No Evidence of Benefit for Chloroquine and Hydroxychloroquine in COVID-19 Patients, Study Finds

At the end of the study period, around one in 11 patients in the control group had died in hospital (9.3 percent, 7,530/81,144). All four of the treatments were associated with a higher risk of dying in hospital. Of those treated with chloroquine or hydroxychloroquine alone, around one in six patients had died (16.4 percent, 307/1,868 chloroquine and 18.0 percent, 543/3,016 hydroxychloroquine). When the drugs were used in combination with a macrolide, the death rate rose to more than one in five for chloroquine (22.2 percent, 839/3,783) and almost one in four for hydroxychloroquine (23.8 percent, 1,479/6,221).

Some of the difference in the rates of mortality is due to underlying differences between patients who received the treatments and those who didn’t. After accounting for factors including age, race, body mass index and underlying health conditions including heart disease, lung disease and diabetes, the researchers found the drug regimens were associated with an increased risk of death.

They estimated that the excess risk attributable to the use of the drug regimen rather than other factors such as co-morbidities ranged from 34 percent to 45 percent. The authors explain that if the rate of mortality is 9.3 percent in the control group, after adjustment for the other clinical factors, the rate attributable to the use of the drug regimens would rise to 12.4-13.4 percent. However, the researchers caution that it is not possible to exclude the possibility that other, unmeasured factors were responsible for the apparent link between treatment with these drugs and the decrease in patient survival because such is the design of observational studies, and randomized trials are urgently needed.

The team also found that serious cardiac arrhythmias, which cause the lower chamber of the heart to beat rapidly and irregularly, were more common in the groups receiving either of the four treatment regimens.

The biggest increase was seen in the group treated with hydroxychloroquine in combination with a macrolide, where 8 percent of patients developed a heart arrhythmia (502/6,221) compared with 0.3 percent patients in the control group (226/81144). After accounting for demographic factors and pre-existing conditions, the team calculated that treatment with this combination of drugs is associated with a more than five-fold increase in risk of developing a serious heart arrhythmia while in hospital (as an example, an increase from 0.3 percent to 1.5 percent would be attributable to the drug regimen after adjustment for other clinical factors). Similarly, it is not possible to conclusively infer cause and effect between treatment with these medications and the onset of heart arrhythmias. Randomized clinical trials will be required before any conclusion can be reached regarding benefit of harm of these agents in COVID-19 patients.

Prof. Dr. Frank Ruschitzka, Director of the Heart Center at University Hospital Zurich, who also co-authored the study said: “Several countries have advocated use of chloroquine and hydroxychloroquine, either alone or in combination, as potential treatments for COVID-19. Justification for repurposing these medicines in this way is based on a small number of anecdotal experiences that suggest they may have beneficial effects for people infected with the SARS-CoV-2 virus. However, previous small-scale studies have failed to identify robust evidence of a benefit and larger, randomized controlled trials are not yet completed. However, we now know from our study that the chance that these medications improve outcomes in COVID-19 is quite low.”

Writing in a linked The Lancet “Comment” article – titled “Chloroquine or Hydroxychloroquine for COVID-19: Why Might They Be Hazardous?” — Professor Christian Funck-Brentano, of the Sorbonne University in Paris, France (who was not involved in the study), said: “This well-conducted observational study adds to preliminary reports suggesting that chloroquine, hydroxychloroquine, alone or with azithromycin is not useful and may be harmful in hospitalized COVID-19 patients.”

“Several countries have advocated use of chloroquine and hydroxychloroquine, either alone or in combination, as potential treatments for COVID-19,” Frank Ruschitzka, director of the Heart Center at University Hospital Zurich and co-author of the study, told

“We now know from our study that the chance that these medications improve outcomes in COVID-19 is quite low.”

Stephen Griffin, associate professor at the University of Leeds’ School of Medicine told Patrick Galey of MedicalExpress that The Lancet research was “potentially a landmark study for COVID-19 therapy.”

“The indications are that these drugs certainly ought not to be used outside of a trial setting where patients can be monitored for complications,” said Griffin, who was not involved in the study.

“It is clear that high profile endorsements of taking these drugs without clinical oversight is both misguided and irresponsible.”