Clinical outcomes and adverse events in patients hospitalised with COVID-19, treated with off-label hydroxychloroquine and azithromycin
The authors confirm that the Principal Investigator (PI) for this paper is Professor Colm Bergin and that he had direct clinical responsibility for patients. The PI confirms that we have complied with our institution's policies concerning research involving human subjects and the NREC policies for protection of human subjects.
Abstract
Aims
To assess clinical outcomes and adverse drug events in patients hospitalised with COVID-19 treated with off-label hydroxychloroquine (HCQ) and azithromycin (Az).
Methods
We performed a retrospective analysis of hospitalised patients who had a positive polymerase chain reaction test for SARS-CoV-2 and received HCQ plus Az or no targeted therapy. The primary end point was clinical improvement on day 7 defined as either hospital discharge or an improvement of 2 points on a 6-category ordinal scale. Secondary outcomes included mortality at day 28, intensive care admission, requirement for mechanical ventilation and incidence of adverse events.
Results
Data from a total of 134 patients were evaluated; 82 patients received HCQ/Az and 52 patients received no targeted therapy. Clinical improvement was seen in 26.8% of patients who received HCQ/Az but this was not significant. The rates of intensive care transfer and mechanical ventilation were higher in the treatment group, but these differences were not significant. Mortality at day 28 was significantly higher in the treatment group (P = .03). Hypoglycaemia elevated liver function tests and QT prolongation were monitored in both groups. The risk of QT prolongation was significantly higher in the treatment group. Treatment was stopped early in 6 (7.3%) patients due to adverse events.
Conclusion
Although patients who received HCQ/Az were more severely ill the administration of these repurposed drugs did not result in clinical improvement and was associated with a significant increase in toxicity. This descriptive study highlights the importance of monitoring all repurposed agents for adverse events.
What is already known about this subject
- There are currently no licensed antiviral medications for the treatment of COVID-19.
- Hydroxychloroquine has shown some antiviral efficacy in some in vitro studies.
- Hydroxychloroquine and azithromycin have a well-defined side effect profile including risk of QT prolongation, hypoglycaemia and liver function test elevation.
What this study adds
- When repurposing medications for new indications we need to be mindful that safety data cannot always be extrapolated to the new indication.
- QT prolongation was significantly increased in patients who received treatment.
- Clear protocols should be in place to ensure all patients initiated on novel treatments are monitored closely for adverse events, ideally in the structure of a clinical trial.
1 INTRODUCTION
Since December 2019, the newly emergent coronavirus (SARS-CoV-2) has caused an ongoing pandemic of COVID-19.1-3 The disease spectrum can range from a mild, uncomplicated illness managed in a community setting to severe disease requiring intensive care support, which may progress to death. In Ireland, as of 8 June 2020, there have been 25 198 cases diagnosed, 1691 deaths and a hospitalisation rate of 13.18%.4
There are no specific anti-viral agents licensed to treat this novel coronavirus and the World Health Organisation states that there is no current evidence to recommend any specific anti-COVID-19 treatment for patients with confirmed COVID-19.1
International and national health authorities in addition to pharmaceutical regulators are currently reviewing emerging evidence to determine which therapeutic agents may seem reasonable to use in patients based on limited evidence whilst clinical experience is accumulating.5
In Ireland, the Health Service Executive released interim guidance in March 2020 (Version 2 March 2020, Version 3 April 2020) detailing therapeutic agents that may have benefit in treating COVID 19. These included the drugs chloroquine/hydroxychloroquine (HCQ) in combination with azithromycin (Az).6 The national guidance has changed in accordance with international guidelines and now specifies that Az is no longer advised as part of treatment and single drug use of HCQ or other agents should be considered in the context of a clinical trial or as per set criteria.1
2 METHODS
2.1 Study design and population
We performed a retrospective analysis of patients who had a positive polymerase chain reaction test for SARS-CoV-2 and received HCQ plus Az over a 2-week period from 20 March to 3 April 2020. We compared these to a group of SARS-CoV-2-positive patients who did not receive targeted therapy between 1 March and 9 May 2020. Ethical approval was obtained from the Office of the National Research Ethics Committees (Ref: 20-NREC-COV-004).
2.2 Data collection
Patients positive for SARS-CoV-2 were obtained from the diagnostic laboratory reports. Those receiving HCQ/Az were found using prescription reports from the electronic prescribing system. Baseline patient demographics, comorbidities, laboratory markers, oxygen requirements and requirement for intensive care (ICU) were collected. The recommended regimen at the time of the study from national guidance was HCQ 400 mg twice daily on day 1 followed by 200 mg twice daily on day 2–5 (if creatinine clearance was >30 mL/min) in addition to Az 500 mg on day 1 followed by 250–500 mg on days 2 and 3. Day 0 for the treatment group was day of medication initiation and day 0 for the nontreatment group was day of admission; if a patient was already an inpatient, day 0 was day of onset of symptoms. The median day 0 in the treatment group was the same as the date of admission.
The electronic record of each patient was reviewed to detect adverse drug events during treatment. We specifically recorded any elevation of transaminases—referred to as liver function tests (LFTs)— and change in QTc; these are recognised side effects of HCQ and Az.7, 8 We also recorded episodes of hypoglycaemia, as this is associated with HCQ use.9, 10 Adverse drug events were categorised using the National Cancer Institute Common Terminology Criteria for Adverse Events.11
2.3 Outcomes measured
The primary end point was clinical improvement on day 7 defined as either hospital discharge or an improvement of 2 points on a 6-category clinical improvement scale.
- Not hospitalised
- Hospitalised not on oxygen
- Hospitalised requiring oxygen
- Hospitalised on high flow nasal cannula or noninvasive ventilation
- Hospitalised on invasive ventilation
- Death
The secondary outcomes evaluated included mortality at day 28, ICU admission at any point of inpatient stay, requirement for mechanical ventilation and any adverse drug effects from HCQ/Az therapy.
2.4 Statistical analysis
Normally and non-normally distributed quantitative data between patient groups were compared using the Student t-test and Mann–Whitney U-test, respectively. Statistical analyses of the study findings were performed using IBM Statistical Package for the Social Sciences (SPSS; version 24.0), and P < .05 was considered statistically significant.
3 RESULTS
Over the study period, there were 82 patients in the treatment group and 52 in the nontreatment group. The demographics of the 2 cohorts were similar. Those receiving treatment were significantly more unwell than the nontreatment group, with higher C-reactive protein and fraction of inspired oxygen requirements at baseline. These measures were repeated at day 5, with the treatment group still having significantly higher C-reactive protein and fraction of inspired oxygen requirements. The total white cell count (WCC) was also significantly higher in the treatment group at day 5 when compared to the nontreatment group. The demographics of the groups and results at day 0 and day 5 are shown in Table 1.
| Parameter | Treatment group (n = 82) | Nontreatment group (n = 52) | Significance |
|---|---|---|---|
| Female, n (%) | 27 (33%) | 24 (46%) | ns |
| Age (y), median (IQR) | 64.8 (29–93) | 68 (21–91) | ns |
| Comorbidities (mean) | 2.5 | 3 | ns |
| WCC (× 109/L) median day 0 | 6.2(1–32) | 7.3 (2.7–17) | ns |
| WCC (× 109/L) median day 5 | 7.3 (1–20) | 6.1 (2.7–17.2) | P = .03 |
| CRP median day 0 | 81.5 (1–311) | 28 (1–374) | P < .0001 |
| CRP median day 5 | 40 (1–346) | 29 (1–350) | P = .03 |
| FiO2 requirements median day 0 | 24% (21–100) | 21% (21–100) | P < .0001 |
| FiO2 requirements median day 5 | 21% (21–100) | 21% (21–100) | P < .0001 |
| LFTs >ULN day 0 | 43 (52) | 29 (55) | ns |
| LFTs >ULN day 5 | 51 (62) | 36 (69) | ns |
| CIS day 0 | 3 (2–5) | 2 (2–5) | P < .0001 |
| CIS day 7 | 3 (1–6) | 2 (1–5) | ns |
- IQR = interquartile range; WCC = white cell count; CRP = C-reactive protein; FiO2, fraction of inspired oxygen; LFTs = liver function tests; ULN = upper limit normal; CIS = clinical improvement scale; ns = nonsignificant (P > .05)
Three categories of adverse events were recorded: elevated liver function tests, hypoglycaemia, and development of prolonged QTc. The overall incidence of adverse events (AEs) was 42% (35/82) in the treatment group and 42% (22/52) in the nontreatment group. There was no significant difference between the groups in terms of abnormal liver function tests or hypoglycaemia. All episodes of hypoglycaemia were deemed mild; capillary blood glucose was >3.2 mmol/L. Elevated LFTs accounted for the majority of AEs in both the treatment and nontreatment groups; 65 and 52% respectively. In the treatment and nontreatment groups, 28 and 13.4% of patients had abnormal LFTs at baseline. There was no significant difference in LFT elevations in the treatment and nontreatment groups.
The incidence of QT prolongation was significantly higher in the treatment group (11/82) compared to the nontreatment group (1/52; P = .028). This resulted in the discontinuation of therapy in 4 cases. On review of the cases with prolonged QTc, concomitant risk factors included female sex (5 patients), other QT-prolonging medication (3 patients), previous cardiac history (8 patients), thyroid disease history (2 patients) and 1 patient had electrolyte disturbance (hypokalaemia) whilst on treatment. In the nontreatment group, the patient who experienced QT prolongation had an electrolyte disturbance (hypokalaemia) and no other risk factors for QT prolongation.
Clinical improvement was defined as an improvement of 2 categories on the modified 6-category ordinal scale of clinical status or if the patient was discharged. There was no significant improvement in the clinical improvement score in the treatment group (P = .49) or the nontreatment group (P = .87) between day 0 and day 7.
ICU transfer was higher in the treatment group (31%) than the nontreatment group (19%), but this was not statistically significant.
However, mortality was significantly higher in the treatment group. These outcomes are shown in Figure 1. There was no significant difference between the HCQ/Az and the nontreatment group and the risk of mechanical ventilation.
4 DISCUSSION
Currently there are no licensed and effective drug therapies for COVID-19. As new treatment options are being explored, efforts to repurpose existing medications that are freely available and have a known safety profile is an attractive option for clinicians.12 Vigilance is required when repurposing older medications for new indications: the clinical features of the new indication as well as its use in new drug combinations means safety data cannot always be extrapolated.12
The Health Service Executive interim guidance (V1 March 2020) advised that a combination of HCQ and Az may be considered in patients who are COVID+ and are either hypoxic with an increasing O2 requirement and/or have infiltrates on X-ray. Given these guidelines, it was expected that there would be significant differences in disease severity between treatment and nontreatment groups, and this was borne out in this study.
Our treatment group, however, also had no improvement in the primary endpoint, which was clinical improvement score. They also had more severe disease at day 5 than the nontreatment group, with increased inflammatory markers, white cells and oxygen requirements. The mortality rate in the treatment group was also significantly higher, and increased mortality has also been demonstrated in patients treated with HCQ alone.13
These results show little benefit to treatment and that treatment is not without risks. The significantly higher rate of QTc prolongation in the treatment group is concerning, given that this potentially fatal condition is asymptomatic and requires active surveillance. A randomised controlled trial of high-dose chloroquine was halted prematurely due to cardiac toxicity and higher fatalities in the chloroquine group.14 Az is also known to prolong QT and there are sparse data evaluating the safety of HCQ/Az therapy; however in vivo studies have not demonstrated synergistic arrhythmic effects of this combination.15 Our findings would support the cardiotoxic nature of these drugs.
5 CONCLUSION
This pragmatic study highlights the need for caution when prescribing therapy that is off-label or experimental, even in the setting of an unprecedented global pandemic. Although patients who received HCQ/Az were more severely ill the administration of these repurposed drugs did not result in clinical improvement, and was associated with a significant increase in toxicity.
6 LIMITATIONS
The major limitations of our study include that it is retrospective in nature and our nontreatment group was not a true comparator group. Confounders were not adjusted for when measuring adverse drug events in this descriptive study. Our study groups were small with 82 patients and 52 patients in the treatment and nontreatment groups, respectively. Body mass index was not measured for all patients in this study and was not included as a demographic; other studies have found a correlation with worse outcomes in patients with high body mass index.
ACKNOWLEDGEMENTS
We would like to thank the IMS department at St James's Hospital, especially Fionnuala Nevin and Sinead Kelly, the pharmacy department and Department of Genitourinary and Infectious disease (GUIDe) at St James's Hospital for their help and contribution to this project. Thank you to all the patients for their contribution to this study.
COMPETING INTERESTS
There are no competing interests to declare.
CONTRIBUTORS
M.K. and R.O'C. undertook data collection, wrote the manuscript and edited the manuscript after reviewer's comments. L.T. and M.C. performed statistical analysis and advised on clinical parameters. All authors read and approved the final manuscript. B.C., G.M., M.M. and E.R. provided advice on consultation regarding adverse events to choose to monitor in this patient cohort and provided final article review. C.D., R.O.R., S.C., C.M. and C.Ba. provided on clinical parameters (oxygen requirements) and provided final article review. C.Be. undertook responsibility of PI, advised on structure and parameters of research, and provided final sign off.
Open Research
DATA AVAILABILITY STATEMENT
Data available on request due to privacy/ethical restrictions.
