Sales of "COVID kit" drugs and adverse drug reactions reported by the Brazilian Health Regulatory Agency / Vendas de "kit-COVID" e reações adversas a esses medicamentos relatadas pela Agência Nacional de Vigilância Sanitária / Ventas de medicamentos del "kit-COVID" y reacciones adversas a los medicamentos notificadas por la Agencia Nacional de Vigilancia Sanitaria

Off-label use of azithromycin, hydroxychloroquine, and ivermectin (the "COVID kit") has been suggested for COVID-19 treatment in Brazil without clinical or scientific evidence of efficacy. These drugs have known adverse drug reactions (ADR). This study aimed to analyze if the sales of drugs in the "COVID kit" are correlated to the reported number of ADR after the COVID-19 pandemic began. Data was obtained from the Brazilian Health Regulatory Agency (Anvisa) website on reported sales and ADRs for azithromycin, hydroxychloroquine, and ivermectin for all Brazilian states. The period from March 2019 to February 2020 (before the pandemic) was compared to that from March 2020 to February 2021 (during the pandemic). Trend adjustment was performed for time series data and cross-correlation analysis to investigate correlation between sales and ADR within the same month (lag 0) and in the following months (lag 1 and lag 2). Spearman's correlation coefficient was used to assess the magnitude of the correlations. After the pandemic onset, sales of all investigated drugs increased significantly (69.75% for azithromycin, 10,856,481.39% for hydroxychloroquine, and 12,291,129.32% for ivermectin). ADR levels of all medications but azithromycin were zero before the pandemic, but increased after its onset. Cross-correlation analysis was significant in lag 1 for all drugs nationwide. Spearman's correlation was moderate for azithromycin and hydroxychloroquine but absent for ivermectin. Data must be interpreted cautiously since no active search for ADR was performed. Our results show that the increased and indiscriminate use of "COVID kit" during the pandemic correlates to an increased occurrence of ADRs.

No Brasil, o uso off label de azitromicina, hidroxicloroquina e ivermectina (o "kit-COVID") foi sugerido para tratar COVID-19 sem que tivéssemos evidências clínicas ou científicas de sua eficácia. Estas drogas têm causado reações adversas (RA) em quem as tomam. Este estudo almejou analisar se a venda dos medicamentos que compõem o "kit-COVID" correlaciona-se com o número relatado de RAs após o início da pandemia da COVID-19. Os dados sobre vendas e RA associados a azitromicina, hidroxicloroquina e ivermectina foram obtidos no site da Agência Nacional de Vigilância Sanitária (Anvisa) para todos os estados brasileiros. Comparamos o período entre março de 2019 e fevereiro de 2020 (antes da pandemia) ao de março de 2020 a fevereiro de 2021 (durante a pandemia). Ajustamos tendências para os dados de séries temporais e as análises de correlação cruzada para investigar a correlação entre vendas e RA em um mesmo mês (lag 0) e nos seguintes (lag 1 e 2). O coeficiente de correlação de Spearman foi utilizado para avaliar a magnitude das correlações. Após o início da pandemia, as vendas de todos os medicamentos investigados aumentaram significativamente (69,75% para azitromicina, 10.856.481,39% para hidroxicloroquina e 12.291.129,32% para ivermectina). Os níveis de RAs de todos os medicamentos (com exceção de azitromicina) eram zero antes da pandemia mas aumentaram após seu início. A análise de correlação cruzada foi significativa no lag 1 para todas as drogas em todo o país. A correlação de Spearman foi moderada para azitromicina e hidroxicloroquina, mas ausente para ivermectina. Os dados devem ser interpretados com cautela, uma vez que não realizamos uma busca ativa por RA. Nossos resultados mostram que o uso aumentado e indiscriminado do "kit-COVID" durante a pandemia se correlaciona com uma ocorrência aumentada de RAs.

Se ha sugerido el uso fuera de lo establecido de azitromicina, hidroxicloroquina e ivermectina (el "kit-COVID") para el tratamiento de la COVID-19 en Brasil sin evidencia clínica o científica de su eficacia. Estos medicamentos tienen reacciones adversas (RAM) conocidas. Este estudio pretendía analizar si las ventas de medicamentos del "kit-COVID" están correlacionadas con el número de reacciones adversas notificadas tras el inicio de la pandemia de COVID-19. Los datos se obtuvieron del sitio web de la Agencia Nacional de Vigilancia Sanitaria (Anvisa) sobre las ventas y las RAM notificadas para la azitromicina, la hidroxicloroquina y la ivermectina para todos los estados brasileños. Se comparó el periodo de marzo de 2019 a febrero de 2020 (antes de la pandemia) con el de marzo de 2020 a febrero de 2021 (durante la pandemia). Se realizó un ajuste de tendencia para los datos de las series de tiempo y un análisis de correlación cruzada para investigar la correlación entre las ventas y la RAM dentro del mismo mes (lag 0) y en los meses siguientes (lag 1 y lag 2). Se utilizó el coeficiente de correlación de Spearman para evaluar la magnitud de las correlaciones. Tras el inicio de la pandemia, las ventas de todos los medicamentos investigados aumentaron significativamente (69,75% para la azitromicina, 10.856.481,39% para la hidroxicloroquina y 12.291.129,32% para la ivermectina). Los niveles de RAM de todos los medicamentos, excepto la azitromicina, eran nulos antes de la pandemia, pero aumentaron tras su inicio. El análisis de correlación cruzada fue significativo en el lag 1 para todos los medicamentos a nivel nacional. La correlación de Spearman fue moderada para la azitromicina y la hidroxicloroquina, pero no para la ivermectina. Los datos deben interpretarse con cautela, ya que no se realizó una búsqueda activa de RAM. Nuestros resultados muestran que el uso creciente e indiscriminado del "kit-COVID" durante la pandemia se correlaciona con una mayor aparición de las RAM.

Justificativa e Desenho do Ensaio Clínico Randomizado COVID-19 Outpatient Prevention Evaluation (COPE - Coalition V): Hidroxicloroquina vs. Placebo em Pacientes Não Hospitalizados / Rationale and Design of the COVID-19 Outpatient Prevention Evaluation (COPE - Coalition V) Randomized Clinical Trial: Hydroxychloroquine vs. Placebo in Non-Hospitalized Patients

Resumo Fundamento Apesar da necessidade de opções terapêuticas específicas para a doença do coronavírus 2019 (covid-19), ainda não há evidências da eficácia de tratamentos específicos no contexto ambulatorial. Há poucos estudos randomizados que avaliam a hidroxicloroquina (HCQ) em pacientes não hospitalizados. Esses estudos não indicaram benefício com o uso da HCQ; no entanto, avaliaram desfechos primários diferentes e apresentaram vieses importantes na avaliação dos desfechos. Objetivo Investigar se a HCQ possui o potencial de prevenir hospitalizações por covid-19 quando comparada ao placebo correspondente. Métodos O estudo COVID-19 Outpatient Prevention Evaluation (COPE) é um ensaio clínico randomizado, pragmático, duplo-cego, multicêntrico e controlado por placebo que avalia o uso da HCQ (800 mg no dia 1 e 400 mg do dia 2 ao dia 7) ou placebo correspondente na prevenção de hospitalizações por covid-19 em casos precoces confirmados ou suspeitos de pacientes não hospitalizados. Os critérios de inclusão são adultos (≥ 18 anos) que procuraram atendimento médico com sintomas leves de covid-19, com randomização ≤ 7 dias após o início dos sintomas, sem indicação de hospitalização na triagem do estudo e com pelo menos um fator de risco para complicações (> 65 anos, hipertensão, diabetes melito, asma, doença pulmonar obstrutiva crônica ou outras doenças pulmonares crônicas, tabagismo, imunossupressão ou obesidade). Todos os testes de hipótese serão bilaterais. Um valor de p < 0,05 será considerado estatisticamente significativo em todas as análises. Clinicaltrials.gov: NCT04466540. Resultados Os desfechos clínicos serão avaliados centralmente por um comitê de eventos clínicos independente cegado para a alocação dos grupos de tratamento. O desfecho primário de eficácia será avaliado de acordo com o princípio da intenção de tratar. Conclusão Este estudo apresenta o potencial de responder de forma confiável a questão científica do uso da HCQ em pacientes ambulatoriais com covid-19. Do nosso conhecimento, este é o maior estudo avaliando o uso de HCQ em indivíduos com covid-19 não hospitalizados.

Abstract Background Despite the need for targeting specific therapeutic options for coronavirus disease 2019 (COVID-19), there has been no evidence of effectiveness of any specific treatment for the outpatient clinical setting. There are few randomized studies evaluating hydroxychloroquine (HCQ) in non-hospitalized patients. These studies indicate no benefit from the use of HCQ, but they assessed different primary outcomes and presented important biases for outcome evaluation. Objective To evaluate if HCQ may prevent hospitalization due to COVID-19 compared to a matching placebo. Methods The COVID-19 Outpatient Prevention Evaluation (COPE) study is a pragmatic, randomized, double-blind, placebo-controlled clinical trial evaluating the use of HCQ (800 mg on day 1 and 400 mg from day 2 to day 7) or matching placebo for the prevention of hospitalization due to COVID-19 in early non-hospitalized confirmed or suspected cases. Inclusion criteria are adults (≥ 18 years) seeking medical care with mild symptoms of COVID-19, with randomization ≤ 7 days after symptom onset, without indication of hospitalization at study screening, and with at least one risk factor for complication (> 65 years; hypertension; diabetes mellitus; asthma; chronic obstructive pulmonary disease or other chronic lung diseases; smoking; immunosuppression; or obesity). All hypothesis tests will be two-sided. A p-value < 0.05 will be considered statistically significant in all analyses. Clinicaltrials.gov: NCT04466540. Results Clinical outcomes will be centrally adjudicated by an independent clinical event committee blinded to the assigned treatment groups. The primary efficacy endpoint will be assessed following the intention-to-treat principle. Conclusion This study has the potential to reliably answer the scientific question of HCQ use in outpatients with COVID-19. To our knowledge, this is the largest trial evaluating HCQ in non-hospitalized individuals with COVID-19.

Outcomes associated with Hydroxychloroquine and Ivermectin in hospitalized patients with COVID-19: a single-center experience

SUMMARY OBJECTIVE: Hydroxychloroquine and Ivermectin are advocated as potential treatments for coronavirus disease 2019 (COVID-19) despite the lack of supportive clinical evidence. In this study, outcomes associated with Hydroxychloroquine and/or Ivermectin were determined in a series of patients with confirmed COVID-19 from a single institution in Brazil. METHODS: Consecutive patients admitted between March and July 2020 were retrospectively analyzed and divided into four treatment categories: no treatment (Group 0), Ivermectin only (Group I), Hydroxychloroquine only (Group II), and Hydroxychloroquine and Ivermectin (Group III). Intensive care unit admission, mechanical ventilation, and death were compared between the Groups. RESULTS: A total of 230 patients were included, with the following treatment distribution: 35.2% (0), 9.1% (I), 48.3% (II), and 7.4% (III). Groups I, II, and III had the higher rates of Intensive care unit admission, mechanical ventilation, or death (0: 23.5% versus I: 38.1% versus II: 37.8% versus III: 70.6%, p=0.002), and the greatest mortality was found in Group III (0 versus III: 13.6% versus 35.3%, p=0.03). In the multivariate analysis, Hydroxychloroquine remained significantly associated with death (OR 3.3, 95%CI 1.1-9.6, p=0.03). CONCLUSION: In a series of consecutive hospitalized patients with COVID-19, Ivermectin was not associated with improved outcomes and Hydroxychloroquine may have resulted in a harmful effect.

The impact of hydroxychloroquine and azithromycin on the corrected qt interval in patients with the novel Coronavirus disease 2019

SUMMARY OBJECTIVE: With the coronavirus disease 2019 (COVID-19) continuing to spread all over the world, although there is no specific treatment until now, hydroxychloroquine and azithromycin have been reported to be effective in recent studies. Although long-term use of hydroxychloroquine and azithromycin has been reported to cause QT prolongation and malign arrhythmia, there is not enough data about the effect of short-term use on arrhythmia. Therefore, this study aims to assess the effect of hydroxychloroquine alone and hydroxychloroquine + azithromycin on corrected QT (QTc). METHODS: A baseline electrocardiogram and on-treatment baseline electrocardiogram were retrospectively collected in COVID-19 patients who received hydroxychloroquine and/or azithromycin. The QTc interval was calculated, and the baseline and peak QTc intervals were compared. In addition, the peak QTc intervals of monotherapy and combination therapy were compared. RESULTS: Of the 155 patients included, 102 (65.8%) patients were using hydroxychloroquine, and 53 (34.2%) patients were using hydroxychloroquine + azithromycin combination. The use of both hydroxychloroquine alone and hydroxychloroquine + azithromycin combined therapy significantly prolonged the QTc, and the QTc interval was significantly longer in patients receiving combination therapy. QTc prolongation caused early termination in both groups, 5 (4.9%) patients in the monotherapy group and 6 (11.3%) patients in the combination therapy group. CONCLUSION: In this study, patients who received hydroxychloroquine for the treatment of COVID-19 were at high risk of QTc prolongation, and concurrent treatment with azithromycin was associated with greater changes in QTc.

Evaluation of retinal and choroidal microvascular changes in patients who received hydroxychloroquine by optical coherence tomography angiography / Avaliação de alterações microvasculares da retina e coroide em pacientes sob hidroxicloroquina através da angiografia por tomografia de coerência óptica

ABSTRACT Purpose: The aim of the study is to evaluate the retinal and choroidal microvascular changes via optical coherence tomography angiography in patients who received hydroxy­chloroquine. Methods: In total, 28 eyes of 28 patients (24 females, and 4 males) receiving treatment with hydroxy­chloroquine were assessed in this cross-sectional cohort study (hydroxychloroquine group). The high-and low-risk groups consisted of patients receiving hydroxychloroquine for ≥5 years (14 eyes of 28 patients) and <5 years (14 eyes of 28 patients), respectively. A total of 28 age- and gender-matched volunteers were enrolled as the control group. The macular flow area (superficial, deep, and choriocapillaris), superficial and deep vessel density, foveal avascular zone area, central foveal thickness, and subfoveal choroidal thickness parameters were measured by optical coherence tomography angiography. Results: The mean age of the 28 patients who received hydroxychloroquine and the 28 age-matched controls was 45.5 ± 11.1 years (range: 29-70 years) and 44.5 ± 13.9 years (range: 28-70 years), respectively. In patients who received hydroxychloroquine, the values for the superficial, deep, and choriocapillaris macular flow areas were 13.578 ± 0.30, 13.196 ± 0.31, and 17.617 ± 0.42, respectively. In controls, these values were 16.407 ± 0.95, 13.857 ± 0.31, and 18.975 ± 0.76, respectively (p<0.05 for all). The superficial, deep, and cho­riocapillaris flow areas were significantly smaller in patients who received hydroxychloroquine than those in controls (p<0.05 for all). Superficial and deep vessel densities were significantly reduced in patients who received hydroxychlo­roquine in all regions (i.e., foveal, parafoveal, temporal, superior, nasal, and inferior) (p<0.05 for all). Moreover, significant difference was observed between the groups in the foveal avascular zone area (superficial and deep), central foveal thickness, and subfoveal choroidal thickness (p<0.05 for all). Conclusions: Retinochoroidal microvascular flow and vessel density of the macular area were significantly decreased in patients who received hydroxychloroquine. Hy­droxychloroquine may damage the retinochoroidal mi­cro­vascular architecture. Optical coherence tomography angiography may contribute to the early detection of hy­dro­xychloroquine-induced retinal toxicity.

RESUMO Objetivo: O objetivo do estudo foi de avaliar as alterações microvasculares da retina e da coroide em pacientes sob hidroxicloroquina, através da angiografia por tomografia de coerência óptica. Métodos: Este é um estudo transversal de coorte que avaliou um total de 28 olhos de 28 pacientes (24 mulheres e 4 homens) submetidos a tratamento com hidroxicloroquina (grupo da hidroxicloroquina). Catorze olhos de 28 pacientes em uso de hidroxicloroquina por mais de 5 anos foram definidos como sendo o grupo de alto risco, ao passo que o grupo de baixo risco consistiu em 14 olhos de 28 pacientes em uso de hidroxicloroquina por menos de 5 anos. Foram ainda incluídos 28 voluntários como grupo de controle, pareados por idade e sexo. Através de angiografia por tomografia de coerência óptica, foram medidos os seguintes parâmetros: área do fluxo macular (superficial, profundo e coriocapilar), densi­dade vascular superficial e profunda, área da zona avascular foveal e espessura da coroide subfoveal. Resultados: Foram recrutados para o estudo um total de 28 pacientes sob tratamento com hidroxicloroquina, com idade média de 45,5 ± 11,1 (29-70) anos, e 28 membros do grupo de controle, pareados por idade e sexo, com idade média de 44,5 ± 13,9 (28-70) anos. As áreas superficial, profunda e coriocapilar do fluxo macular foram respectivamente de 13,578 ± 0,30, 13,196 ± 0,31 e 17,617 ± 0,42 nos pacientes em tratamento com hidroxicloroquina e, respectivamente de 16,407 ± 0,95, 13,857 ± 0,31 e 18,975 ± 0,76 no grupo de controle (p<0,05 para todos os valores). As três medições de área do fluxo macular foram significativamente menores nos pacientes em uso de hidroxicloroquina em comparação com os indivíduos do grupo de controle (p<0,05 para todos os valores). As densidades vasculares superficial e profunda mostraram-se significativamente reduzidas em todas as regiões (foveal, parafoveal, temporal, superior, nasal e inferior) nos pacientes em uso de hidroxicloroquina (p<0,05 para todos os valores). Finalmente, também foi observada uma diferença significativa entre os grupos em relação à área da zona avascular foveal (superficial e profunda), à espessura foveal central e à espessura da coroide subfoveal (p<0,05 para todos os valores). Conclusão: O fluxo microvascular retinocoroidal e a densidade vascular da área macular mostraram-se significativamente diminuídos nos pacientes sob hidroxicloroquina. Este fármaco pode danificar a arquitetura microvascular retinocoroidal e a angiografia por tomografia de coerência óptica pode contribuir para a detecção precoce da toxicidade retiniana induzida pela hidroxicloroquina.

Hydroxychloroquine with azithromycin in patients hospitalized for mild and moderate COVID-19

ABSTRACT Objectives: To assess the efficacy of hydroxychloroquine in combination with azithromycin in terms of clinical and biochemical outcomes in adult patients with COVID-19 hospitalized for acute respiratory distress syndrome (ARDS), and to describe the occurrence of adverse events. Method: Retrospective comparative study, based in a quaternary private hospital in Rio de Janeiro, Brazil, involving 193 adult patients hospitalized for mild and moderate COVID-19 related ARSD, analyzing treatment efficacy based on clinical and biochemical outcomes. Results: The active group comprised 101 (52.3%) patients using hydroxychloroquine associated with azithromycin and the control group 92 (47.7%) patients who did not take these medications. Median age was 59 (47-70) in the active group and 65 (47−77) in the control group (p < 0.05). Patients in the control group had greater extent of pulmonary involvement on baseline chest CT scans (p < 0.05). All other baseline variables (BMI, comorbidities, previous use of medications and biochemical assessments) were similar between groups. In the medication group, 25% (25 out of 101) were admitted to the ICU, compared to 21% (19 out of 92) in the control group (p > 0.05). No difference in mortality, duration of non-invasive oxygen use or duration of hospitalization was seen between groups. The therapeutic regimen was well tolerated, with only eight (7.9%) patients presenting gastrointestinal symptoms and eight (7.9%) patients withdrawn treatment due to QTc prolongation. Conclusions: Patients treated with hydroxychloroquine combined with azithromycin and the control group had similar clinical outcomes. This therapeutic regimen was considered ineffective in hospitalized patients with mild to moderate COVID-19 related ARDS and was associated with few non-severe adverse events.

Cloroquina e hidroxicloroquina: medicamentos potencialmente inapropriados a idosos? / Chloroquine and hydroxychloroquine: potentially inappropriate medications for older adults?

INTRODUÇÃO: Medicamentos potencialmente inapropriados a idosos (MPII) provocam mais efeitos adversos do que benefícios. Os critérios de Beers (CB) da American Geriatrics Society 2019 (CB2019) consideraram cinco situações clínicas como MPII. A análise de medicamentos por essas situações pode auxiliar na prescrição a idosos? Procurando exemplo prático dessa questão, optou-se por análise de fármacos atualmente questionados quanto ao seu uso seguro em idosos. OBJETIVO: Verificar se cloroquina e hidroxicloroquina se enquadram como MPII e se essa análise é aplicável clinicamente. METODOLOGIA: Sistematizou-se o objetivo pelas cinco situações clínicas definidas como MPII pelos CB2019. RESULTADOS: Ambos os fármacos preenchem respectivamente quatro (cloroquina) e cinco (hidroxicloroquina) dessas situações clínicas. Esta análise permitiu a provável definição de MPII para esses medicamentos de forma simples, por intermédio de breve análise de literatura acessível. CONCLUSÃO: Cloroquina e hidroxicloroquina podem ser considerados MPII. Espera-se replicar essa análise para outros medicamentos e reduzir iatrogenias em idosos.

INTRODUCTION: Potentially inappropriate medications (PIMs) for older adults cause more adverse effects than benefits. The 2019 American Geriatrics Society Beers Criteria (2019BC) considered five clinical situations as PIM use in older adults. Can drug analysis, according to these situations, assist in the act of making prescriptions for older people? Seeking a practical example for this question, we assessed drugs currently questioned as to their safe use among older people. OBJECTIVE: To check if chloroquine and hydroxychloroquine fit the PIM criteria for older adults and whether this analysis is clinically applicable. METHODS: We systematized the objective based on the five clinical situations defined as PIM use in older adults by the 2019BC. RESULTS: Chloroquine and hydroxychloroquine fulfill, respectively, four and five of these clinical situations. This evaluation allowed the likely definition of these drugs as PIMs for older adults in a simple way, based on a brief analysis of the available literature. CONCLUSION: Chloroquine and hydroxychloroquine may be considered PIMs for older adults. We expect that this analysis can be replicated with other drugs and reduce iatrogenesis in older people.

Seguridad de la cloroquina y la hidroxicloroquina para el tratamiento de pacientes con COVID-19 / Safety of chloroquine and hydroxychloroquine for treating COVID-19 patients

Introducción: La cloroquina y su análogo hidroxicloroquina han mostrado presentar efectos antivirales y antiinflamatorios, por lo que podría ser una alternativa de tratamiento ante el nuevo coronavirus SARS-CoV-2. Objetivo: Describir seguridad de la cloroquina e hidroxicloroquina para el tratamiento de la COVID-19 según la evidencia científica actual. Método: Se empleó la estrategia de búsqueda coronavirus OR COVID-19 OR SARS-CoV2 AND Cloroquina AND Hidroxicloroquina y se utilizaron las bases de datos Pubmed, SciELO, Lilacs, Cochrane Library y Web of Science. Se obtuvo un total de 32 referencias bibliográficas, seleccionándose a partir de criterios de selección. Conclusiones: La eficacia de la cloroquina y la hidroxicloroquina no ha sido probada del todo, pues los resultados no han sido concluyentes y se ha encontrado diferencias entre ellos, además de que no se han estudiado muestras suficientemente representativas. Las reacciones adversas de este medicamento, siendo las cardiovasculares las más peligrosas, no se deben ignorar ya que se han presentado con cierta frecuencia y en relación con la dosis administrada. Por ello, es necesario la realización de más ensayos clínicos aleatorizados, con mayor control de sesgos y muestras representativas, que evalúen la eficacia y seguridad de este medicamento(AU)

Introduction: Chloroquine and its analogue hydroxychloroquine have shown antiviral and anti-inflammatory effects, so it could be an alternative treatment to the new SARS-CoV-2 coronavirus. Objective: To describe the safety of chloroquine and hydroxychloroquine for treating COVID-19 according to current scientific evidence. Method: We used the search strategy for coronavirus OR COVID-19 OR SARS-CoV2 AND Chloroquine AND Hydroxychloroquine, and Pubmed, SciELO, Lilacs, Cochrane Library and Web of Science databases were used. Thirty two bibliographic references were recovered, selection followed the selection criteria. Conclusions: The efficacy of chloroquine and hydroxychloroquine has not been fully proven, since the results have not been conclusive and differences have been found between them, In addition to the fact that sufficiently representative samples have not been studied. The adverse reactions of these drugs, and the cardiovascular ones are the most dangerous, should not be ignored since they have occurred with certain frequency and in relation to the administered dose. Therefore, it is necessary to carry out more randomized clinical trials, with greater control of biases and representative samples, to evaluate the efficacy and safety of these drugs(AU)

Hidroxicloroquina: Mensajes desde la cardiología en tiempos de pandemia por Coronavirus / Hydroxychloroquine. Cardiology's viewpoint in times of coronavirus pandemic

Ante la pandemia de COVID-19 (del inglés coronavirus disease 2019), uno de los fármacos propuesto para su tratamiento es la hidroxicloroquina. Se revisan aquí aspectos cardiológicos del uso de cloroquina e hidroxicloroquina. Se realizó una revisión no sistemática en la literatura médica orientada a la búsqueda de información acerca de su seguridad y eficacia como antimaláricos y antivirales, así como en el tratamiento prolongado de enfermedades reumatológicas. Se halló un efecto antiinflamatorio con reducción de eventos cardiovasculares a largo plazo, una cardiopatía muy infrecuente por un efecto lisosomal del fármaco, y a nivel hemodinámico hipotensión, taquicardia, y prolongación del intervalo QT, exacerbado si se combina con azitromicina. Sin embargo, la tasa de eventos adversos cardíacos de la hidroxicloroquina y la cloroquina fue baja.

Due to the coronavirus disease 2019 (COVID-19) pandemic, a wide number of compounds are under scrutiny regarding their antiviral activity, one of them being hydroxychloroquine. Cardiac aspects of the use of chloroquine and hydroxychloroquine are reviewed in this manuscript. A non-systematic review of the medical literature was performed. Information about their safety and efficacy as antimalarials, antivirals, as well as in the long-term treatment of rheumatic diseases was collected. We found an anti-inflammatory effect with reduction of long-term cardiovascular events, a very infrequent heart disease due to a lysosomal effect of the drug, and at the hemodynamic level hypotension, tachycardia, and QT interval prolongation, exacerbated when combined with azithromycin. However, the rate of adverse cardiac events of hydroxychloroquine (and chloroquine) was low.

Sepsis por celulitis necrotizante en paciente embarazada con sindrome antifosfolípido en tratamiento / Necrotizing sepsis cellulitis pregnant patient with antiphospholipid syndrome treatment

Introducción: El término ''síndrome antifosfolipídico'' (SAF) describe la asociación de los anticuerpos antifosfolipídicos (AAF) con un cuadro clínico de hipercoagulabilidad caracterizado por trombosis a repetición y abortos recurrentes. Objetivo: Presentar un caso de celulitis severa de periné en paciente con SAF y tratamiento con hidroxicloroquina. Caso clínico: Paciente de 39 años con embarazo de término con SAF tratado con hidroxicloroquina y anticoagulación que desarrolló una infección severa de partes blandas del periné que fue tratado con interrupción del embarazo, drenaje agresivo del periné y tratamiento antibiótico extenso con buena evolución. Conclusión: La asociación del tratamiento con hidroxicloroquina, embarazo y una complicación séptica es incierta. El tratamiento con inmunosupresión no es estándar y podría haber favorecido el mal pronóstico del cuadro clínico. (AU)

Objetive: To present a case of severe perineal cellulitis in a pregnant patient with Antiphospholipid syndrome treated wiht hidroxicloroquine. Case report: A 39 years old female pregnant patient with AFS treated with hidroxicloroquine and heparin developed severe perineal infection with systemic impairment. Final treatment included aggressive perineal drainage in multiple sessions, pregnancy delivered and systemic treatment with wide spectrum antibiotics and general measures. Discusion and Conclusion: Treatment with hidroxicloroquine, pregnancy and septic complication is infrequent. This approach is not standard and it could favored worst prognostic of the general syndrome. (AU)

Efetividade e toxicidade da cloroquina e da hidroxicloroquina associada (ou não) à azitromicina para tratamento da COVID-19. O que sabemos até o momento? / Effectiveness and toxicity of chloroquine and hydroxychloroquine associated (or not) with azithromycin for the treatment of COVID-19. What do we know so far?

Objetivos: identificar as evidências científicas existentes até o presente momento sobre a efetividade do uso da cloroquina, da hidroxicloroquina associada (ou não) à azitromicina para tratamento da afecção pelo coronavírus e seus possíveis efeitos adversos e tóxicos aos seres humanos. Métodos: a revisão narrativa utilizou-se das bases de dados PubMed, LILACS, SciElo e Google Acadêmico. Nessas, buscaram-se estudos, utilizando-se dos descritores "covid", "coronavirus", "SARS-CoV-2", "chloroquine", "hydroxychloroquine", "azithromycin" e "adverse effects" junto com os operadores booleanos "AND" e "OR". Resultados: sete artigos, das trinta publicações encontradas, atenderam aos critérios de inclusão, sendo utilizados para compor a presente revisão. Dos sete ensaios clínicos analisados, cinco apresentaram resultados de cura e/ou remissão dos sintomas e/ou redução da carga viral dos pacientes, no entanto apresentaram muitas limitações. Conclusão: a literatura científica é escassa e divergente quanto à efetividade dos medicamentos cloroquina e hidroxicloroquina associada (ou não) à azitromicina no tratamento da COVID-19, pela rápida disseminação e instalação da pandemia na esfera global. É necessário a realização de ensaios clínicos pragmáticos, envolvendo um número maior de pacientes, para que seja possível analisar a efetividade no combate ao coronavírus, bem como a segurança do uso desses fármacos.(AU)

Objective: to identify the scientific evidence existing to date on the effectiveness of the use of chloroquine, hydroxychloroquine associated (or not) to azithromycin for the treatment of COVID-19 disease and its possible adverse drug events and toxicity to human health. Methods: the narrative review was performed using the PubMed, LILACS, SciElo and Google Academic databases. In these, studies were sought, using the descriptors "covid", "coronavirus", "SARS-CoV-2", "chloroquine", "hydroxychloroquine", "azithromycin", "adverse effects" and "toxicity", together with the Boolean operator "AND" and "OR". Results: seven studies of thirty publications met the inclusion criteria and were used in the present review. Of the seven clinical trials analyzed, five showed results of cure and/or remission of symptoms and/or reduction of patients' viral load, however these studies had many limitations. Conclusion: scientific literature is scarce and divergent as to the effectiveness of the drugs chloroquine and hydroxychloroquine associated (or not) with azithromycin in the treatment of COVID-19, due to the rapid spread and installation of the pandemic in the global sphere. It is necessary to carry out pragmatic clinical trials, involving a larger number of patients, so that it is possible to analyze the effectiveness in combating the coronavirus, as well as the safety of the use of these drugs.(AU)

El escándalo de la cloroquina / The chloroquine scandal

El autor aborda el caso de la cloroquina y la hidroxicloroquina en el contexto de la actual pandemia de COVID-19, a través de dos ejes centrales. Por un lado, el escándalo a nivel editorial y de comunicación de la evidencia, y por otro, el de la toma de decisiones en salud pública. Describe flagrantes debilidades en la cadena de generación, difusión y aplicación del nuevo conocimiento. Adicionalmente, explora iniciativas y propuestas que podrían contribuir a solucionar estos problemas. (AU)

The author addresses the case of chloroquine and hydroxychloroquine in the context of the current COVID-19 pandemic, through two central axes. On the one hand, the scandal at the editorial and communication level of the evidence, and on the other, that of decision-making in public health. He describes flagrant weaknesses in the chain of generation, diffusion,and application of new knowledge. Additionally, it explores initiatives and proposals that could contribute to solving these problems. (AU)

La evidencia en tiempos de coronavirus (COVID-19) / Evidence in times of coronavirus (COVID-19)

La pandemia de COVID-19 está generando información epidemiológica y clínica en una escala sin precedentes para una enfermedad de reciente aparición. Aunque ya se han iniciado numerosos ensayos clínicos de fármacos antiguos y nuevos como potenciales antivirales específicos, la mayor parte de la información publicada hasta ahora carece de los controles básicos para la evaluación de la eficacia de un medicamento. Los medios de comunicación amplifican estos resultados preliminares y suman presión a los médicos asistenciales y a los decisores de políticas públicas. Este artículo revisa las pruebas disponibles sobre los cuatro tratamientos antivirales específicos más prometedores: hidroxicloroquina, lopinavir/ritonavir, remdesvir e interferones alfa y beta. Se comprueba en todos ellos que no hay demostración suficiente de eficacia como para recomendar su uso fuera de una investigación experimental adecuadamente controlada. En el uso individual de un medicamento no hay forma de saber si está beneficiando o perjudicando al paciente. Es erróneo asumir que la eventual curación se debe al fármaco y un mal desenlace debe atribuirse a la enfermedad. Sólo la comparación entre grupos de pacientes asignados al tratamiento experimental o a un control adecuado permite conocer la eficacia y seguridad de las intervenciones. El desafío es conciliar la urgencia de actuar con la generación de nuevos conocimientos.Aunque no resulta sencillo organizar ensayos clínicos en este contexto, las instituciones pueden sumarse a los proyectos en marcha a nivel nacional e internacional. El uso de estos fármacos debe considerarse experimental, por lo que es necesario obtener el consentimiento informado del paciente. (AU)

The COVID-19 pandemic is generating epidemiological and clinical information on an unprecedented scale for a newly emerging disease. Although numerous clinical trials of old and new drugs as potential specific antivirals have already been started, most of the information published so far lacks basic controls for evaluating drug efficacy. The media amplify these preliminary results and add pressure to doctors and policymakers. This article reviews the available evidence for the four most promising specific antiviral treatments: hydroxychloroquine, lopinavir / ritonavir, remdesvir, and alpha and beta interferons. The findings show that none of them has sufficient demonstration of efficacy to recommend its use outside ofthe adequately controlled experimental study. In the individual use of a drug there is no way of knowing if it is benefiting orharming the patient. It is wrong to assume that the eventual cure is due to the drug and a poor outcome must be attributed to the disease. Only the comparison between groups of patients assigned to the experimental treatment or to an adequate control can establish the efficacy and safety of the interventions. The challenge is to reconcile the urgency to act with the generation of new knowledge. Although it is not easy to organize clinical trials in this context, the institutions can join theongoing projects at the national and international levels. The use of these drugs should be considered experimental, so it is necessary to obtain the informed consent of the patient. (AU)

Antimaláricos y SARS-CoV-2: nuevas propiedades en el 2020 / Antimalarials and SARS-CoV-2: new properties in 2020

La reciente emergencia sanitaria provocada por el nuevo coronavirus SARS-CoV-2 nos ha enfrentado a una nueva pandemia mundial. Al ser una nueva cepa viral, la población no posee inmunidad contra él, y luego del contagio, se ha observado que muchos de los pacientes pueden ser asintomáticos, a diferencia de otros, que hacen cuadros graves y agresivos, especialmente respiratorios, que ha llevado a numerosas muertes, no solo en pacientes de riesgo, sino también en individuos sanos. Frente a esta emergencia se ha iniciado una búsqueda de medicamentos que controlen esta infección y que eviten la progresión hacia un cuadro inflamatorio sistémico grave. Mientras se encuentra una vacuna, se han utilizado diferentes fármacos en pacientes graves, algunos han demostrado eficacia y otros no. Dentro de los fármacos que han demostrado detener efectos inflamatorios están los antimaláricos como la cloroquina y la hidroxicloroquina. Estos tienen efectos antiinflamatorios ya conocidos en el área de la reumatología, pero en el último tiempo han demostrado tener efectos antivirales que han ayudado disminuir los síntomas de gravedad.

The recent health emergency caused by the new SARS-CoV-2 coronavirus has brought us face with a new global pandemic. As a new viral strain, individuals do not have immunity against it and, and after the infection, it has been seen that many of the patients may be asymptomatic and others have severe and aggressive symptoms, especially respiratory, which has led to numerous deaths, not only in patients with risk but also in healthy individuals. Faced with this emergency, a drug search has been started, that controls this infection and prevents progression towards a severe systemic inflammatory condition. While a vaccine is found, different drugs have been used in critically ill patients, some have shown efficacy and some have not. Among the drugs that have been shown to stop inflammatory effects are antimalarials such as chloroquine and hydroxychloroquine. These have anti-inflammatory effects already known in the area of rheumatology, but in recent times they have been shown to have antiviral effects that have helped decrease symptoms of severity.

Implicaciones cardiovasculares de la infección por SARS-CoV-2: revisión de literatura / Cardiovascular implications of SARS-CoV-2 infection: a literature review

En diciembre de 2019 se reportó en Wuhan, China, la aparición de una nueva cepa de coronavirus SARS-CoV-2 que producía un compromiso pulmonar severo y progresaba a estrés respiratorio agudo. A la fecha, son más de diecisiete millones los casos confirmados y más de medio millón los fallecidos en todo el mundo a causa de COVID-19. Los estudios reportan que los pacientes con enfermedad cardiovascular son más susceptibles a contraer esta enfermedad y a presentar más complicaciones. El propósito de esta revisión es proporcionar información actualizada para los profesionales de la salud que atienden a pacientes con COVID-19 y que tienen además enfermedad cardiovascular y por ende un riesgo elevado de complicaciones y mortalidad. Realizamos una búsqueda de bibliografía científica acerca de la asociación de enfermedad cardiovascular y COVID-19 en diferentes bases de datos como Scopus, MEDLINE vía PubMed y Cochrane Library. El tratamiento con inhibidores de la enzima convertidora de angiotensina y bloqueadores del receptor de angiotensina ha sido motivo de discusión y no hay evidencia sólida para contraindicarlo en pacientes con COVID-19. Respecto al tratamiento con hidroxicloroquina asociado o no con azitromicina, hay evidencia que demuestra un mayor riesgo con su utilización, que beneficio clínico y/o disminución de mortalidad. En este contexto, los pacientes con insuficiencia cardíaca representan un grupo importante de riesgo por su condición per se y por el dilema diagnóstico generado al evaluar un paciente con COVID-19, en el que los signos de insuficiencia cardíaca aguda podrían enmascararse. Por otro lado, en los pacientes con síndrome coronario agudo, el enfoque terapéutico inicial podría cambiar en el contexto de la pandemia, aunque sólo sobre la base de opiniones de expertos. Quedan, sin embargo, muchos temas en controversia que serán motivo de investigaciones futuras.

In December 2019, a new strain of the SARS-CoV-2 coronavirus was reported in Wuhan, China, which produced severe lung involvement and progressed to respiratory distress. To date, more than seventeen million confirmed cases and more than half a million died worldwide from COVID-19. Patients with cardiovascular disease are more susceptible to contracting this disease and presenting more complications. We did a literature search on the association of cardiovascular disease and COVID-19 in databases such as Scopus, PubMed/MEDLINE, and the Cochrane Library. The purpose of this review is to provide updated information for health professionals who care for patients with COVID-19 and cardiovascular disease, given that they have a high risk of complications and mortality. Treatment with angiotensin-converting enzyme inhibitors and receptor blockers is controversial, and there is no evidence not to use these medications in patients with COVID-19. Regarding treatment with hydroxychloroquine associated or not with azithromycin, there is evidence of a higher risk with its use than clinical benefit and decreased mortality. Likewise, patients with heart failure are an important risk group due to their condition per se. Patients with heart failure and COVID-19 are a diagnostic dilemma because the signs of acute heart failure could be masked. On the other hand, in patients with acute coronary syndrome, the initial therapeutic approach could change in the context of the pandemic, although only based on expert opinions. Nonetheless, many controversial issues will be the subject of future research.

Primum non nocere - Are chloroquine and hydroxychloroquine safe prophylactic/treatment options for SARS-CoV-2 (covid-19)?

ABSTRACT Chloroquine (CQ) and its analog hydroxychloroquine (HCQ) were recently included in several clinical trials as potential prophylactic and therapeutic options for SARS-COV-2 infection/covid-19. However, drug effectiveness in preventing, treating, or slowing the progression of the disease is still unknown. Despite some initial promising in vitro results, rigorous pre-clinical animal studies and randomized clinical trials have not been performed yet. On the other hand, while the potential effectiveness of CQ/HCQ is, at best, hypothetical, their side effects are factual and most worrisome, particularly when considering vulnerable groups of patients being treated with these drugs. in this comment, we briefly explain the possible mechanisms of action of CQ/HCQ for treating other diseases, possible actions against covid-19, and their potent side effects, in order to reinforce the necessity of evaluating the benefit-risk balance when widely prescribing these drugs for SARS-COV-2 infection/covid-19. We conclude by strongly recommending against their indiscriminate use.