Study Design and Participants
This prospective observational cohort study took place at the Ministry of National Guard Health Affairs (MNGHA) in Riyadh, Saudi Arabia, which includes King Abdulaziz Medical City, a 1500-bed hospital, and King Abdullah Specialist Children’s Hospital, a 600-bed hospital that was also utilized for COVID-19-infected patients during the outbreak. In total, the facilities provide 100 adult intensive care unit (ICU) beds, which was increased to 200 beds during the peak of COVID-19 cases. Patients seen at the facility were MNGHA-eligible patients, MNGHA employees and later throughout the study period, as a directive from the Ministry of Health, any patient in Saudi Arabia, regardless of status, who would be eligible for treatment at any governmental hospital if infected with COVID-19.
We prospectively identified adult patients (aged ≥ 18 years) who were diagnosed with a laboratory-confirmed case of COVID-19 from April 12 to June 1, 2020, who had a valid mobile contact number in our electronic medical records (EMR) and were willing to participate in the study. Laboratory testing for COVID-19 was done using the reverse transcription-polymerase chain reaction (RT-PCR). No sample size calculation was performed; it was determined by the study period. The list of patients with a COVID-19-positive result was obtained daily throughout the study period. The study was approved by the ethics committee of King Abdullah International Medical Research Center (KAIMRC) for both participating centers, King Abdulaziz Medical City and King Abdullah Specialist Children’s Hospital. The study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments. A telephone consent form was developed and approved by the IRB.
Exposure of Interest: Use of Ibuprofen and Other NSAIDs
The exposure of interest was patients’ acute use of ibuprofen or NSAIDs (including aspirin) during infection and chronic NSAID use before the confirmed COVID-19 infection. The exposures of interest were divided into four groups: group 1: acute ibuprofen users during infection only; group 2: other aspirin/NSAID acute use during infection; group 3: aspirin/NSAID chronic users; group 4: any NSAID users, acute/chronic combined. Non-NSAID users were the control group.
Owing to the common use of these drugs as OTC medications, information about patient exposure was captured through a short telephone questionnaire in addition to electronic prescription filling information from the patient’s EMR to identify chronic NSAID use. Chronic NSAID use was defined as > 1 (30-day) filling in a 6-month period prior to the index date or patient self-reported chronic use.
All patients, whether admitted or not, were interviewed via telephone to identify OTC antipyretics used during infection and chronic aspirin/NSAID use. The questionnaire was administered within 5 days of the confirmed laboratory result to minimize the risk of recall bias. Patients who were unable to answer or had their telephone switched off were excluded from the study.
Questionnaire Administered by Telephone to COVID-19-Positive Patients
The questionnaire included questions about the onset of symptoms, whether the patient experienced fever, use of antipyretics including acetaminophen, ibuprofen or any other NSAID during the infection (patients were given a list of common brand names of ibuprofen) and chronic use of aspirin/NSAIDs within the past 6 months.
Data Collection
We recorded data from the patients' EMR on demographics, comorbidities, admission for COVID-19, electronic prescription of antipyretics including NSAIDs during infection and, within the past 6 months, standard of care received, number of antibiotics prescribed during the infection and the outcomes of interest listed below.
Outcomes
The primary outcome was 30-day mortality. Secondary analysis included severe COVID-19 infection and hospital admission.
Additional outcomes for admitted patients included time to clinical improvement, oxygen support required and length of hospital stay.
Time to clinical improvement was defined as the time from admission to an improvement of 2 points (from the status at admission) on the World Health Organization’s recommended seven-category ordinal scale or live discharge from the hospital, whichever came first [19].
Additional outcome for patients not admitted included a prescription for an antibiotic during the patient’s infection with COVID-19, indicating worse symptoms in patients not admitted.
Patients were followed up from the index date until primary outcome occurrence, discharge or up to 30 days.
Statistical Analysis
All descriptive statistics were reported as counts or means. For comparison of demographic variables and comorbidities among cohorts, independent-sample t tests were used for numeric variables, while χ2 or Fisher exact tests were used for categorical variables.
We estimated hazard ratios (HRs) with 95% confidence intervals for mortality using the Cox proportional hazards model. Log-binomial regression models were used to determine whether any of the NSAID groups were associated with an increase in the relative risk (RR) of outcomes upon adjustment for covariates. The time to clinical improvement and length of stay were portrayed by Kaplan-Meier plot and compared with a log-rank test.
Adjusted models included the following covariates: age, sex and comorbidities: hypertension, diabetes mellitus (DM), dyslipidemia, asthma or chronic obstructive pulmonary disease (COPD), cardiovascular disease (CVD), renal or liver impairment, and malignancy.
The institutional review board (IRB) at King Abdullah International Medical Research Center (KAIMRC) (protocol RC20/209/R) approved this study for both King Abdulaziz Medical City and King Abdullah Specialist Children’s Hospital. A telephone consent form was developed and approved by the IRB; all participants verbally consented.