Research led by scientists from the University of Lyon in France into the use of hydroxychloroquine (HCQ), prescribed during the first wave of Covid-19, suggests nearly 17 000 people subsequently died, highlighting the potential hazards of drug repurposing without firm and proven supporting evidence.
The team focused on estimated deaths induced by compassionate use of (HCQ), which was prescribed in hospitalised patients with Covid-19 despite low-level evidence of its effectiveness.
In South Africa, despite being widely used off-label, the drug was never officially endorsed or recommended for treatment by the national Department of Health, which along with the World Health Organisation and numerous other countries, advised against it and declared it ineffective for Covid treatment.
It is one of many treatments that have been repurposed with varying degrees of success, like dexamethasone, remdesivir, or a combination of lopinavir and ritonavir, based on their effectiveness against other pathogens with similar structure or mechanism of action to SARS-CoV-2.
But subsequent studies of HCQ documented unfavourable risk-benefit balance, including the RECOVERY trial that showed a significant increase in cardiac mortality as well as a trend for increased all-cause mortality risk, wrote the authors of the latest research in Biomedicine & Pharmacotherapy.
In a meta-analysis of 14 trials testing HCQ in hospitalised patients with various doses, it was associated with an 11% (95%CI 2–20%) increase in all-cause mortality, they found.
The main objective of the study was to estimate the mortality attributed to compassionate use of HCQ in the context of Covid-19 before the publication of reliable randomised controlled trials (RCTs).
Hospitalised
They conducted a systematic review and a meta-analysis of cohort studies to estimate the mortality rates and the proportion of HCQ exposure in hospitalised patients in each country represented in the available studies.
They also did a literature search to identify all published studies reporting the number of patients on all treatments examined in Covid-19.
They did not consider studies containing only ICU patients because too many external parameters could influence the results, they said. From the selected studies, they independently extracted the type of study, inclusion dates, mortality rates, percentages of ICU admissions, countries of study, and the number of patients receiving HCQ.
They extracted the mortality rate in hospitalised patients with Covid-19 from the PREMIER database for USA (12.5%), nationwide sources for France (17.4%), Belgium (21.8%), and Spain (29.1%) , and region-wide analysis for Turkey (4.5%) and Italy (28.0%) .
Using these data for estimates, the median number of HCQ-related deaths in Belgium, Turkey, France, Italy, Spain, and the USA was 240 (range not estimable), 77 (range 75–105), 299 (range not estimable), 2 237 (range 1 437–2 533), 2799 (range 2 179–3 094) and 7 583 (range 1 990–9 288), respectively. Using median estimates of HCQ use in each country, 13 226 in-hospital deaths (range 6 211–15 530) may be related to HCQ prescription in the six assessed countries.
The main finding was that HCQ might have been associated with more than 16 990 deaths during the first wave of pandemic in the six countries for which data were available.
Some estimates could not be calculated due to missing or incomplete information, such as the number of hospitalisations in China, South Korea, Russia and Qatar.
The number of deaths related to HCQ worldwide was obviously under-estimated because of the lack of studies in regions like East Europe, United Kingdom, Germany, Scandinavia, Africa, and South America, they said.
Since the number of inhabitants living in the countries included in the present study was ≈ 600m, the authors speculated that the real number of HCQ-induced deaths might be significantly higher, given the wide use of HCQ during the first and subsequent waves in numerous countries.
In addition, the number of deceased outpatients exposed to HCQ is unknown.
Accordingly, the present results should be viewed as rough estimates only.
However, importantly, they wrote, this study illustrates the limitations of treatment-effect extrapolation from chronic to severe conditions without accurate data and the need to produce quickly high-level evidence from RCTs in case of emergent diseases.
Study details
Deaths induced by compassionate use of hydroxychloroquine during the first COVID-19 wave: an estimate
Alexiane Pradelle , Sabine Mainbourg, Steeve Provencher , Emmanuel Massy , Guillaume Grenet , Jean-Christophe Lega.
Published in Biomedicine & Pharmacotherapy in February 2024
Highlights
• Hydroxychloroquine was prescribed in hospitalised patients with Covid-19 despite of the low-level evidence.
• Subsequently, HCQ use was associated with an 11% increase in the mortality rate in a meta-analysis of randomised trials.
• The number of hydroxychloroquine related deaths in hospitalised patients is estimated at 16 990 in six countries.
• These findings illustrate the hazard of drug repurposing with low-level evidence for the management of future pandemics.
Abstract
Background
During the first wave of Covid-19, hydroxychloroquine (HCQ) was used off-label despite the absence of evidence documenting its clinical benefits. Since then, a meta-analysis of randomised trials showed that HCQ use was associated with an 11% increase in the mortality rate. We aimed to estimate the number of HCQ-related deaths worldwide.
Methods and findings
We estimated the worldwide in-hospital mortality attributable to HCQ use by combining the mortality rate, HCQ exposure, number of hospitalised patients, and the increased relative risk of death with HCQ. The mortality rate in hospitalised patients for each country was calculated using pooled prevalence estimated by a meta-analysis of published cohorts. The HCQ exposure was estimated using median and extreme estimates from the same systematic review. The number of hospitalised patients during the first wave was extracted from dedicated databases. The systematic review included 44 cohort studies (Belgium: k = 1, France: k = 2, Italy: k = 12, Spain: k = 6, Turkey: k = 3, USA: k = 20). HCQ prescription rates varied greatly from one country to another (range 16–84%). Overall, using median estimates of HCQ use in each country, we estimated that 16,990 HCQ-related in-hospital deaths (range 6267–19256) occurred in the countries with available data. The median number of HCQ-related deaths in Belgium, Turkey, France, Italy, Spain, and the USA was 240 (range not estimable), 95 (range 92–128), 199 (range not estimable), 1822 (range 1170–2063), 1895 (range 1475–2094) and 12739 (3244− 15570), respectively.
Conclusions
Although our estimates are limited by their imprecision, these findings illustrate the hazard of drug repurposing with low-level evidence.
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