Hydroxychloroquine and chloroquine, with or without azithromycin or clarithromycinIt does not offer benefits in treating patients with COVID-10 and, conversely, is associated with ventricular arrhythmias and higher mortality rates, according to a large new international study.
In the largest observational study of its kind, including nearly 100,000 people in 671 hospitals on six continents, the researchers compared results in 15,000 patients with COVID-19 treated with hydroxychloroquine and chloroquine alone or in combination with macrolides with 80,000 control patients with COVID-19 do not accept this agent.
Treatment with one of these drugs, either alone or in combination, is associated with an increase in mortality during hospitalization: compared with about 10% in control group patients, the death rate ranges from more than 16% to almost 24% in the treated group.
Patients treated with hydroxychloroquine plus macrolide show the highest rates of serious cardiac arrhythmias, and, even after taking into account demographic and comorbid factors, this combination was found to be associated with a more than 5-fold increase in the risk of developing serious arrhythmias. when in the hospital.
“In this real-world study, the largest, we saw 100,000 patients [with COVID-19] on 6 continents and found not the slightest benefit and risk, and the data is quite easy, “study co-author Frank Ruschitzka, MD, director of the Heart Center at the University Hospital, Zurich, Switzerland, told theheart.org | Medscape Cardiology.
That research published online May 22nd Lancet.
‘Not conclusive’ evidence
The absence of effective treatment for COVID-19 has led to “repurposing” of the antimalarial drug chloroquine and its analogues hydroxychloroquine, which is used to treat autoimmune diseases, but this approach is based on anecdotal evidence or open label trials that have “largely been inconclusive.” , “wrote the authors.
Additional agents used to treat COVID-19 are second-generation macrolides (azithromycin or clarithromycin), in combination with chloroquine or hydroxychloroquine, “despite limited evidence” and the risk of ventricular arrhythmias, note the authors.
“Our main question is whether there are benefits associated with the use of hydroxychloroquine, chloroquine, or a combination regimen with macrolides in treating COVID-19, and – if there are no benefits – will there be any harm?” lead author Mandeep R. Mehra, MD, MSc, Distinguished Chairperson William Harvey in Advanced Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, said theheart.org | Medscape Cardiology.
The researchers used data from a multinational registry consisting of 671 hospitals that included patients (n = 96,032, median age 53.8 years, 46.3% women) who had been hospitalized between 20 December 2019, and 14 April 2020, with confirmed COVID-19 infection. .
They also collected data on demographics, underlying comorbidities and medical history, and medications that patients consumed at baseline.
Patients who received treatment (n = 14,888) were divided into four groups: those who received chloroquine alone (n = 1868), those who received chloroquine with macrolide (n = 3783), those who received hydroxychloroquine alone (n = 3016) and those who received chloroquine with macrolide (n = 3783), those who received hydroxychloroquine alone (n = 3016) received hydroxychloroquine with macrolides (n = 6221).
The remaining patients who were not treated with this regimen (n = 81,144) were considered a control group.
Most of the patients (65.9%) were from North America, followed by Europe (17.39%), Asia (7.9%), Africa (4.6%), South America (3.7%), and Australia (0.6%). Most (66.9%) were white, followed by patients from Asia (14.1%), black patients (9.4%), and Hispanic patients (6.2%).
Comorbidity and Underlying Conditions
|Obesity (BMI ≥30 kg / m2)||30.7|
|Chronic obstructive pulmonary disease||3.3|
|The underlying immunosuppressant condition||3.0|
|History of coronary artery disease||12.6|
|History of congestive heart failure||2.5|
|History of arrhythmias||3.5|
The researchers conducted several analyzes to control for confounding variables, including Cox proportional hazard regression and trend score matching analysis.
“In an observational study, there is always an opportunity to confuse residuals, which is why we do a match analysis based on a trend score,” Ruschitzka explained.
No significant differences were found in the demographic distribution and comorbidity between groups.
As good as it gets
“We found no benefit in any of the treatment regimens for patients hospitalized with COVID-19 but we did see a higher mortality and serious ventricular arrhythmia in these patients, compared with controls,” Mehra reported.
Among patients in the control group, about 9.3% died during hospitalization compared with 16.4% of patients treated with chloroquine alone, 18.0% of those treated with hydroxychloroquine alone, 22.2% of those treated with chloroquine and macrolide, and 23.8% of those treated with hydroxy chloroquine and macrolide.
After accounting for confounding variables, the researchers estimated that the risk of excess deaths from the use of a drug regimen ranged from 34% to 45%.
Patients treated with one of the four regimens maintained more serious arrhythmias compared to those in the control group (0.35), with the greatest increase seen in the group treated with the combination of chloroquine hydroxy plus macrolide (8.1%), followed by chloroquine with macrolide (6.5%), hydroxychloroquine alone (6.1%), and chloroquine alone (4.3%).
“We are quite convinced that, although this research is observational, the signal is strong and consistent in all regions of the world in diverse populations, and we do not see any signal, depending on the region,” Mehra commented.
“Two months ago, we all scratched our heads about how to treat patients with COVID-19, and then medicine came. [hydroxychloroquine] with some anecdotal evidence but now we have more than 2 months experience, and we are looking for knowledge to provide some answers, “said Ruschitzka.
“Although this is not a randomized controlled trial, so we don’t have a definitive answer, the data provided in this [large, multinational] “real-world studies are as good as what we get and the best data we have,” he concluded.
“Let Science Speak for Themselves”
Comment on study for theheart.org | Medscape Cardiology, Christian Funck-Brentano, MD, from Pitie-Salpetriere Hospital and Sorbonne University in Paris, France, said that although this study was observational and therefore not as reliable as randomized controlled trials, it “remains well documented, studying study large numbers of people, and use several sensitivity methods, all of which show the same results. “
Funck-Brentano, who is a co-author accompanying editorial and not involved with this research, said that “we now have no evidence that hydroxychloroquine and chloroquine alone or in combination with macrolides are beneficial, and we have potential evidence that they harm and kill people.”
Also comment on the study for theheart.org | Medscape Cardiology, David Holtgrave, PhD, dean of the University at Albany School of Public Health said that, “while there is not just one observational study that will lead to strong clinical recommendations, I think it will be very helpful for doctors and public health officials to find out about these findings. peer-reviewed observational studies to date and NIH COVID-19 treatment guidelines and FDA statement on drug safety issues “about hydroxychloroquine to inform their decision making as we await the results of randomized clinical trials of this drug for the treatment of COVID-19,” said Holtgrave, who was not involved with the study.
He added that, to his knowledge, “there is still no published research on the prophylactic use of this drug to prevent COVID-19.”
Mehra stressed that the main principle in practicing medicine is “first, don’t harm” and “even in situations where you believe a disease of despair requires desperate action, the doctor in charge must take a step back and ask if we are doing damage, and until we can say we are not, I think it would be unwise to push something like this without good efficacy data. “
Ruschitzka added that those who encourage the use of these agents “must review their decisions based on today’s data and let science speak for itself.”
This research was supported by William Harvey Distinguished Chair in Advanced Cardiovascular Medicine at Brigham and Women’s Hospital (Boston, MA, USA). Mehra reports personal expenses from Abbott, Medtronic, Janssen, Mesoblast, Portola, Bayer, Baim Institute for Clinical Research, NuPulseCV, FineHeart, Leviticus, Roivant, and Triple Gen. Ruschitzka has been paid for the time spent as committee members for clinical trials, advisory boards, other forms of consultation, and lectures or presentations; This payment was made directly to the University of Zurich and no personal payment was received in connection with this trial or other activity. Funck-Brentano, co-author, and Holtgrave did not state relevant financial relationships.
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