Dr. Anant Patil refers to a significant study which claims that treatment with antimalarial drug chloroquine or hydroxychloroquine taken with or without macrolides offers no benefit for COVID-19 patients and may in fact increase risk of death and ventricular arrhythmia.

For our comprehensive coverage and latest updates on COVID-19 click here.

Hydroxychloroquine or chloroquine is being used often with macrolide (azithromycin) for the treatment of coronavirus disease (COVID-19). At this moment, there is no strong and conclusive evidence for their benefit in the treatment of COVID-19.

In this article, important results along with strengths and limitations of this study are discussed.

Enrolment of patients in the study [1] gives important insights regarding clinical and epidemiological aspects. First important point which makes the study and its results relevant for discussion is the large number of patients and different geographical areas from which patients were included in the study.

This large study involved 96032 hospitalised patients. All patients were PCR-confirmed COVID-19 infection from multiple geographic locations. Out of six continents, patients from North America (65.9%) were maximum in this study. The study included 7555 and 13519 patients from Asia and Asian origin respectively. [1]

Secondly, authors divided the hospitalised patients into five groups with fairly large number of patients in each group i.e. four treatment groups [hydroxychloroquine (n=3016), hydroxychloroquine with macrolide (n=6221), chloroquine (n=1868), chloroquine with macrolide (n=3783)] and a control group (n=81144). Patients in the control group did not receive any of these treatments. [1] Classifying patients into distinct treatment groups helps to give clear idea about comparative baseline characteristics as well as outcomes in individual treatment group as compared to control.

Patients who received treatment with hydroxychloroquine, chloroquine alone or with macrolide within 48 hours of diagnosis were enrolled. This suggests that the study included admitted COVID-19 patients in whom early treatment with hydroxychloroquine or chloroquine was initiated. Importantly, patients on mechanical ventilation or those who received remdesivir were not considered in this study. [1]

In terms of outcomes, overall in-hospital mortality rate and mortality rates in the control group, hydroxychloroquine, hydroxychloroquine with macrolide, chloroquine and chloroquine with macrolide group were 11.1%, 9.3%, 18%, 23.8%, 16.4% and 22.2% respectively. These numbers suggest higher rates of in-hospital mortality with hydroxychloroquine, hydroxychloroquine with macrolide, chloroquine and chloroquine with macrolide group as compared to control group. The rates of de-novo ventricular arrhythmia in all four treatment groups was also higher than control group (0.3%); highest for hydroxychloroquine with macrolide (8.1%). After controlling multiple confounding variables, results of hazard ratio and 95% confidence interval suggested that all four treatment groups are independently associated with higher risk of in-hospital mortality and de-novo ventricular arrhythmia during hospitalisation. The rates of de-novo ventricular arrhythmia were higher when macrolide was added to chloroquine or hydroxychloroquine. [1]

Important to note- hypertension, diabetes, coronary artery disease and history of arrhythmia were present in 26.9%, 13.8%, 12.6% and 3.5% of the study population respectively. The group of Asian origin was associated with reduced in-hospital mortality risk. Similarly, in-hospital mortality risk was lower in females and those treated with angiotensin converting enzyme inhibitors or statin. [1]

Understanding the limitations of this study is also important before interpreting and extrapolating the results. Among the different study designs, randomised controlled trials are considered as gold standard in clinical research evaluating effectiveness of the treatment as they reduce the bias and help rigorous examination of cause and effect analysis of intervention and outcome. [2]

The study published by Mehra and Colleagues [1] is observational (registry) in nature, hence cause and effect relationship between intervention and outcome cannot be established. Moreover, being an observational study, influence of some unmeasured confounding factors on the results cannot be ruled out, which authors have also mentioned in the article.

About two months back, the Indian Council of Medical Research (ICMR) issued an advisory on the use of hydroxyl-chloroquine as prophylaxis against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in high risk people. [3]

On 22nd May 2020, a revised advisory on the use of hydroxychloroquine as a prophylaxis for SARS-CoV-2 infection was released. [4] There is a possibility that some people may link results of the study by Mehra and colleagues [1] with recommendation from ICMR regarding use of hydroxychloroquine for prophylaxis in defined high risk population. [4]

The following should be noted:

1. The recommendation by ICMR is for prophylaxis in a defined group of high risk people and not for the treatment of COVID-19 patients. [4]
2. The recommendations regarding prophylaxis with hydroxychloroquine in the revised advisory are based on the results of an in-vitro study, safety profile of hydroxychloroquine in healthcare workers and three other studies (a retrospective case control study, another study from three central government hospitals in New Delhi and a prospective observational study among healthcare workers at AIIMS) with hydroxychloroquine for prophylaxis against SARS-CoV-2 infection. [4]
3. Contraindications and precautions for use of hydroxychloroquine are clearly listed in the advisory by ICMR. [4]
4. Macrolide is not recommended along with hydroxychloroquine for prophylaxis in the advisory by ICMR. [4]
5. Dosage, schedule and duration of use of hydroxychloroquine reported in the study by Mehra and colleagues[1] is different than that recommended in the advisory from ICMR. [4]

Disclaimer- The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

The author, Dr. Anant Patil is Assistant Professor of Pharmacology.