Physicians and patients should be aware of several rare but potentially life-threatening adverse effects of chloroquine, hydroxychloroquine and azithromycin, even during short courses of treatment, warns an overview in the Canadian Medical Association Journal. Meanwhile, a US study in veterans hospitals found that 28% who were given hydroxychloroquine plus usual care died, versus 11% of those getting routine care alone.
Authored by Dr David Juurlink, division of clinical pharmacology and toxicology, Sunnybrook Health Sciences Centre, and a senior scientist at ICES, the review provides an overview of potential harms associated with these drugs as well as their management based on the best available evidence.
Potential adverse effects include:
Cardiac arrhythmias
Hypoglycaemia
Neuropsychiatric effects, such as agitation, confusion, hallucinations and paranoia
Interactions with other drugs
Metabolic variability (some people metabolize chloroquine and hydroxychloroquine poorly and a small percentage metabolize them rapidly, which affects the response to treatment)
Overdose (chloroquine and hydroxychloroquine are highly toxic in overdose and can cause seizures, coma and cardiac arrest)
Drug shortages (patients with autoimmune disorders such as rheumatoid arthritis, lupus and other chronic diseases, who take hydroxychloroquine to treat these conditions could have problems accessing this drug)
The review summarises the poor quality of evidence suggesting that these treatments might be beneficial in patients with COVID-19 and cautions that it is possible that these treatments could worsen the disease.
"Despite optimism (in some, even enthusiasm) for the potential of chloroquine or hydroxychloroquine in the treatment of COVID-19, little consideration has been given to the possibility that the drugs might negatively influence the course of disease," say Juurlink. "This is why we need a better evidence base before routinely using these drugs to treat patients with COVID-19."
The drug widely touted by President Donald Trump for treating the new coronavirus showed no benefit in a large analysis of its use in US veterans hospitals. According to MarketWatch, researchers reported that there were more deaths among those given hydroxychloroquine versus standard care.
The report says the nationwide study was not a rigorous experiment. But with 368 patients, it’s the largest look so far of hydroxychloroquine with or without the antibiotic azithromycin for COVID-19.
The study by researchers at the Dorn Research Institute, Columbia VA Health Care System, the University of Virginia and the University of South Carolina was posted on an online site for researchers and has been submitted to the New England Journal of Medicine, but it has not been reviewed by other scientists. Grants from the National Institutes of Health and the University of Virginia paid for the work.
Researchers analysed medical records of 368 male veterans hospitalised with confirmed coronavirus infection at Veterans Health Administration medical centres who died or were discharged by 11 April. About 28% who were given hydroxychloroquine plus usual care died, versus 11% of those getting routine care alone. About 22% of those getting the drug plus azithromycin died, too, but the difference between that group and those receiving usual care was not considered large enough to rule out other factors that could have affected survival.
Hydroxychloroquine made no difference in the need for a breathing machine, either.
The report says researchers did not track side effects but noted hints that hydroxychloroquine might have damaged other organs. The drug has long been known to have potentially serious side effects, including altering the heartbeat in a way that could lead to sudden death. Earlier this month, scientists in Brazil stopped part of a hydroxychloroquine study after heart-rhythm problems developed in one-quarter of people given the higher of two doses being tested.
The report says many doctors have been leery of the drug. At the University of Wisconsin, Madison, “I think we’re all rather underwhelmed” at what’s been seen among the few patients there who’ve tried it, said Dr. Nasia Safdar, medical director of infection control and prevention. The report says patients asked about it soon after Trump started promoting its use “but now I think that people have realized we don’t know if (hydroxychloroquine) works or not” and that the matter needs more study, said Safdar, who had no role in the VA analysis.
The NIH and others have more rigorous tests underway.
Abstract (non-peer-reviewed)
Background: Despite limited and conflicting data on the use of hydroxychloroquine in patients with Covid-19, the U.S. Food and Drug Administration has authorized the emergency use of this drug when clinical trials are unavailable or infeasible. Hydroxychloroquine, alone or in combination with azithromycin, is being widely used in Covid-19 therapy based on anecdotal and limited observational evidence.
Methods: We performed a retrospective analysis of data from patients hospitalized with confirmed SARS-CoV-2 infection in all United States Veterans Health Administration medical centers until April 11, 2020. Patients were categorized based on their exposure to hydroxychloroquine alone (HC) or with azithromycin (HC+AZ) as treatments in addition to standard supportive management for Covid-19. The two primary outcomes were death and the need for mechanical ventilation. We determined the association between treatment and the primary outcomes using competing risk hazard regression adjusting for clinical characteristics via propensity scores. Discharge and death were taken into account as competing risks and subdistribution hazard ratios are presented.
Results: A total of 368 patients were evaluated (HC, n=97; HC+AZ, n=113; no HC, n=158). Rates of death in the HC, HC+AZ, and no HC groups were 27.8%, 22.1%, 11.4%, respectively. Rates of ventilation in the HC, HC+AZ, and no HC groups were 13.3%, 6.9%, 14.1%, respectively. Compared to the no HC group, the risk of death from any cause was higher in the HC group (adjusted hazard ratio, 2.61; 95% CI, 1.10 to 6.17; P=0.03) but not in the HC+AZ group (adjusted hazard ratio, 1.14; 95% CI, 0.56 to 2.32; P=0.72). The risk of ventilation was similar in the HC group (adjusted hazard ratio, 1.43; 95% CI, 0.53 to 3.79; P=0.48) and in the HC+AZ group (adjusted hazard ratio, 0.43; 95% CI, 0.16 to 1.12; P=0.09), compared to the no HC group.
Conclusions: In this study, we found no evidence that use of hydroxychloroquine, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with Covid-19. An association of increased overall mortality was identified in patients treated with hydroxychloroquine alone. These findings highlight the importance of awaiting the results of ongoing prospective, randomized, controlled studies before widespread adoption of these drugs.
Authors
Joseph Magagnoli, Siddharth Narendran, Felipe Pereira, Tammy Cummings, James W Hardin, S Scott Sutton, Jayakrishna Ambati
[link url="https://www.sciencedaily.com/releases/2020/04/200408125521.htm"]Canadian Medical Association Journal material[/link]
[link url="https://www.cmaj.ca/content/early/2020/04/08/cmaj.200528"]CMAJ review[/link]
[link url="https://www.marketwatch.com/story/hydroxychloroquine-treatment-for-covid-19-shows-no-benefit-and-more-deaths-in-va-study-2020-04-21"]Full MarketWatch report[/link]
[link url="https://www.medrxiv.org/content/10.1101/2020.04.16.20065920v1"]medRxiv abstract (non-peer-reviewed)[/link]