Hydroxychloroquine Safety Outcome within Approved Therapeutic Protocol for COVID-19 Outpatients in Saudi Arabia.

BACKGROUND: Global healthcare is challenged following the COVID-19 pandemic, since late 2019. Multiple approaches have been performed to relieve the pressure and support existing healthcare. The Saudi Arabian Ministry of Health (MOH) launched an initiative to support the National Healthcare System. Since the 5th of June 2020, 238 outpatient fever clinics were established nationwide. This study aimed to assess the safety outcome and reported adverse events from hydroxychloroquine use among suspected COVID-19 patients.
METHOD: A cross-sectional study included 2,733 patients subjected to MOH treatment protocol (hydroxychloroquine) and followed-up within 3-7 days after initiation. Data was collected through an electronic link and cross-checked with the national database (Health Electronic Surveillance Network, HESN) and reports from the MOH Morbidity and Mortality (M&M) Committee.
RESULTS: 240 patients (8.8%) discontinued treatment because of side effects (4.1%) and for non-clinical reasons in the remaining (4.7%). Adverse effects were reported among (6.7%) of all studied participants, including mainly cardiovascular (2.5%, 0.15% with QTc prolongation), and gastrointestinal (2.4%). No Intensive Care Unit admission or death were reported among these patients.
CONCLUSION: Our results show that hydroxychloroquine for COVID-19 patients in mild to moderate cases in an outpatient setting, within the protocol recommendation and inclusion/exclusion criteria, is safe, highly tolerable, and with minimum side effects.

BACKGROUND

COVID-19 has rapidly emerged as a pandemic infection that has caused significant morbidity and mortality worldwide. Global healthcare systems had faced multiple challenges varying from the high number of visitors to lack of approved therapeutically options, since the outbreak of SARS-CoV-2 late 2019. Extensive efforts have been made to explore effective therapeutics against the virus globally [1]. The World Health Organisation (WHO) states that there is no current evidence to recommend any specific anti-COVID-19 treatment for patients with confirmed COVID-19 [2].

Hydroxychloroquine has antiviral effects in vitro, and, in association with azithromycin, was suggested to decrease SARS-CoV-2 viral load in a small, non-randomised study [3], [4]. However, observational studies have suggested no beneficial effect of chloroquine or hydroxychloroquine in hospitalised patients with COVID-19 [5], [6].

The Saudi Arabian Ministry of Health (MOH) has launched an initiative to support the National Healthcare System. Since the 5th of June 2020, 238 outpatient fever clinics were established across the Kingdom, under the direct supervision of the Primary Healthcare Deputyship at the MOH. The target population for these clinics was suspected COVID-19 patients showing mild to moderate symptoms (based on MOH protocol) [7], and the implemented protocol was based on hydroxychloroquine with zinc sulphate as the recommended treatment of choice.

Given the hydroxychloroquine safety profile, multiple exclusion criteria, and several recommendations for patient safety were implemented to the protocol. Baseline ECG and electrolyte results were requested before initiation to overcome and follow-up the risk of cardiac arrhythmias leading to sudden death (if happened). In addition to a follow-up ECG and electrolyte test within three to seven days of therapy initiation. On the other hand, high-risk patients for developing side effects, especially cardiac, were excluded from the hydroxychloroquine use and advised to follow standard supportive care.

Evidence regarding the potential effect and safety of hydroxychloroquine therapy, whether given alone or in combination with zinc sulphate, for COVID-19 patients, is not clear and limited. In addition, several reports raised concerns about hydroxychloroquine safety. Therefore, this study aimed to assess the safety outcomes and reported adverse events among COVID-19 patients attending outpatient fever clinics and subjected to the MOH approved treatment protocol within 3-7 days in Saudi Arabia. This publication is part of a national project to assess the safety outcomes from the national fever clinic initiative in Saudi Arabia.

OBJECTIVES

To determine the reported adverse events among suspected COVID-19 patients subjected to the MOH approved treatment protocol and assessed within 3-7 days, including the development of treatment-related adverse effects, medication tolerability, hospitalisation, Intensive Care Unit (ICU) admission, and death.

METHODS

Study design and setting

A cross-section study was conducted from the 5th of June to the 7th of July 2020, in (238) outpatient fever clinics in Saudi Arabia.

Study participants

The sample size included 2,733 eligible COVID-19 suspected patients subjected to MOH treatment protocol before receiving PCR results. Out of 60,738 consecutive COVID-19 suspected patients who attended clinics during the study period, 23,043 (37.9%) eligible patients were given the approved treatment protocol. Out of these, 2,733 patients who revisited the clinics within 3-7 days and fulfilled the inclusion criteria were included in the sample and reassessed for adverse events and safety outcome of the approved treatment protocol. Mild to moderate cases are defined based on the MOH protocol as patients with symptoms (no oxygen requirements/no evidence of pneumonia but with other symptoms of COVID-19 e.g. fever) [7].

The study included patients aged 19 years and above, presenting with subjective fever (> 38 ⁰C), and with one or more COVID-19 symptoms including; sore throat, cough, diarrhoea, shortness of breath, headache, and myalgia and those who revisited the clinics within 3-7 days. The study excluded morbidly obese patients, pregnant and lactating females, those with G6PD deficiency, and patients with known cardiac-related issues. The study did not exclude other comorbidities.

Study tools

Data from patient health records was entered into pre-designed advanced online forms by data entry officers upon first visit to the clinic at the local Medical Affairs. The data collected through an electronic link and cross-checked with the national health electronic surveillance network database and reports from the MOH Morbidity and Mortality (M&M) Committee. All collected data were sent to the District Medical Affairs for follow-up and investigation to determine the safety outcome of the treatment protocol during the first three-seven days, including medication discontinuation, reported adverse drug reactions especially of GI symptoms and ECG abnormalities (by the treating physician), complete recovery of COVID-19 symptoms, hospitalisation, ICU admission, and death. ECG changes are defined as; QTc prolongation (difference compared to baseline > 470 milliseconds (ms), or increase by > 40 ms), nonspecific changes such as sinus tachycardia, or T wave inversion.

A standardised prescription form was written and distributed within the written treatment protocol. The prescription list hydroxychloroquine for five days total duration, starting with 400 mg twice for day one, followed by 200 mg twice daily for the remaining four days duration. No dose adjustment was recommended for renal or hepatic impaired patients. The prescription also includes zinc sulphate 60 mg orally once daily for five days, paracetamol and antihistamine. The prescription did not include azithromycin into it.

Statistical analysis

The outcome variables included reported adverse events and safety outcome of the treatment protocol used, including the percentages of patients hospitalised, admitted to ICU, death, medication discontinuation, and developed side effects, e.g., ECG changes compared to baseline, GI symptoms. All data were analysed using SPSS® version 21.

Ethical consideration

This research has met, approved, and been followed closely by the MOH Institutional Review Board (IRB). Informed consent was taken, by the treating physician, from the participants after explanation of the study. Those who refused to participate in the study were excluded and continued with stander supportive care. All collected information will be kept confidential and will not be used for other purposes than the study. Hydroxychloroquine therapy was discontinued at any time in patients who reported any possible medication-related adverse events. Unstable patients at presentation or those who showed clinical progression/deterioration at day three-seven were referred to the hospital and continuously followed up by the research team for outcomes.

RESULTS

Table 1 presents the socio-demographic characteristics among studied participants. Out of 2,733 patients, 56.89% were PCR positive, and the remaining were either PCR negative or their results were not obtained. Most of them were males (69.4% and 71.8% of both groups respectively). More than one third (36.3%) of the studied patients were aged 31-40 years, and (20.6%) were 41-50 years old. When the patients were reassessed within 3-7 days, a total of 183 patients (6.7%) had developed medication-related adverse effects, and 240 patients (8.8%) had discontinued the treatment protocol.

Table 1

Socio-demographic characteristics among studied both PCR positive and negative participants (n = 2,733).

		PCR positive(n = 1555)		PCR Negative /NA(n = 1178)		Total(n = 2733)
		Frequency	%	Frequency	%	Frequency	%
Gender	Male	1079	69.4	846	71.8	1925	70.4
	Female	476	30.6	332	28.2	808	29.6
Age	19-30	447	28.7	372	31.6	819	30.0
	31-40	567	36.5	426	36.2	993	36.3
	41-50	320	20.6	243	20.6	563	20.6
	51-64	215	13.8	135	11.5	350	12.8
	65+	6	0.4	2	0.2	8	0.3
Discontinuation of treatment	Yes	143	9.2	97	8.2	240	8.8
	No	1412	90.8	1081	91.8	2493	91.2
Medication side effects	Yes	100	6.4	83	7.0	183	6.7
	No	1455	93.6	1095	93.0	2550	93.3

Out of 240 patients who discontinued the treatment protocol, one hundred and twelve patients (46.7%, 4.1% of total) developed medication adverse effects, and the remaining 128 patients (53.3%, 4.6% of total) discontinued the treatment protocol for non-clinical reasons not related to medication adverse effects (Table 2 ). One of the most common non-clinical reasons was patient unwilling or unconvinced to continue therapy.

Table 2

The frequency of developed medication side effects among patients who discontinued the treatment protocol (n = 240)

		Cases discontinued treatment (n = 240)
		Frequency	%
Medication side effects	Medication side effects	112	46.7
	No medication side effects	128	53.3
	Total	240	100

Out of the 183 patients (6.7% of total) who developed medication adverse effects, one hundred and twelve (61.2%, 4.1% of total) discontinued the treatment protocol, and the remaining 71 patients (38.8%, 2.6% of total) continued the treatment irrespective of adverse effects (Table 3 ).

Table 3

Discontinuation of the approved treatment protocol among patients who developed side effects (n = 183).

		Cases reported medication side effects (n = 183)
		No.	%
Cases discontinued treatment	Discontinued treatment	112	61.2
	Continued treatment	71	38.8
	Total	183	100

Table 4 explains the frequency of the reported medication adverse effects among studied participants. The most common reported adverse effect was cardiovascular adverse events (69 patients, 37.7%, 2.5% of total), which include palpitation, chest pain, and ECG changes. Cardiovascular symptoms reported included subjective palpitation, chest pain, and shortness of breath without sequelae or adverse clinical outcomes (65 patients, 35.9%, 2.4% of total), nonspecific ECG changes other than QTc prolongation was included in this group. QTc prolongation > 470 ms or increase more than 40 ms from baseline was reported in four patients only (2.2%, 0.15 % of total), out of the four patients, two presented with QTc prolongation (492 ms and 507 ms). The second most common adverse effect was GI symptoms, including nausea, vomiting, abdominal pain, diarrhoea.

Table 4

The frequency of reported side effects among studied PCR positive cases (n = 183).

	PCR positive cases (n = 100)		Patients who developed side effects (n = 183)		Percentage from total patients who revisited the clinic on day 3-7(n = 2,733)
	No.	%	No.	%	%
Cardio-vascular symptoms (palpitation, chest pain, ECG changesa) *	45	45.0	69	37.7	2.5
GI symptoms (Nausea, vomiting, abdominal pain & diarrhoea)	27	27.0	65	35.5	2.4
Cardio-vascular symptoms + GI symptoms	3	3.0	5	2.7	0.2
Itching/medication hypersensitivity	2	2.0	6	3.3	0.2
Visual complication	3	3.0	3	1.6	0.1
Dizziness	0	-	2	1.1	0.07
Electrolyte abnormalities compared to baselineb	1	1.0	2	1.1	0.07
Others (less commonly reported)c	19	19.0	31	16.9	1.1
Total	100	100.0	183	100.0	6.6

ECG changes: changes in ECG reading compared to baseline, QTc prolongation, sinus tachycardia, nonspecific T wave changes.

* QTc prolongation (baseline more than 470 ms or increase more than 40 ms from baseline ECG) was reported in 4 patients.

Electrolytes abnormality: hypomagnesemia, hypokalaemia.

Others: symptoms reported by the patients not directly related to hydroxychloroquine eg. Low back pain, fatigue, muscle pain.

In all reported cases with medication-related adverse effects, no ICU admission or death was reported in patients who received hydroxychloroquine. Final adverse events reported cases would be revised with the final ongoing project analysis.

DISCUSSION

The study included 2,733 eligible patients who were subjected to MOH treatment protocol and revisited the clinics within 3-7 days after initiation of therapy. Most of them were males (70.4%) in the age group 19-30 and 31-40 years (30.0% and 36.3% respectively). On reassessment of the studied participants within 3-7 days, 240 patients (8.8%) discontinued the treatment protocol because of the development of side effects (46.7%) and for other non-clinical reasons not related to medication side effects in the remaining (53.7%).

Hooks et al. studied the effects of hydroxychloroquine treatment on QTc interval among 734 patients (mean age = 64.0 ± 10.9 years), of whom (90%) were men. They recorded an increase in mean QTc from (424.4 ± 29.7 ms) to (432.0 ± 32.3 ms) (P < 0.0001) during hydroxychloroquine treatment and found that Chronic Kidney Disease (CKD), history of atrial fibrillation (AF), and heart failure were independent risk factors for prolonged QTc [8]. A more frequent prolongation of the corrected QT interval among patients receiving hydroxychloroquine, alone or with azithromycin, than in those who were not receiving either agent was also documented by Cavalcanti et al. and Lagier et al. (among 0.67% of patients) [9], [10].

The current study recorded medication adverse effects among (6.7%) of all studied participants, including mainly cardiovascular symptoms (37.7%, 2.5% of total), e.g., palpitation, chest pain, ECG changes followed by GI symptoms, e.g., nausea, vomiting, abdominal pain, diarrhoea. Among those developed adverse effects, (61.2%, 4.1% of total) discontinued the treatment protocol. Although cardiovascular symptoms were reported by patients during treatment course, we cannot exclude the effect of COVID-19 overall symptoms to overlap patients reported adverse effects.

A higher percentage of adverse events was reported by Tang et al. and Lofgren et al. among hydroxychloroquine recipients’ patients (30%) compared to hydroxychloroquine non-recipient patients (9%), with patients reporting serious adverse events, the most common being diarrhoea, reported in 7/70 (10%) patients [11], [12]. Similarly, Lofgren et al. reported a higher frequency of adverse effects (84%) and medication adverse effects (27%) among hydroxychloroquine recipients mainly; upset stomach (25% with daily, 18% with twice vs 23% for daily, 16% twice weekly for placebo), nausea (12% weekly, vs 6% for placebo) followed by diarrhoea, vomiting, or abdominal pain [12]. This finding was inconsistent with Satlini et al., who found that patients with incident vomiting or diarrhoea were rare [13].

Other adverse events were recorded by Eljaalya et al. meta-analysis who investigated the pooled adverse effects of hydroxychloroquine among nine randomised trials in 916 patients and found that hydroxychloroquine caused significantly more skin pigmentation than placebo (Peto OR, 4.64; 95% CI, 1.13 to 19.00; P = 0.033; I2  = 0%) [14]. While they found other adverse events were not statistically significant; rash (Peto OR, 1.11; 95% CI, 0.3 to 3.77; P = 0.03; I2== = 0%); gastrointestinal (GI) adverse events (Peto OR, 1.43; 95% CI, 0.55 to 3.72; P = 0.46; I2 = 15.17%); headache (Peto OR, 1.94; 95% CI, 0.65 to 5.78; P = 0.23; I2== = 9.99%); dizziness (Peto OR, 1.32; 95% CI, 0.49 to 3.52; P = 0.58; I2== = 0%); fatigue (Peto OR, 2.13; 95% CI, 0.76 to 5.98; P = 0.15; I2  = 0%); and visual adverse events (Peto OR, 1.61; 95% CI, 0.76 to 3.41; P = 0.22; I2== = 0%). Inconsistent with our study, cardiac toxicity was not reported.

The current study recorded no ICU admission or death among studied participants related to hydroxychloroquine. While Lagier et al. reported fatality rate cases were (0.9%) but they noticed a decreased risk of ICU admission and death (Hazard ratio (HR) 0.18 0.11 0.27), decreased risk of hospitalisation ≥ ten days (OR 95% CI 0.38 0.27-0.54) among these patients treated with hydroxychloroquine-azithromycin combination. In our study, low incidence of side effects might be related to selected dosing regimen (400 mg twice a day for 1 day followed by 200 mg twice a day), comparing to other RCTs Skipper et al. which used 800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 more days showed higher incidence of side effects (43 %) in HCQ vs (22%) placebo arm [15].

The present study recorded (8.8%) discontinuation of hydroxychloroquine among studied participants due to the development of adverse effects (46.7%, 4.1% of total) and non-clinical reasons in the remaining (53.3%, 4.6% of total), which was consistent with Satlini et al. who found that (89%) of their patients completed the hydroxychloroquine course. Only three patients discontinued therapy because of QT prolongation [13].

Out of 23,043 patients who received hydroxychloroquine and did not revisit the clinic on day 3 – 7, variables of safety measures were not obtained in this population. Nevertheless, the data regarding hospitalization and death was cross-matched with that of the national M&M Committee, and regional Medical Affairs across Saudi Arabia and there was no reported hospitalisation, or death regarding hydroxychloroquine adverse effects.

CONCLUSION

Overall, results show that hydroxychloroquine was tolerable within our patients and with a very minimum reported adverse effect. In addition, mortality and hospitalisation directly related to hydroxychloroquine treatment were not reported. Thus, our result can assure that the use of hydroxychloroquine for COVID-19 patients in mild to moderate cases in the outpatient setting, within the protocol recommendation and inclusion/exclusion criteria, is safe, highly tolerable, and with minimum side effects.

FUNDING

This research was conducted under the umbrella of the Saudi Arabian Ministry of Health and did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

ETHICAL APPROVALS

This research has met, approved, and been followed closely by the MOH Institutional Review Board (IRB), log number: 20-129 M. Informed consent was taken, by the treating physician, from the participants after explanation of the study. Those who refused to participate in the study were excluded and continued with stander supportive care. All collected information was kept confidential and will not be used for other purposes than the study.

CONFLICT OF INTEREST

All authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. All authors have no conflict of interest to declare.

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.