#17,856
During the first year of the COVID pandemic a number of potential - but largely unproven - treatments were tried in hospitals, and by doctors and individuals, around the world. Some showed early promise, but in the end were deemed to be an ineffective - or worse, detrimental - treatment.
Based primarily on in vitro studies Hydroxychloroquine (HCQ) - an antimalarial drug also used to treat autoimmune diseases - was considered as a candidate treatment for COVID, and for a time was approved under an EUA by the FDA (see below).
On March 28, 2020, the FDA issued an Emergency Use Authorization (EUA) to allow hydroxychloroquine sulfate and chloroquine phosphate products donated to the Strategic National Stockpile(SNS) to be distributed and used for certain hospitalized patients with COVID-19.
June 15, 2020 Update: Based on ongoing analysis and emerging scientific data, FDA has revoked the emergency use authorization (EUA) to use hydroxychloroquine and chloroquine to treat COVID-19 in certain hospitalized patients when a clinical trial is unavailable or participation is not feasible. We made this determination based on recent results from a large, randomized clinical trial in hospitalized patients that found these medicines showed no benefit for decreasing the likelihood of death or speeding recovery.
But with COVID deaths increasing, and few proven therapeutic options available, many hospitals, doctors, and individuals continued to use HCQ as an `off-label' treatment. Some people who took the drug, recovered, and attributed their survival to its use.
But hospital studies continued to show little or no benefit, and a significant risk for adverse effects.
HCQ wasn't alone in that respect. Over the course of 2020 several other potential treatments were tried and proven ineffective (see WHO Solidarity Therapeutics Trial: Remdesivir, HCQ, Lopinar/Ritonavir & Interferon Disappoint).
Interim results from the Solidarity Therapeutics Trial, coordinated by the World Health Organization, indicate that remdesivir, hydroxychloroquine, lopinavir/ritonavir and interferon regimens appeared to have little or no effect on 28-day mortality or the in-hospital course of COVID-19 among hospitalized patients.
The study, which spans more than 30 countries, looked at the effects of these treatments on overall mortality, initiation of ventilation, and duration of hospital stay in hospitalized patients. Other uses of the drugs, for example in treatment of patients in the community or for prevention, would have to be examined using different trials.
Since then we've seen the early enthusiasm for Convalescent Plasma therapy dry up (see BMJ: Clinical Trial On Convalescent Plasma Showed Little Benefit For COVID-19) and recent studies have cautioned against the use of statins (see Statin Use in Relation to COVID-19 and Other Respiratory Infections: Muscle and Other Considerations) due to high rates of rhabdomyolysis in hospitalized COVID-19 patients.
In 2021 HCQ use was associated with an estimated 11% increase in COVID patient mortality (see Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials).
But it is entirely possible that some of the other treatments from early in the pandemic would have similarly dismal outcomes. Inappropriate antibiotic use, and high intensity ventilation, have both been linked to increased COVID mortality.
First the link, and some excerpts from today's study, after which I'll return with a postscript.
(SNIP)
Deaths induced by compassionate use of hydroxychloroquine during the first COVID-19 wave: an estimate
Alexiane PRADELLE a, Sabine MAINBOURG a b c, Steeve PROVENCHER d, Emmanuel MASSY c e, Guillaume GRENET a f, Jean-Christophe LEGA a c e fShow more
https://doi.org/10.1016/j.biopha.2023.116055Get rights and content
Under a Creative Commons license
HighlightsAbstract
- 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 randomized 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.
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.
In conclusion, the number of HCQ-related deaths is estimated at 16990, even though this number is probably underestimated because of the lack of data from most countries. More importantly, 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.
Like it or not, a lot of medicines we use every day (both Rx and OTC) are of questionable value. Some may actually do us harm, while others simply provide no measurable benefit. Although evidence-based medicine is heavily touted, often the evidence is scant or even contradictory.
In 2010, in RCTs: All That’s Gold Standard Doesn’t Glitter, I wrote about my own experience as a paramedic in the 1970s, and the use of Bi-carb (NaHCO3) for cardiac arrests.
Back then every doctor knew that the very first thing you did for someone in cardiac arrest (after initiating CPR) was to give them a bolus of 1 or 2 amps of Sodium Bicarb to reverse the inevitable acidosis brought on by respiratory arrest.
By 1986 several scientific studies had demonstrated that rapid provision of effective ventilation and artificial circulation were entirely adequate means of managing the small amount of respiratory- (or metabolic)- acidosis that accompanied common cardiac arrests.You did this even before attempting to defibrillate, since conventional wisdom said that you couldn't cardiovert an acidotic heart.
Administration of even 1 amp of Bicarb was linked to poorer outcomes, and so the automatic administration of it was removed from the ACLS protocols in 1986.
But wasn't the end of it. Nearly 4 decades later, the debate still continues in this 2022 clinical paper in the journal Resuscitation. While the benefit appears to be limited to patients with non-shockable rhythms, this illustrates how hard it can be to reach a consensus.
Sara M. Niederberger Remle P. Crowe David D. Salcido James J. Menegazzi
Published:November 17, 2022 DOI:https://doi.org/10.1016/j.resuscitation.2022.11.007
Just as the next pandemic is inevitable, so too will be the use of questionable or unproven medicines to treat it. I suspect that many of the therapies that failed against COVID will be trotted out against the next virus.
And who knows - depending on the pathogen du jour - one of them might actually work next time.
But in those opening weeks and months - when we know little about what works and what doesn't - the smart money should be on prevention, not an unproven treatment.
At least, that's where I'll be putting my efforts.
