The Effect of Early Hydroxychloroquine-based Therapy in COVID-19 Patients in Ambulatory Care Settings: A Nationwide Prospective Cohort Study

Abstract

BACKGROUND: Currently, there is no proven effective therapy nor vaccine for the treatment of SARS-CoV-2. Evidence regarding the potential benefit of early administration of hydroxychloroquine (HCQ) therapy in symptomatic patients with Coronavirus Disease (COVID-19) is not clear. METHODS: This observational prospective cohort study took place in 238 ambulatory fever clinics in Saudi Arabia, which followed the Ministry of Health (MOH) COVID-19 treatment guideline. This guideline included multiple treatment options for COVID-19 based on the best available evidence at the time, among which was Hydroxychloroquine (HCQ). Patients with confirmed COVD-19 (by reverse transcriptase polymerase chain reaction (PCR) test) who presented to these clinics with mild to moderate symptoms during the period from 5-26 June 2020 were included in this study. Our study looked at those who received HCQ-based therapy along with supportive care (SC) and compared them to patients who received SC alone. The primary outcome was hospital admission within 28-days of presentation. The secondary outcome was a composite of intensive care admission (ICU) and/or mortality during the follow-up period. Outcome data were assessed through a follow-up telephonic questionnaire at day 28 and were further verified with national hospitalisation and mortality registries. Multiple logistic regression model was used to control for prespecified confounders. RESULTS: Of the 7,892 symptomatic PCR-confirmed COVID-19 patients who visited the ambulatory fever clinics during the study period, 5,541 had verified clinical outcomes at day 28 (1,817 patients in the HCQ group vs 3,724 in the SC group). At baseline, patients who received HCQ therapy were more likely to be males who did not have hypertension or chronic lung disease compared to the SC group. No major differences were noted regarding other comorbid conditions. All patients were presenting with active complaints; however, the HCQ groups had higher rates of symptoms compared to the SC group (fever: 84% vs 66.3, headache: 49.8 vs 37.4, cough: 44.5 vs 35.6, respectively). Early HCQ-based therapy was associated with a lower hospital admission within 28-days compared to SC alone (9.4% compared to 16.6%, RRR 43%, p-value <0.001). The composite outcome of ICU admission and/or mortality at 28-days was also lower in the HCQ group compared to the SC (1.2% compared to 2.6%, RRR 54%, p-value 0.001). Adjusting for age, gender, and major comorbid conditions, a multivariate logistic regression model showed a decrease in the odds of hospitalisation in patients who received HCQ compared to SC alone (adjusted OR 0.57 [95% CI 0.47-0.69], p-value <0.001). The composite outcome of ICU admission and/or mortality was also lower for the HCQ group compared to the SC group controlling for potential confounders (adjusted OR 0.55 [95% CI 0.34-0.91], p-value 0.019). CONCLUSION: Early intervention with HCQ-based therapy in patients with mild to moderate symptoms at presentation is associated with lower adverse clinical outcomes among COVID-19 patients, including hospital admissions, ICU admission, and/or death.

Disentangling the association of hydroxychloroquine treatment with mortality in Covid-19 hospitalized patients through Hierarchical Clustering

“…Specifically, we tested and observed both additive and interactive associations of HCQ and Covid-19 subtypes. Indeed, the high risk cluster was consistently associated with increased mortality across all models, while treatment with HCQ was generally associated with a halving of death risk, in line with previous evidence from both observational [6][7][8][9][10][11][12][13] and intervention studies [19]. While we already reported evidence suggesting a protective influence of HCQ against mortality in a largely overlapping sample [13], here we have further deepened this relationship by testing and reporting a significant association between cluster-by-HCQ interaction and mortality, which was driven by a differential association within the two clusters.…”

“…Despite these elements and initial suggestive evidence of efficacy based on daily clinical practice, in the last months the potential benefit of HCQ for Covid-19 patients has been harshly debated [3,5]. In particular, evidence supporting protective effects from observational studies [6][7][8][9][10][11][12][13] was in contrast with that suggesting no effect at all by recent randomized clinical trials (RCTs) [14][15][16][17][18].…”

Hydroxychloroquine and mortality in COVID-19 patients: a systematic review and a meta-analysis of observational studies and randomized controlled trials

“…Data from 3 independent cohorts were extracted from the study of Kim et al [ 46 ]; 7 articles were not published in peer reviewed journals; 4 observational studies reported unadjusted relative risks for the association between HCQ and mortality; 13 studies have been conducted in Europe, 17 in North America (Canada, USA or Mexico), 3 in Asia (China, Saudi Arabia) and three in other countries. The outcome considered was total mortality, with the exception of Geleris et al [ 18 ] in which the authors used a combined endpoint formed by intubation or death; the mortality was intra-hospital, with the exception of the studies [ 28 , 33 , 35 , 36 ], in which death was all-cause, all-location. All studies included hospitalized patients, with the exclusion of three ones which included ambulatory [ 28 , 36 ] or non-hospitalized individuals [ 35 ].…”

Randomized Controlled Trials of Early Ambulatory Hydroxychloroquine in the Prevention of COVID-19 Infection, Hospitalization, and Death: Meta-Analysis

“…Our findings are consistent with the results of several non-randomized controlled evaluations of HCQ outpatient therapy for COVID-19, which have reported substantial effectiveness. 4 5 6 7 8 9 In addition, a number of studies examining HCQ use in the hospitalized setting—particularly use starting within 24-48 hours of admission—have also shown benefit. 19 20 21 22 23 24 That modern, well-conducted non-randomized trials and observational studies would yield results similar to those of RCTs is not surprising as it is the common finding across numerous medical disciplines.…”

“…A large number of non-randomized but controlled trials have now shown benefit of HCQ when used early for treatment of high-risk outpatients. 4 5 6 7 8 9 Various randomized trials of HCQ for pre-exposure prophylaxis, post-exposure prophylaxis, and outpatient treatment have been performed. Individually, these clinical trials have yielded estimates of effectiveness that have not reached statistical significance.…”