Hydroxychloroquine – ABC CARDIOL

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Editorial

Our Patients Deserve More

Clinical decision-making implies that multiple options are possible for any given medical situation. Fortunately, science is constantly evolving and will continue to do so incrementally. Thus, physicians should routinely analyze previous outcomes of similar circumstances to increase the probability of selecting the most appropriate alternative. Discerning data that may assist in decision-making from inconsistent scientific information is a fundamental requirement of evidence-based medicine (EBM).

For over 40 years, EBM has been the cornerstone of clinical practice, improving the efficacy and safety involved with medical decisions, according to the most current scientific knowledge. Nevertheless, publications do not always adhere to validated methodological concepts and may rely solely on non-scientific motivations. When personal beliefs overshadow medical science, it invariably occurs to the detriment of patient care. Conversely, EBM provides a systematic and organized method to appraise scientific information in various medical literature forms.

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Original Article

Real-Life Data on Hydroxychloroquine or Chloroquine with or Without Azithromycin in COVID-19 Patients: A Retrospective Analysis in Brazil

Maíra Viana Rego Souza-Silva et al. Daniella Nunes Pereira Magda Carvalho Pires Isabela Muzzi Vasconcelos … Alexandre Vargas Schwarzbold Diego Henrique de Vasconcelos Elayne Crestani Pereira Euler Roberto Fernandes Manenti Felício Roberto Costa Filipe Carrilho de Aguiar Fernando Anschau Frederico Bartolazzi Guilherme Fagundes Nascimento Heloisa Reniers Vianna Joanna d’Arc Lyra Batista Juliana Machado-Rugolo Karen Brasil Ruschel Maria Angélica Pires Ferreira Leonardo Seixas de Oliveira Luanna Silva Monteiro Menezes Patricia Klarmann Ziegelmann Marcela Gonçalves Trindade Tofani Maria Aparecida Camargos Bicalho Matheus Carvalho Alves Nogueira Milton Henriques Guimarães-Júnior Rúbia Laura Oliveira Aguiar Danyelle Romana Alves Rios Carisi Anne Polanczyk Milena Soriano Marcolino

Abstract

Background

Despite no evidence showing benefits of hydroxychloroquine and chloroquine with or without azithromycin for COVID-19 treatment, these medications have been largely prescribed in Brazil.

Objectives

To assess outcomes, including in-hospital mortality, electrocardiographic abnormalities, hospital length-of-stay, admission to the intensive care unit, and need for dialysis and mechanical ventilation, in hospitalized COVID-19 patients who received chloroquine or hydroxychloroquine, and to compare outcomes between those patients and their matched controls.

Methods

A retrospective multicenter cohort study that included consecutive laboratory-confirmed COVID-19 patients from 37 Brazilian hospitals from March to September 2020. Propensity score was used to select matching controls by age, sex, cardiovascular comorbidities, and in-hospital use of corticosteroid. A p-value <0.05 was considered statistically significant.

Results

From 7,850 COVID-19 patients, 673 (8.6%) received hydroxychloroquine and 67 (0.9%) chloroquine. The median age in the study group was 60 years (46 – 71) and 59.1% were women. During hospitalization, 3.2% of patients presented side effects and 2.2% required therapy discontinuation. Electrocardiographic abnormalities were more prevalent in the chloroquine/hydroxychloroquine group (13.2% vs. 8.2%, p=0.01), and the long corrected QT interval was the main difference (3.6% vs. 0.4%, p<0.001). The median hospital length of stay was longer in the HCQ/CQ + AZT group than in controls (9.0 [5.0, 18.0] vs. 8.0 [4.0, 14.0] days). There was no statistical differences between groups in intensive care unit admission (35.1% vs. 32.0%; p=0.282), invasive mechanical ventilation support (27.0% vs. 22.3%; p=0.074) or mortality (18.9% vs. 18.0%; p=0.682).

Conclusion

COVID-19 patients treated with chloroquine or hydroxychloroquine had a longer hospital length of stay, when compared to matched controls. Intensive care unit admission, invasive mechanical ventilation, dialysis and in-hospital mortality were similar.

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Original Article

Hydroxychloroquine for Non-Hospitalized COVID-19 Patients: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Rosa Lucchetta et al. Jessica Y. Matuoka Haliton Alves de Oliveira Junior Gustavo Oliveira … Alexandre Biasi Cavalcanti Luciano Azevedo Otavio Berwanger Renato Delascio Lopes Regis Goulart Rosa Viviane Cordeiro Veiga Álvaro Avezum

Abstract

Background:

Previous systematic reviews have identified no benefit of hydroxychloroquine and chloroquine in non-hospitalized COVID-19 patients. After publication of these reviews, the results of COPE, the largest randomized trial conducted to date, became available.

Objectives:

To conduct a systematic review and meta-analyses of randomized clinical trials (RCTs) to synthesize the evidence on the efficacy and safety of hydroxychloroquine and chloroquine for non-hospitalized COVID-19 patients compared to placebo or standard of care.

Methods:

Searches were conducted in PubMed, Embase, The Cochrane Library, and ClinicalTrials.gov complemented by manual search. Pairwise meta-analyses, risk of bias, and evidence certainty assessments were conducted, including optimal information size analysis (OIS). A level of significance of 0.05 was adopted in the meta-analysis. PROSPERO: CRD42021265427.

Results:

Eight RCTs with 3,219 participants were included. COVID-19 hospitalization and any adverse events rates were not significantly different between hydroxychloroquine (5.6% and 35.1%) and control (7.4% and 20.4%) (risk ratio, RR, 0.77, 95% confidence interval, CI, 0.57-1.04, I²: 0%; RR 1.78, 95%-CI 0.90; 3.52, I²: 93%, respectively). The OIS (7,880) was not reached for COVID-19 hospitalization, independently of the simulation for anticipated event rate and RR reduction estimate.

Conclusion:

Evidence of very low certainty showed lack of benefit with hydroxychloroquine in preventing COVID-19 hospitalizations. Despite being the systematic review with the largest number of participants included, the OIS, considering pre-vaccination response to infection, has not yet been reached.

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Original Article

Rationale and Design of the COVID-19 Outpatient Prevention Evaluation (COPE – Coalition V) Randomized Clinical Trial: Hydroxychloroquine vs. Placebo in Non-Hospitalized Patients

Haliton Alves de Oliveira Junior et al. Cleusa P. Ferri Icaro Boszczowski Gustavo B. F. Oliveira … Alexandre B. Cavalcanti Regis G. Rosa Renato D. Lopes Luciano C. P. Azevedo Viviane C. Veiga Otavio Berwanger Álvaro Avezum

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.

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Editorial

The Astronaut and the Jabuticaba

Andre d’Avila et al. Marco F. Vidal Melo

Jabuticaba

Brazil has a peculiar medical environment. Although interventions like hydroxychloroquine and ivermectin disappeared from the international scientific debate once disproved in clinical trials, Brazilian practitioners continue to debate the validity of these studies. Like jabuticaba – a fruit native to and predominant (but not exclusive) in Brazil – this debate is still current only in this country. Previous attempts to discount the results of studies with the argument that they had been conducted abroad and could not be extended to the Brazilian population can no longer be justified as many of these studies have included Brazilian patients. As individuals, we do understand the difficulty in accepting evidence opposing someone’s conviction; however, as a doctor, this attitude is indefensible.

In this context of conviction and belief over evidence and data, several practitioners have created websites and even solicited the government to support and disseminate their practice despite proven inefficacy of the proposed interventions. Even though many are excellent physicians in their fields, this situation has only been possible because, under the auspices of trying to help, almost anything has been allowed in Brazil. If there were any regulation proposing a fine or termination of medical license to those who supported unproven medical practices, none of this would have happened. This regulation would be, in fact, similar to previous decisions of ethics committees in cases of charlatanism, when medical practices based on consensual decisions are not accepted as justification to exempt the infringer. However, these types of regulations are defective or absent in Brazil. Curiously, the term “accountability”, that in English means an obligation or willingness to accept responsibility for one’s actions, does not exist in Portuguese. On the other hand, there is no English word for “jabuticaba”.

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IJCS

Viewpoint

Severe Cardiovascular Complications of COVID-19: a Challenge for the Physician

Nathalie Cristina Crivelari et al. Gisele Queiroz de Oliveira Clarice Hyesuk Lee Park Gregorio da Cruz Riemma … Isabela Bispo Santos da Silva Costa Marcus Vinícius Guimarães de Lacerda Glaucia Maria Moraes de Oliveira Francisco Carlos da Costa Darrieux Luciana Sacilotto Ludhmila Abrahão Hajjar

Introduction

Since December 31, 2019, when China reported the appearance of cases of acute respiratory failure caused by a new species of coronavirus, SARS-CoV-2, which causes the disease called COVID-19, almost 20 million cases were confirmed, causing 726 thousand deaths worldwide. In Brazil, on August 8^th, 2020, there was approximately 3 million cases and 100 thousand death by the disease.

Its rapid spread, its high potential for hospitalization, and its high lethality, especially in the most fragile groups such as geriatric patients and those with comorbidities, particularly cardiovascular ones, make this pandemic a challenge never faced by modern medicine. To date, we have no specific medication that has effective and safe results for the treatment of COVID-19. The scientific community has sought to research drugs with therapeutic plausibility, and controlled and randomized studies are underway. Many therapeutic proposals are based on in vitro experiments. The medications used are described in case records, with no solid scientific evidence for their use, and with a high probability of causing damage due to their adverse effects alone or in combination.

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