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Authors: Lane & Weaver et al. Link to paper: https://www.medrxiv.org/content/10.1101/2020.04.08.20054551v1

Journal/ Pre-Print: MedRxiv

Key Words: Drug Safety, Repurposing Drug, Clinical Research, Epidemiology

RESEARCH HIGHLIGHTS

1. Hydroxychloroquine alone seems comparable in terms of safety when taken short-term (30 day) to equivalent DMARD drug sulfasalazine in meta-analysis of several rheumatoid arthritis cohorts

2. For COVID19 relevance, co-administration of hydroxychloroquine with azithromycin even short-term can increase the risk of cardiovascular events and morbidity in the rheumatoid-arthritis cohort studied. COVID19 incidence/severity is not studied

SUMMARY

One of the most discussed treatments for COVID19 currently is the combination therapy using hydroxychloroquine (HCQ) and azithromycin (AZM), which has received ‘Emergency Use Authorization’ by the FDA. However, studies using this drug combination have failed to provide sufficient evidence for their safety and efficiency. The study of Lane, Weaver et al. is a multi-centre meta-analysis of the drug safety with regards to adverse effects of this treatment in prospective patient cohorts with rheumatoid arthritis, in which this treatment is more commonly used. The authors found a significant increase in cardiovascular adverse event including mortality in patients treated with this drug combination in comparison to a comparable DMARD and antibiotic. This study highlights the need to carefully test different treatment regimens and limit doses and treatment duration.

IMPACT FOR SARS-COV2/COVID19 RESEARCH EFFORTS

Treatment of SARS-CoV2/COVID19 positive individuals

HCQ and AZM are popular treatment options for critically ill patients and are currently investigated in several clinical trials for their effectiveness, however short- and long-term safety drug profiles are crucial to consider this drug combination.

Safety of drug candidates for SARS-CoV2

The article uses patient follow-up data to investigate the short- and long-term effects in other patient cohorts (here: rheumatoid arthritis patients).

STUDY TYPE

· Clinical Cohort study (here: Meta-Analysis of multi-centre patient cohorts)

STRENGTHS AND LIMITATIONS OF THE PAPER

Novelty: Limited, however its main point that HCQ+AZM combination therapy increases adverse cardiovascular events is important for the COVID19 research field as cardiovascular patients (due to high ACE2 expression) are among particular risk groups for SARS-CoV2 infection.

Standing in the field: Treatment options for COVID19 are currently still largely unavailable. One of the first drugs that was suggested to work was HCQ. Since a study published by Gautret et al. (2020), public debate about the effectiveness of combination treatment is discussed. The study is generally regarded as very controversial as both our COVID19 literature initiative (see our summary) and others have voiced their concerns regarding the study design and claims. HoweverNevertheless, HCQ with and without AZM are currently being tested in controlled clinical trials. With regards to the fact that cardiovascular disease patients, notably hypertension patients, have an increased risk of SARS-CoV2 infection, this study provides an interesting additional point of consideration of this combination therapy against COVID19.

Appropriate statistics: Without being the mostWhile we are not experts in this type of statistical analysis, it seems accurate. Using a self-controlled case series study design seems appropriate to limit the effect of confounders. Further propensity score stratification removes additional confounders from analysis.

Viral model used: NA, study was performed on rheumatoid-arthritis cohorts without SARS-CoV2 infection.

Translatability: The results can have a direct impact on ongoing studies to reviewi terms of their safety profile in particular and to consider notingpaying attention toin particular adverse cardiovascular events during and following the treatment period.

Main limitations: The authors discuss many of the limitations ofto their study (e.g. reporting issues, patients being included in multiple datasets), however our main criticism remains towards the impact this study has to the current SARS-CoV2 patient cohort. The individuals studied here are all RA patients and therefore potentially differently confounded in comparison to patients with COVID19. Furthermore, the study does not distinguish between different HCQ doses and treatment duration in detail