Therapy for COVID-19, particularly during the early stages of infection, is urgently required. Although COVID-19 is mostly self-limited, up to 20% of symptomatic cases will develop severe or critical disease with clinical manifestations, including pneumonia, acute respiratory distress syndrome, multiorgan system dysfunction, hypercoagulation and hyperinflammatory manifestations. Over 47 million cases of COVID-19 globally have resulted in >1.2 million deaths (1).

The FDA has approved only one drug, remdesivir, for the treatment of COVID-19. In addition, the FDA has granted an emergency use authorization for the use of baricitinib (Olumiant; used for the treatment of rheumatoid arthritis) for the treatment of COVID-19 in some cases. For this reason, investigators have paid considerable attention to the association between the administration of commonly used drugs with the outcome of patients with COVID-19. Aspirin (2-5) has been reported to reduce mortality. However, as regards other drugs, some studies have recommended that ibuprofen should be avoided (6-8). In addition, the use of omeprazole has been shown to increase mortality (9). At least one report has indicted that famotidine decreases mortality (10), while another indicates that the use of famotidine leads to a poorer prognosis (11).

UK Biobank (UKB). UKB data were used to assess the association of common drugs with COVID-19 mortality. Electronic linkage between UKB records and National Health Service COVID-19 laboratory test results in the UK were available from March 16, to April 26, 2020, including the peak of daily COVID-19 laboratory-confirmed cases. During this time period, the testing of older age groups was largely restricted to hospital inpatients exhibiting clinical signs of infection. Thus, test positivity is considered a good marker of severe COVID-19(12). COVID-19 mortality in the UK was recorded as 900 deaths per day at this time.

For the data used in the present study, the inclusion criteria were a positive test for COVID-19, and the exclusion criteria were negative COVID-19 test or no test results.

The present study evaluated data from 376 subjects, 49% female, 51% male. The age of the subjects was 55.7±9.1 (mean ± SD) years. The COVID-19 mortality rate was 20.5%.

The association between the use of aspirin, ibuprofen, paracetamol (acetaminophen), ranitidine, omeprazole and laxatives with mortality in 376 subjects, 517 responses is shown in Table I. The variability was significant (P=0.011, two-tailed Fisher's exact test).

As regards the use of Fisher's exact test, it should be noted that this is a statistical test used to determine whether there are non-random associations between categorical variables. Only in Table I does such an association exist, suggesting that the variation in mortality rates of aspirin, ibuprofen, paracetamol (acetaminophen), ranitidine, omeprazole and laxatives is meaningful. In the other tables, variability was not significant, suggesting that the differing mortalities may not be meaningful. Given the large number of agents examined, the present study performed as few comparison tests as possible. When performing hypothesis tests with multiple comparisons, eventually a result could occur that appears to demonstrate statistical significance in the dependent variable, even when there is none.

Aspirin and omeprazole were associated with an increased mortality. Ibuprofen-related mortality was lower than laxative-related mortality. Aspirin users were significantly older (P<0.001, one-way ANOVA; Fig. 1).

The association with mortality of cholesterol-lowering medications, blood pressure-lowering medications, insulin, hormone replacement and oral contraceptives in 134 female subjects and 173 responses is shown in Table II. The variability was insignificant (P=0.077, two-tailed Fisher's exact test). The age (mean ± SD) of the female subjects by medication are shown in Fig. 2. Oral contraceptive users were significantly younger than hormone replacement users (P<0.05, Tukey's range test). The hormone replacement users were significantly younger than the users of cholesterol-lowering medications and blood pressure-lowering medications (P<0.05, Tukey's range test). The effect of age on survival was significant; however, the effect of hormones on survival was not (Table III).

The association of nutritional supplements with mortality is shown in Table IV. The lower mortality linked to vitamin D and vitamin B supplementation, presumably B complex, has been previously observed (14,15). There was no significant difference in the mean age (P=0.071, one-way ANOVA; data not shown).

The association of mineral and other dietary supplements with mortality, in 294 subjects, 456 responses is shown in Table V. The variability was insignificant (P=0.983, two-tailed Fisher's exact test).

In hospitalized UKB COVID-19 patients, common comorbidities are hypertension, coronary heart disease, atrial fibrillation, type 2 diabetes and dementia. All these conditions are associated with an increased mortality (12).

Coagulopathy and blood clots are a significant adverse event in patients with COVID-19. Aspirin inhibits the coagulation due to its effect on platelets and has been reported to improve patient prognosis (3-5). The present study was not able to confirm this observation as the patients on aspirin in the current sample were significantly older and therefore less likely to survive. Many patients were no doubt using aspirin for cardioprotection and/or arthritis. Clinical trials, as for example, the FREEDOM-COVID study (ClinicalTrials.gov identifier: NCT04512079), are attempting to determine the best anticoagulant strategy for patients admitted to general medical wards. The ranitidine bismuth citrate combination has been shown to suppress SARS-CoV-2 replication and to relieve virus-associated pneumonia in Syrian hamsters (16); however, this effect may not occur in patients with COVID-19 taking ranitidine. In the present study, ibuprofen-related mortality (12.4%) was lower than laxative-related mortality (30.8%), suggesting that ibuprofen does not worsen the clinical outcome (7,8).

Cholesterol-lowering medications, blood-pressure lowering medications, hormone replacement therapy and oral contraceptives seem to have minimal effects on patient outcome. The younger age of subjects on hormone replacement therapy and oral contraceptive users most probably explains their reduced mortality.

Nutritional supplements may increase survival. Mortality in an Italian nursing home during the COVID-19 pandemic was shown to be reduced with vitamin D supplementation (14). A vitamin D/magnesium/vitamin B12 combination in older-aged COVID-19 patients was associated with a significant reduction in the proportion of patients with clinical deterioration requiring oxygen support, intensive care support, or both (15). Vitamin D may be a critical host factor to prevent COVID-19(17), although this hypothesis remains controversial (18,19). To prevent the cytokine storm, the use of N-acetylcysteine in both the prevention and adjuvant therapy of COVID-19 has been suggested; however, the UKB did not have information on this substance (20).

In conclusion, although some of the associations described herein among drugs and COVID-19 are not novel, the present study demonstrates the utility of a new source, the UKB, in further examining these associations. The association of lifestyle, comorbidities, medication and phenotypic information with patient outcomes will become an invaluable source as more UKB data become available on subjects tested for COVID-19(21).