Hydroxychloroquine Safety Outcome within Approved Therapeutic Protocol for COVID-19 Outpatients in Saudi Arabia
Abstract
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.
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) ].
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.
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)
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 ]. 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 ]. This finding was inconsistent with Satlini et al., who found that patients with incident vomiting or diarrhoea were rare Credited to Abdulrhman Mohana
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