Blog

The absence of an effective treatment against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection has led clinicians to redirect drugs that are known to be effective for other medical conditions to the treatment of COVID-19. The most important among these repurposed therapeutic agents are the antimalarial drug, chloroquine and its analogue hydroxychloroquine, which are used for the treatment of autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis. Lab tests showed promising results against SARS-CoV-2, but accumulating trial and observational evidence is casting doubts on any meaningful clinical benefits for patients with covid-19.

COVID-19 is exemplified by initial viral replication followed by enhanced systemic inflammation. The use of chloroquine or hydroxychloroquine in combination with a macrolide is designed to use their antimicrobial properties in a synergistic manner. Macrolides, such as azithromycin and clarithromycin, are antibiotics with immunomodulatory and anti-inflammatory effects. Therefore, Hydroxychloroquine or chloroquine, often in combination with a second-generation macrolide, are being widely used for treatment of COVID-19.

On March 28, 2020, the US FDA issued an emergency use authorization for hydroxychloroquine and chloroquine in patients, if clinical trial access was unavailable. Other countries, such as China, issued guidelines allowing the use of chloroquine in COVID-19. Several countries have been stockpiling the drugs, and shortages of them for approved indications have been encountered. These drugs are generally safe when used for approved indications such as autoimmune disease or malaria, but the safety and benefit of these treatment regimens are poorly evaluated in COVID-19.

A multinational registry analysis of the use of hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19 was done by Mehra et al and published in The Lancet (May 22, 2020). The registry comprised data from 671 hospitals in six continents. Patients were included into one of the four treatment groups (chloroquine alone, chloroquine with a macrolide, hydroxychloroquine alone, or hydroxychloroquine with a macrolide) if they received the study drugs within 48 hours of diagnosis , and patients who received none of these treatments formed the control group.

96,032 patients (mean age 53·8 years, 46·3% women) with COVID-19 were hospitalized during the study period and met the inclusion criteria. Of these, 14,888 patients were in the treatment groups and 81,144 patients were in the control group. The study cohort included 63,315 (65·9%) patients from North America, 16,574 (17·3%) from Europe, 7,555 (7·9%) from Asia, 4,402 (4·6%) from Africa, 3,577 (3·7%) from South America, and 609 (0·6%) from Australia.

The primary outcome of interest was the association between use of a treatment regimen containing chloroquine or hydroxychloroquine (with or without a second-generation macrolide) when initiated early after COVID-19 diagnosis with the endpoint of in-hospital mortality. The secondary outcome of interest was the association between these treatment regimens and the occurrence of clinically significant ventricular arrhythmias (defined as the first occurrence of a non-sustained [at least 6 sec] or sustained ventricular tachycardia or ventricular fibrillation) during hospitalization.

After controlling for age, sex, race or ethnicity, underlying comorbidities, and disease severity at baseline, the use of all four regimens was associated with an increased hazard for de-novo ventricular arrhythmia and death in hospital.

There was no evidence of benefit of hydroxychloroquine or chloroquine when used either alone or with a macrolide. Evidence in previous studies was derived from either small anecdotal studies or inconclusive small randomized- trials. This observational study included a large number of patients across multiple geographic regions and provides the most robust real-world evidence to date on the usefulness of these treatment regimens. The use of a regimen containing hydroxychloroquine or chloroquine (with or without a macrolide) was associated with no evidence of benefit, but instead was associated with an increase in the risk of ventricular arrhythmias and a greater hazard for in-hospital death with COVID-19.

A retrospective observational review of 368 men with COVID-19 treated at the US Veterans Affairs hospitals raised concerns that the use of hydroxychloroquine was associated with a greater hazard of death; however, the baseline characteristics among the groups analyzed were dissimilar and the possibility of bias cannot be ruled out. Another observational study in 181 patients from France reported that the use of hydroxychloroquine at a dose of 600 mg per day was not associated with a measurable clinical benefit in patients with COVID-19 pneumonia.

There are concerns of cardiovascular toxicity with chloroquine and hydroxychloroquine, particularly because of their known relationship with electrical instability, characterized by QT interval prolongation (the time taken for ventricular depolarization and repolarization). The prolonged QT interval increases the risk of sudden cardiac death. Individuals with structural cardiovascular disease, and cardiac injury are more susceptible to such arrhythmias. Such cardiac injury has been reported to occur with high frequency during COVID-19 illness. Furthermore, individuals with cardiovascular disease represent a vulnerable population that experience worse outcomes with COVID-19. Whether patients with underlying cardiovascular disease and those that experience de-novo cardiovascular injury have a greater predilection to ventricular arrhythmias with chloroquine or its analogues remains uncertain.

In a preliminary analysis, Borba and colleagues reported a double-blind, randomized trial with 81 adult patients who were hospitalized with severe COVID-19 at a tertiary care facility in Brazil. This study suggested that a higher dose of chloroquine represented a safety hazard, especially when taken concurrently with azithromycin and oseltamivir. In another cohort study of 90 patients with COVID-19 pneumonia, Mercuro and colleagues found that the concomitant use of a macrolide was associated with a greater change in the corrected QT interval.

The World Health Organization halted all its trials involving hydroxychloroquine due to the concerns raised in the study (published in The Lancet) about its efficacy and safety. The Health Ministry of France had approved hydroxychloroquine for emergency prescriptions in COVID-19 cases in late March. But the French government has revoked a decree that had allowed hospitals to prescribe hydroxychloroquine in some COVID-19 cases, saying that there is no proof that it helps patients, citing data that shows it could cause heart problems and other health risks. This move to bar hospitals from prescribing the drug for coronavirus patients came two days after the World Health Organization halted all the clinical trials of hydroxychloroquine. Now the US Food and Drug Administration (FDA) is also warning against use outside clinical trials or hospital settings due to the risk of heart rhythm problems. The various observational studies and randomized controlled trials suggest that these drug regimens should not be used rampantly, especially outside of clinical trials. Urgent confirmation from randomized clinical trials is needed.

References:

1. Prof Mandeep R Mehra MD, Sapan S Desai MD, Prof Frank Ruschitzka MD, Amit N Patel, MD Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Published: May 22, 2020

2. Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med 2012; 366: 1881–90.

3. Giudicessi JR, Noseworthy PA, Friedman PA, Ackerman MJ. Urgent guidance for navigating and circumventing the QTc-prolonging and torsadogenic potential of possible pharmacotherapies for coronavirus disease 19 (COVID-19). Mayo Clin Proc 2020; published online April 7. DOI:10.1016/j.mayocp.2020.03.024.

4. Peschken CA. Possible consequences of a shortage of hydroxychloroquine for patients with systemic lupus erythematosus amid the COVID-19 pandemic. J Rheumatol 2020; published online April 8. DOI:10.3899/jrheum.200395

5. US Food and Drug Administration. Emergency use authorization: coronavirus disease 2019 (COVID-19) EUA information.

6. Gao J, Tian Z, Yang X. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends 2020; 14: 72–73.

7. Magagnoli J, Narendran S, Pereira F, et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with COVID-19. medRxiv 2020; published online April 23. DOI:10.1101/2020.04.16.20065920 (preprint).

8. Mahevas M, Tran V-T, Roumier M, et al. No evidence of clinical efficacy of hydroxychloroquine in patients hospitalised for COVID-19 infection with oxygen requirement: results of a study using routinely collected data to emulate a target trial. medRxiv2020; published online April 14. DOI:10.1101/2020.04.10.20060699 (preprint).

9. Shi S, Qin M, Shen B, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol 2020; published online March 25. DOI:10.1001/jamacardio.2020.0950.

10. Guo T, Fan Y, Chen M, et al. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020; published online March 27. DOI:10.1001/jamacardio.2020.1017.

11. Mehra MR, Desai SS, Kuy S, Henry TD, Patel AN. Cardiovascular disease, drug therapy, and mortality in COVID-19. N Engl J Med2020; published online May 1. DOI:10.1056/NEJMoa2007621.

12. Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020; 395: 1417–18.

13. Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal. J Heart Lung Transplant 2020; 39: 405–07.

14. Lee N, Wong CK, Chan MCW, et al. Anti-inflammatory effects of adjunctive macrolide treatment in adults hospitalized with influenza: a randomized controlled trial. Antiviral Res 2017; 144: 48–56.

15. Borba MGS, Val FFA, Sampaio VS, et al. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial. JAMA Netw Open 2020; 3: e208857