2 lower respiratory tract infection The Effect of Chloroquine, Hydroxychloroquine and Azithromycin on the Corrected QT 330 Interval in Patients with SARS-CoV-2 Infection Disease-332 modifying antirheumatic drugs are associated with a reduced risk for cardiovascular disease in 333 patients with rheumatoid arthritis: a case control study Hydroxychloroquine Use Is Associated With Decreased Incident Cardiovascular Events in 336 Rheumatoid Arthritis Patients Long-Term Hydroxychloroquine 338 Therapy and Risk of Coronary Artery Disease in Patients with Systemic Lupus Erythematosus The association between hydroxychloroquine treatment and 341 cardiovascular morbidity among rheumatoid arthritis patients Association of Hydroxychloroquine Use 343 and Incident Atrial Fibrillation in Systemic Lupus Erythematosus: A Retrospective Study Risk 346 of QT Interval Prolongation Associated With Use of Hydroxychloroquine With or Without 347 Concomitant Azithromycin Among Hospitalized Patients Testing Positive for Coronavirus 348 Disease 2019 (COVID-19) Effects of hydroxychloroquine 350 treatment on QT interval QT Interval Prolongation and Torsade De Pointes in Patients 354 with COVID-19 treated with Hydroxychloroquine/Azithromycin Chloroquine and hydroxychloroquine are associated with reduced cardiovascular risk: a 357 systematic review and meta-analysis 359 Metabolic and cardiovascular benefits of hydroxychloroquine in patients with rheumatoid 360 arthritis: a systematic review and meta-analysis Myth-busting: Azithromycin does not cause torsade de pointes or increase 364 mortality Suppress Ventricular Contraction, but Will Not Induce Torsade de Pointes Azithromycin therapy reduces cardiac inflammation and 371 mitigates adverse cardiac remodeling after myocardial infarction: Potential therapeutic targets 372 in ischemic heart disease Pharmacovigilance Memorandum -Review of Hydroxychloroquine-374 Chloroquine Inflammation and thrombosis Mechanisms of action of hydroxychloroquine and 380 chloroquine: implications for rheumatology Hydroxychloroquine as an anti-thrombotic in antiphospholipid syndrome