A research team led by investigators from Brigham and Women’s Hospital has evaluated real-world evidence related to outcomes for COVID-19 patients who were treated with hydroxychloroquine or chloroquine analogues (with or without a macrolide). Investigators found no evidence that either drug regimen reduced the death rate among patients. Patients treated with hydroxychloroquine or chloroquine regimens were far more likely to experience abnormal, rapid heart rhythms (known as ventricular arrhythmias) than their counterparts who had not received the drugs. The team’s findings are published in The Lancet.
“No matter which way you examine the data, use of these drug regimens did not help,” said corresponding author Mandeep R. Mehra, MD, executive director of the Brigham’s Center for Advanced Heart Disease. “If anything, patients had a higher likelihood of death. We also saw a quadrupling in the rate of significant ventricular arrhythmias in patients with COVID-19 who had been treated with hydroxychloroquine or chloroquine regimens.”
Mehra and colleagues conducted their study using the Surgical Outcomes Collaborative database, an international registry comprised of de-identified data from 671 hospitals across six continents. The analysis included data on more than 96,000 patients hospitalized with COVID-19. This included almost 15,000 patients who had received the anti-malarial drug chloroquine or its analog hydroxyquinone with or without an antibiotic (macrolides such as azithromycin and clarithromycin) early after COVID-19 diagnosis. The study’s primary endpoint was death or discharge from the hospital.
Mehra and colleagues found that 10,698 patients died in the hospital (11.1 percent) and 85,334 survived to discharge. The team compared death rates for those taking one of the drug regimens to that of a control group, after accounting for confounding variables, such as age, sex and underlying risk factors. The death rate among the control group was 9.3 percent. Each of the drug regimens of chloroquine or hydroxychloroquine alone, or in combination with a macrolide, was associated with an increased risk of in-hospital death with COVID-19.
In addition, each of the drug regimens was associated with an increase in the risk of ventricular arrhythmia. Among the treatment groups, between 4 and 8 percent of patients experienced a new ventricular arrhythmia, compared to 0.3 percent of patients in the control group.
Chloroquine and hydroxychloroquine have been known to cause cardiovascular toxicity and previous studies have shown that macrolides can increase the risk of sudden cardiac death. A preliminary analysis of patients in Brazil treated with chloroquine and an antibiotic has suggested a high dose of chloroquine may be a safety hazard. Results from randomized, controlled clinical trials are not expected until the summer.
The authors caution that the current study is observational in nature — this means that it cannot absolutely answer the question of whether the drug regimens were solely responsible for the changes in survival. Randomized clinical trials will be required before any conclusion can be reached regarding harm.
“These findings suggest that these drug regimens should not be used outside of the realm of clinical trials and urgent confirmation from randomized clinical trials is needed,” the authors conclude.
The development and maintenance of the Surgical Outcomes Collaborative database was funded by the Surgisphere Corporation. The present analysis was supported by the William Harvey Distinguished Chair in Advanced Cardiovascular Medicine at Brigham and Women’s Hospital, Boston. Mehra reports no direct conflicts pertinent to the development of this paper. Other general conflicts include consulting relationships with Abbott, Medtronic, Janssen, Mesoblast, Portola, Bayer, NupulseCV, FineHeart, Leviticus, Roivant and Triple Gene. Dr. Desai is the founder of Surgisphere Corporation, Chicago. The other authors have no pertinent conflicts to report.
Paper cited: Mehra M et al. “Hydroxychloroquine or Chloroquine with or without a Macrolide and Outcome in COVID-19: A Multinational Registry Analysis” The Lancet DOI: 10.1016/S0140-6736(20)31180-6
Media Statement - 5/29
The authors leveraged the data available through Surgisphere to provide observational guidance to inform the care of hospitalized Covid-19 patients in the absence of a large, robust and publicly available dataset on hydroxychloroquine or chloroquine, and the lack of scientific evidence regarding the safety and benefits of these treatments for hospitalized Covid-19 patients.
As articulated in the study, the authors have underscored the importance and value of randomized, clinical trials and articulated that such trials will be necessary before any conclusions can be reached. However, results are not anticipated from such trials until the summer and, given the urgency of the situation, leveraging the available dataset was an intermediary step.
Last week, The Lancet made the co-authors aware of a discrepancy in the data reported by Australian hospitals. Subsequently, the authors discovered that a hospital in Asia had mistakenly been included in the Australian data. The co-authors reported the updated data to The Lancet, and a correction was published. In addition, the co-authors have initiated an independent academic review of the data. The results, findings and overall interpretations reported in the study remain unchanged.
Media Statement - 6/2
Independent of Surgisphere, the remaining co-authors of the recent studies published in The Lancet and the New England Journal of Medicine have initiated independent reviews of the data used in both papers after learning of the concerns that have been raised about the reliability of the database. The goal of the independent third-party auditor is to verify the source data and assess the accuracy of the database and the authors’ findings. Upon completion of the reviews, the auditor will simultaneously provide its findings directly to the editors of the journals and to the co-authors, independent of Surgisphere.
The data available through Surgisphere were leveraged to provide observational guidance to inform the care of hospitalized Covid-19 patients amidst this global pandemic. I have routinely underscored the importance and value of randomized, clinical trials and articulated that such trials will be necessary before any conclusions can be reached. Until findings from such studies are available, given the urgency of the situation, using the available dataset was an intermediary step. I eagerly await word from the independent audits, the results of which will inform any further action.
-- Dr. Mandeep R. Mehra