Co-medications administered with hydroxychloroquine in COVID-19 inpatients: prevalence and ethical implications

Stéphanie Baggio, Caroline Samer, Thomas Agoritsas, Alexandra Calmy, Frédérique Jacquerioz, Angèle Gayez-Ageron, David Legouis, Arnaud Perrier, Jean-Luc Reny, Jérôme Stirnemann, Pauline Vetter, Hans Wolff,Dina Zekry, Nathalie Vernaz, Virginie Prendki

 

From the beginning of the SARS-CoV-2 pandemic, the off-label use of hydroxychloroquine to treat severe COVID-19 has been widely debated. A liberal approach to off-label use occurred in some countries, despite little evidence and presence of a risk of prolonging the QT interval. Little empirical information has been collected regarding co-administration of drugs at risk of prolonging the QT interval with hydroxychloroquine. In our cohort of inpatients hospitalised during the first wave of the pandemic at the Geneva University Hospitals, Switzerland, we found that 11.8% of patients for whom hydroxychloroquine was not recommended or had to be used with caution (prolonged QT or receiving medications at risk for prolonged QT) nonetheless received hydroxychloroquine. These patients had a longer hospital stay but no increase in in-hospital mortality in comparison with other patients. This raises further ethical issues because of the uncertainty regarding additional harm for COVID-19 patients, such as harm resulting from drug-drug and drug-disease interactions inducing cardiac arrhythmia. Because of some unpredictable consequences for patients’ health and medical ethics, research and precautionary measures are necessary. Off-label drug use should be a shared decision between patients and physicians.

 

During the first wave of the SARS-CoV-2 pandemic, hydroxychloroquine attracted considerable attention in many countries around the world [1]. Due to encouraging in-vitro and preliminary clinical results, it was widely used as a compassionate “off-label” medication, prescribed beyond the indications approved by regulatory agencies [2]. Substantial political pressure also occurred in several countries around the world, especially Brazil, France and the USA, leading to an even more liberal approach to its off-label use [3].

Adverse events and safety risks have been well documented [4–8], but the co-administration of QT-interval-prolonging drugs and their consequences have not been described in the COVID-19 literature. A few studies have mentioned the risk of drug-drug and drug-disease interactions [3, 9], but none have reported original data on medication co-administered to patients who were prescribed hydroxychloroquine. In March 2020, COVID-19 treatment guidelines were updated in our institution and hydroxychloroquine became indicated for a subset of patients in the absence of contraindications. Our objective was thus to identify how many patients received hydroxychloroquine when it was not recommended (i.e., in the presence of prolonged QT or with medications at risk of QT prolongation) and clinical outcomes (length of hospital stay, mortality, and potential adverse events) for patients with and without recommendations to receive hydroxychloroquine.

We collected data from patients hospitalised for COVID-19 in the internal medicine wards of Geneva University Hospitals during the first wave of the pandemic (26 February to 30 April 2020, discharged before 31 May2020, ethical approval by the Cantonal Ethics Research Committee of Geneva) [10]. Of the 279 patients who received hydroxychloroquine, 11.8% (n = 33) received concomitant medication(s) associated with a potential risk of QT prolongation (n = 25, medications based on the Liverpool recommendations) [11] or had QT prolongation before hydroxychloroquine administration (n = 8, corrected Bazett QT ≥500 milliseconds).

Descriptive statistics and co-medications are reported in table 1.

Table 1: Descriptive statistics and bivariate associations within the cohort.
	Whole cohort	Hydroxychloroquine prescription	p-value
Not recommended or with caution	No caution
n = 279	n = 33	n = 246
Length of hospitalisation (no. of days)*	10.3 (10.1)	13.2 (16.6)	10.0 (9.9)	0.075
Mortality†	9.0 (25)	9.1 (3)	8.9 (22)	0.978
Gender†				0.925
	Male	67.4 (188)	66.7 (22)	67.5 (166)
	Female (ref.)	32.6 (91)	33.3 (22)	32.5 (80)
Age‡	61.5 (14.6)	65.7 (11.8)	60.9 (14.9)	0.080
Month of hospitalisation†				0.225
	February/March (ref.)	66.3 (185)	75.8 (25)	65.0 (160)
	April	33.7 (94)	24.2 (8)	35.0 (86)
Score mNEWS (0–23)*	7.4 (2.6)	7.9 (2.6)	7.4 (2.6)	0.326
Number of diseases (0–8)*	1.0 (2.0)	1.0 (1.0)	1.0 (2.0)	0.037
	Pulmonary diseases†	11.5 (32)	15.2 (5)	11.0 (27)	–
	Asthma†	2.5 (7)	3.0 (1)	2.4 (6)	–
	Cancer†	6.5 (18)	3.0 (1)	6.9 (17)	–
	Renal impairment†	20.1 (56)	24.2 (8)	19.5 (48)	–
	Diabetes†	20.8 (58)	30.3 (10)	19.5 (48)	–
	Hypertension†	46.2 (129)	63.6 (21)	43.9 (108)	–
	Heart diseases†	18.3 (51)	27.3 (9)	17.1 (42)	–
	Liver diseases†	2.5 (7)	6.1 (2)	2.0 (5)	–
BMI ≥30 kg/m2†	22.6 (63)	33.3 (11)	21.1 (52)	0.120
Co-medications for COVID-19†
	No co-medication (ref.)	28.0 (78)	51.5 (17)	24.8 (61)	–
	Azithromycin	17.9 (50)	15.2 (5)	18.3 (45)	0.092
	Lopinavir-ritonavir	54.1 (151)	33.3 (11)	56.9 (140)	0.002
Reasons why hydroxychloroquine was not recommended
	Co-medication†,§	9.0 (25)	75.8 (25)	0.0 (0)	–
	QT ≥500 msec†	2.9 (8)	24.2 (8)	0.0 (0)	–
BMI = body mass index; mNEWS = modified national early warning signal * Median and interquartile ranges are given, negative binomial regressions. † Percentages and n are given, logistic regressions (multinomial logistic regression for co-medications for COVID-19). ‡ Means and standard deviations are given, linear regression. § Amiodarone (n = 3), citalopram (n = 3), domperidone (n = 1), escitalopram (n = 5), haloperidol (n = 2), levomepromazine (n = 1), lithium (n = 1), metamizole (n = 2), primidone (n = 1), rifampicin (n = 2), venlafaxine (n = 5).

Compared with the other patients, those for whom hydroxychloroquine was not recommended had a significantly longer hospital stay (p = 0.045 in negative binomial regression [12] adjusted for co-medications, gender, COVID-19 severity at admission (modified National Early Warning Score) [13], number of comorbidities (active asthma, chronic obstructive pulmonary disease or sleep apnoea, cancer, renal impairment, diabetes, hypertension, heart disease and cirrhosis, and obesity). There was no difference in mortality between patients with and without a recommendation to receive hydroxychloroquine. Although a single loading dose of 800 mg of hydroxychloroquine was chosen in our hospital in order to mitigate the risks of QT prolongation [10, 14], the administration of hydroxychloroquine was associated with prolonged QT interval worsening without cardiac arrhythmia in four patients and serious haemolytic anaemia in one patient (new diagnosis of glucose-6-phosphate dehydrogenase deficiency).

Overall, the current pandemic illustrates the political pressure on healthcare professionals and agencies to urgently find effective and safe treatment, and raises an important bioethical issue already discussed by Roth et al [3]: “first, do not harm, second be careful, third heal” (“primum non nocere, secundum cavere, tertium sanare”). In the heated societal debate around hydroxychloroquine, there were repeated claims that it would be unethical not to prescribe it to COVID-19 patients, when the only ethical posture was to conduct high-quality randomised controlled trials [15]. Indeed, the randomised controlled trial that followed showed no benefits and resulted in a strong recommendation from World Health Organization against its use in patients with COVID-19 [16]. However, there are many situations in medicine where off-label drugs are prescribed, for example when clinical trials are not implemented or completed and the risk-benefit balance seems to be in favour of prescribing a drug. In our institution, guidelines were carefully written and updated in order to provide guidance on when and how to prescribe off-label drugs.

Hydroxychloroquine has been often prescribed and well tolerated in a variety of settings such as infectious diseases (e.g., malaria and Q fever) and rheumatological conditions (e.g., systemic lupus erythematosus and rheumatoid arthritis), and adverse events, the most serious being cardiac arrhythmia or arrest due to QT prolongation, have been poorly reported to date in this setting [8]. These adverse cardiac effects have been emphasised with COVID-19, which might be explained by the fact that patients with severe infection have a higher risk of cardiac events and by the presence of multi-morbidities and polypharmacy and, consequently, a higher risk of drug-drug interactions. For example, Ho et al have drawn attention to interactions between hydroxychloroquine and commonly used medications in elderly people [9].

Our data emphasise that any potential new off-label treatment against COVID-19 should be carefully prescribed after checking for drug interactions and precautions for use, and weighing the benefit and harm on a case-by-case basis. The off-label prescription was probably more frequent at the beginning of the COVID-19 pandemic when physicians were faced with a new life-threatening medical condition for which there were limited alternatives. However, such a prescription requires carefully balanced shared decision making between patients and physicians, and informing the patient as accurately as possible of the risks and benefits of the treatment. In addition, the stages of drug development should be known to prescribers and the available data should be re-evaluated in the light of the pre-clinical and clinical data gradually becoming available. We should remember that in some countries, the debate on hydroxychloroquine moved far beyond science and has certainly not helped physicians to carefully weigh the risks and benefits. In addition to these potential health and ethical concerns, off-label use during a pandemic could discourage patients and clinicians from participating in clinical trials, which are absolutely necessary to evaluate new therapies and assess their efficacy and safety [17].

In conclusion, the indications for off-label prescriptions should be carefully weighed and may present some ethical challenges. The number of patients included in randomised controlled trials during the COVID-19 pandemic was below expectations, indicating that only a fraction of eligible patients benefited from the standard frame of a protocol-based follow-up. In addition to studies evaluating the efficacy of off-label use of medicines, there is an important need of data focusing on drug-drug and drug-disease interactions, and pharmacovigilance.

 

Stéphanie Baggio, Office of Corrections, Department of Justice and Home Affairs of the Canton of Zurich, Switzerland / Division of Prison Health, Geneva University Hospitals, Geneva, Switzerland, stephanie.baggio[at]hcuge.ch

Caroline Samer, Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland

Thomas Agoritsas, Division of General Internal Medicine & Division of Clinical Epidemiology, University Hospitals of Geneva, Rue Gabriel-Perret-Gentil 4, 1205 Geneva, Switzerland; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada

Alexandra Calmy, Division of Infectious Diseases, HIV/AIDS Unit, Geneva University Hospitals, Geneva, Switzerland

Frédérique Jacquerioz, Division of Primary Care, Division of Tropical and Humanitarian Medicine, Geneva Centre for Emerging Viral Diseases, Geneva University Hospitals, Geneva, Switzerland

Angèle Gayez-Ageron, CRC & Division of clinical-epidemiology, Department of health and community medicine, University of Geneva & University Hospitals of Geneva, Geneva, Switzerland

David Legouis, Division of Intensive Care, Department of Acute Medicine, Laboratory of Nephrology, Department of Medicine and Cell Physiology, Geneva University Hospitals & University of Geneva, Geneva, Switzerland

Arnaud Perrier, Medical Directorate, University Hospitals of Geneva and University of Geneva, Geneva, Switzerland; Department of General Internal Medicine, Geneva University Hospitals, Switzerland

Jean-Luc Reny, Division of General Internal Medicine, University Hospitals of Geneva, Geneva, Switzerland

Jérôme Stirnemann, Division of General Internal Medicine, University Hospitals of Geneva, Geneva, Switzerland

Pauline Vetter, Geneva Center for Emerging Viral Diseases, Geneva University Hospitals, Geneva, Switzerland

Hans Wolff, Division of Prison Health, Geneva University Hospitals, Geneva University, Thônex, Switzerland

Dina Zekry, Division of Internal Medicine for the aged, Geneva University Hospitals, Geneva University, Thônex, Switzerland

Nathalie Vernaz, Medical Directorate, Finance Directorate, Geneva University Hospitals, Geneva University, Geneva, Switzerland

Virginie Prendki, Division of Internal Medicine for the aged, Geneva University Hospitals, Geneva University, Thônex, Switzerland / Division of Infectious Diseases, Geneva University Hospitals, Geneva, Switzerland

 

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