Introduction
During the COVID-19 pandemic, population-wide person-level electronic health record (EHR) data has increasingly gained importance for exploring, modeling, and reporting disease trends to inform healthcare and public health policy [
1]. The increasing availability of COVID-19 digital health data has fostered the interest in the use of real-world data (RWD) [
2], defined as patient data collected from their EHRs, which can be analyzed to generate real-world evidence (RWE) [
3]. Actually, RWE can provide a better image of the actual clinical environments in which medical interventions are carried out when compared to conventional randomized clinical trials (RCTs), given that RWD includes detailed data on patient demographics, comorbidities, adherence, and simultaneous prescriptions [
4,
5]. Moreover, RWE studies are not only cheaper than RCTs but can also be accomplished much faster, an advantage in scenarios in which an urgent decision must be taken, as in the case of a pandemic. In particular, discovering new drugs that could be used as efficient COVID-19 therapies is still an urgent need. Interestingly, much information on drugs, prescribed in COVID-19 patients for other indications, that could affect the progression of the disease is currently available in EHRs. For example, RWE has recently demonstrated that vitamin D has a significant protective effect on COVID-19 hospitalized patients [
6]. Therefore, RWD opens the door to carry out massive drug repurposing studies as well as research on potential adverse effects or interactions of drugs with COVID-19 progression.
Since 2001, the Andalusian Public Health System has systematically stored all the electronic health record (EHR) data of Andalusian patients in the Health Population Base (BPS) [
7], which is currently one of the largest repositories of clinical data in the world (with over 13 million of comprehensive patient registries) [
7]. Because of its size and the detail of the data stored, BPS constitutes a unique and privileged environment to carry out large-scale RWE studies.
Discussion
The drugs associated to the highest survival, bemiparin (DB09258), logarithm of Hazard ratio (LHR)= -1.62, with a 95%, confidence interval (CI) of [-1.95,-1.31], and a False Discovery Rate (FDR) adjusted pvalue = < 10
− 11 and Enoxaparin (LHR= -1.17, 95% CI [-1.36,-0.98], FDR p-value = < 10
− 11), are antithrombotic used, as other heparins, to prevent thrombotic and thromboembolic complications in hospitalized patients. While for bemiparin only weak evidence of its protective effect has been found in the literature [
12], a lower rate mortality in COVID-19 patients was described for enoxaparin when compared to other heparins [
13], in agreement with the results found here. However, this protective effect is not shared by other anticoagulants, such as tinziparin (LHR= -0.34, 95% CI[-1.38, 0.69], FDR p-value = 1), despite its use in pulmonary embolism, or Fondaparinux (LHR=-0.33, 95% CI[-1.64, 0.97], FDR p-value = 1). Calcifediol and Cholecalciferol, already described by us in a previous work [
6], are significantly associated with better patient survival, probably due to the protective role of vitamin D due to its pro-immune and antiinflammatory properties. Other studies suggest also a protective effect of ascorbic acid (vitamin C) [
14]. Table
S2 contains an exhaustive list of the results obtained from the drugs tested.
One of drugs with a significant protective effect is simvastatin, a widely used statin, a group of drugs that reduce the blood level of low-density lipoprotein (LDL) cholesterol. Statins are also known for their pleiotropic effect, exerting an anti-inflammatory and antithrombotic action by inhibiting the NF-Kβ pathway which directly reduces inflammatory cytokines (IL1, IL6, TNF-α), CRP, and neutrophils [
15]. Furthermore, a retrospective study performed in COVID-19 hospitalized patients showed that statins inhibit RAS activation and reduce angiotensin II proinflammatory effects, therefore improving endothelial function and remodeling after vascular injury [
16]. A recent
in-vitro study demonstrates that simvastatin pretreatment in human Calu-3 epithelial lung cells inhibited SARS-CoV-2 binding and entry to the cell by inducing a redistribution of ACE2 receptors, lowering its concentration on the plasma membrane [
17]. Recent retrospective studies also point to the relationship between statin consumption and a reduced risk of mortality in COVID-19 patients [
16,
18]. Another predicted drug is hydrochlorothiazide, a diuretic drug, often combined with ACE-inhibitors such as enalapril as antihypertensive therapy [
19]. It has been reported that patients with hypertension present a higher susceptibility to a severe COVID-19 prognosis [
20], underlying hypertension as a risk factor for increased mortality in infected patients. Although the effect of antihypertensive drugs on COVID-19 patients with hypertension is controversial, the upregulation of ACE2 by ACE-inhibitors was linked to a dampened hyperinflammation and increased intrinsic antiviral responses of the cell in hypertensive COVID-19 patients [
21]. The results presented here, together with these previous reports, suggest that ACE-inhibitors may have a protective effect, in addition to helping to improve the prognosis of hypertensive patients. Dexamethasone has been studied in the context of COVID-19 disease due to its property as an anti-inflammatory drug [
22]. Although ibuprofen and other analgesic like acetaminophen was initially discommended for COVID-19 treatment [
23], further studies based on observational data could not confirm the theoretical risks of ibuprofen and other Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) in SARS-CoV-2 infection [
24]. Moreover, other studies suggested that some NSAID could have antiviral activity in coronaviruses, including SARS-CoV-2 [
25], an activity demonstrated here for ibuprofen. Similarly, tranmadol is an opioid analgesic used to treat moderate to severe pain, that was initially deemed as bad prognosis [
26], but further studies suggested a potential therapeutic effect [
27].
The empagliflozin is an inhibitor of the sodium-glucose cotransporter 2 (
SGLT2) used in the treatment of type 2 diabetes, whose potential utility in patients with COVID-19 has been suggested [
28] but not demonstrated yet. Also for diabetes patients, the available evidence suggests that Sitagliptin may be beneficial in treating COVID-19, particularly in patients with type 2 diabetes who appear to be at high risk of mortality and of cardiorenal or cerebrovascular complications [
29]. Another diabetes treatment, metformin, has also been suggested as an effective in the treatment of COVID-19 [
30].
It has been suggested that steroids used for asthma treatment could have a protective effect in COVID-19 [
31], although specifically beclometasone dipropionate was not assessed. It has also been reported that corticosteroids, including prednisone, are effective in reducing mortality in COVID-19 patients within their therapeutic window [
27], or reduce hospitalization times, like budesinode [
32]. Some studies suggest that formoterol could be used to improve lung function and assist symptom control in COVID-19 patients [
33] however, the available evidence does not suggest any significant interaction between formoterol and COVID-19 [
34]. A recent study suggested that olmesartan could alleviate renal fibrosis induced by SARS-CoV-2 envelope protein by regulating HMGB1 release and autophagic degradation of TGF-β1 [
35]. In the case of omeprazole, a proton pump inhibitor used to treat gastroesophageal reflux disease (GERD), peptic ulcer disease, and other acid-related disorders, several studies have indicated an anti-viral effect [
36], as well as a therapeutic role in combination with other antiviral [
36]. Finally, zithromycin is an antibiotic with potential antiviral and anti-inflammatory properties [
37] although the consensus is that there is no evidence to support the use of azithromycin for the treatment of COVID-19 [
38].
On the other hand, a study suggested that furosemide, a diuretic medication used to treat fluid build-up due to heart failure, liver scarring, or kidney disease and high blood pressure, may have potential therapeutic benefits for COVID-19 patients with acute respiratory distress syndrome [
36], contrarily to what we observed here, supported by the lymphocyte count data (see Table
2 and Supplementary Table
S2). It is important to note that other drugs, which are marginally non-significant because of small sample sizes, have also a potential negative effect on COVID-19 patient survival. These drugs have different mechanisms of action and are used to treat different conditions: latanoprost, used to treat glaucoma and ocular hypertension, ciprofloxacin, an antibiotic, tamsulosin, an alpha-blocker, trazodone and lormetazepam, used to treat insomnia and anxiety, and lormetazepam, a benzodiazepine.
To our knowledge, previous studies either did not identify evidence suggesting any effect on COVID-19 prognosis, or they not have detected the significant protective effects we observed in this study for certain drugs such as diazepam, gliclazide, hydrochlorothiazide, calcium, aspartic acid, codeine, ramipiril, flitucasone furoate, flitucasone furoate, zithromycin and enalapril. The large sample size of this study and the appropriate management of confounding variables allowed us to validate some proposed therapeutic interventions and to expand the number of potential COVID-19 treatments.
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