Use of chronic medications and risk of death due to COVID-19 in hospitalised patients


Discussion

The global pandemic caused by SARS-CoV-2 requires the identification of factors that influence the severity of COVID-19. The literature describes different pharmacology groups that could alter the prognosis of SARS-CoV-2 infection. The present study examines the association between the chronic use of drugs and death in COVID-19 hospitalised patients. We found that COVID-19 hospitalised patients previously using trimethoprim and derivatives, leukotriene receptor antagonists, aldosterone antagonists, propulsives, insulins and analogues, selective immunosuppressants, calcineurin inhibitors and benzodiazepine derivatives (antiepileptics) had potentially higher odds of death than other patients.

In our study, adjustments by age, gender, CCI, arterial hypertension, smoking status, diabetes and obesity were made because these factors have been identified as strong predictors of mortality in people with SARS-CoV-2 infection.22–26 We have found that the mortality rate was 18.6%, which is consistent with other studies performed in COVID-19 hospitalised patients. The study of Roso-Llorach et al found that the highest 30-day mortality rate was reported during the first wave (17%) and decreased afterwards, remaining stable at 13% in the second and third waves (overall 30% reduction).

Regarding the association of drugs and death, the use of the combination of trimethoprim and derivatives is related to a higher incidence of death due to COVID-19. Since this drug is most commonly used as prophylactic treatment for Pneumocystis jirovecii in patients with an impaired immune system due to oncohaematologic diseases,27 HIV28 or organ transplantation,29 we suggest that the increased mortality might be related to the immunosuppression status.

We have also found that the use of leukotriene receptor antagonists, which includes montelukast, was related to a higher mortality rate. Montelukast reduces inflammation and leads to smooth muscle relaxation in the small airways, and has been suggested as a treatment for COVID-19.30 31 The use of montelukast by patients with severe asthma could explain its relationship within higher COVID-19 mortality; however, the relationship between asthma and severe COVID-19 remains uncertain.32 33

Aldosterone antagonists have been identified as risk factors of death due to COVID-19. However, some authors have hypothesised that spironolactone could have a protective effect against COVID-19.34 35 A greater use of these treatments among polymedicated patients with cardiovascular diseases,36 which have been related to a worse prognosis in COVID-19 infection,37 could have impacted our results.

Selective immunosuppressants and calcineurin inhibitors were related to increased risk of death. Some studies have suggested that serum concentrations of pro-inflammatory cytokines are associated with COVID-19 severity, so it could be expected that immunosuppressive drugs could act as a protective factor for severe disease.38 Nevertheless, it is well known that these drugs increase the risk of severe infections39 and involve faster infection disease progression. During the early viral replication phase, immunosuppression therapy may lead to higher viral load peak, higher direct tissue damage and cytokine storm release. Consequently, immunosuppressant therapy (associated with comorbidities) could impair the immune system’s ability to fight the virus and involve a worse prognosis of COVID-19 in transplant recipients29 39 40 and patients with autoimmune diseases,41–43 as has been reported by others.44 45

The positive correlation found between propulsives and poor prognosis may be attributable to various unknown facts. Propulsive drugs are widely used in oncology patients46 47 and palliative care.48 In this group of fragile patients, a higher mortality after COVID-19 is to be expected.49

Insulins and analogues constitute a therapeutic regimen for diabetes mellitus, a chronic and low-grade inflammatory disease. Yu et al
50 conducted a retrospective study analysing hospitalised diabetic patients with COVID-19 and found that insulin was related to higher mortality, as we have observed. Authors have suggested that insulin may have a deleterious effect by increasing the pro-inflammatory cytokine levels and lung inflammation, as has been proven by several in vitro, in vivo and clinical studies.51 52

Benzodiazepine derivatives (antiepileptics) were related to a higher risk of death. Asaadi-Pooya et al
53 and other authors have stated that it is highly likely that some patients with severe COVID-19 have central nervous system involvement and neurological manifestations. 54–56

We did not identify any ATC group related to a lower risk of death, even if other antihistamines for systemic use and β-blocking agents, non-selective among others, showed a tendency towards having a protective effect, as shown in online supplemental figure 1. These ATC groups might have a protective effect that could not be identified as statistically significant in our study due to the limited sample and/or confounders effect.

The pathogenesis of distress syndrome in the clinical context of COVID-19 may be related to the direct effect of SARS-CoV-2 on alveolar epithelial cells and to the indirect effects of infection-related hypoxia, severe inflammatory response and microvascular pulmonary thrombosis.57 Given that the thrombogenic features of COVID-19 potentially cause a progressive disease course, anticoagulation may protect against severe COVID-19; however, evidence regarding the potential beneficial effect of anticoagulants is controversial. In a retrospective cohort study including severely ill COVID-19 patients, a decrease in 28 day-mortality was observed in heparin users versus non-users in specific subgroups of patients.14 Our results did not show any beneficial effect of anticoagulants in COVID-19 patients, as has been found in other retrospective studies.57–59

It has been hypothesised that drugs that act on the renin-angiotensin-aldosterone system (RAAS), such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), may affect the susceptibility to and severity of COVID-19.3 4 60 61 However, currently available results show that the use of ACEIs or ARBs are not associated with an increased risk of severity of COVID-19,3 4 as the results of our study show. Other studies analysing our population, conducted in Spain62 and specifically in Catalonia,63 as well as other European countries,64 agree with our findings.

Finally, glucocorticoids for systemic use have been associated with better outcomes when administered to patients with severe COVID-1913; specifically, the RECOVERY trial has shown that corticoid administration leads to lower mortality in patients requiring oxygen support or mechanical ventilation.65 However, chronic exposure to glucocorticoids was associated with higher odds of hospitalisation in patients with inflammatory bowel disease,66 and rheumatic and musculoskeletal diseases.67 We have found that there was a tendency towards higher risk of death in patients who were chronically exposed to corticoids, and we hypothesise that the time of administration plays a key role in corticosteroids effect: chronic use of systemic corticosteroids may worsen COVID-19 prognosis by suppressing the immune response and allowing virus replication, whereas corticoid use in the hyperinflammation phase of COVID-19 disease may prevent multiple organ failure and acute respiratory distress syndrome.68 69

We found that the mortality rate was 18.6%, which is consistent with other studies performed in COVID-19 hospitalised patients. The study of Roso-Llorach et al found that the highest 30-day mortality rate was reported during the first wave (17%) and decreased afterwards, remaining stable at 13% in the second and third waves (overall 30% reduction).70

Our study has some limitations that might reduce our ability to establish a causal relationship between chronic drug exposure and severe COVID-19, and should be considered when interpreting the results. First, there are biases on exposure; for example, we only analysed the impact of ATC groups that were used by >10 patients because we considered that the information available in these cases was insufficient to draw conclusions. Second, we considered that patients were exposed to treatment if they had an active electronic medical prescription from 3 months before hospital admission; however, we cannot affirm that patients were actually taking their medication. This could lead to an underestimation of these drugs’ impact on COVID-19. Third, we did not evaluate over-the-counter treatments, which could interfere with the results of the prescribed drugs and might cause interaction in their effect. Fourth, we included patients admitted to the hospital due to COVID-19; therefore, even if we detect that chronic exposure to drugs belonging to a certain ATC group is a risk factor for severe COVID-19, this might not apply to the whole population taking the drug in the community. We assumed that patients who were not hospitalised and had COVID-19 overcame the infection and survived, but we cannot affirm that there were not severe COVID-19 cases outside the hospital. Fifth, chronic treatment use is related to certain health conditions or chronic diseases; this implies that exposure to the drug could act as a confounder. We reduced the risk of bias and the confounder effect by adjusting for different parameters including age, gender, CCI, arterial hypertension, diabetes, smoking status and obesity; however, we cannot affirm that the risk of bias was completely erased. Finally, we are aware that multiple comparisons may increase the chances of finding significant results even if they do not exist. Therefore, our study should be interpreted with caution, and the results should help to generate hypotheses.

In this study, we analysed the relationship between exposure to chronic treatments before COVID-19 and the risk of death in hospitalised COVID-19 patients. COVID-19 prognosis depends on a myriad of factors, some of which remain to be identified, making it challenging to detect individual risk or protective factors; however, making efforts to detect drugs that might exert an effect on COVID-19 outcomes is crucial in order to optimise chronic treatments in the context of the SARS-CoV-2 pandemic and potentially identify treatments for COVID-19. We have observed that the use of certain drugs including trimethoprim and derivatives, leukotriene receptor antagonists, aldosterone antagonists, propulsives, insulins and analogues, selective immunosuppressants, calcineurin inhibitors and benzodiazepine derivatives (antiepileptics) are related to a potential higher risk of severe COVID-19. Evidence is not strong enough to advise against the use of any groups of drugs; however, our results have shed some light regarding the impact of chronic treatments on COVID-19 and they should be taken into consideration. Further research is needed in order to increase understanding about the impact of chronic drug exposure on the risk of severe COVID-19.



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