Meta-analysis on outcome-worsening comorbidities of COVID-19 and related potential drug-drug interactions

Abstract

Drug-drug interactions (DDI) potentially occurring between medications used in the course of COVID-19 infection and medications prescribed for the management of underlying comorbidities may cause adverse drug reactions (ADRs) contributing to worsening of the clinical outcome in affected patients. First, we conducted a meta-analysis to determine comorbidities observed in the course of COVID-19 disease associated with an increased risk of worsened clinical outcome from 24 published studies. In addition, the potential risk of DDI between medications used in the course of COVID-19 treatment in these studies and those for the management of observed comorbidities was evaluated for possible worsening of the clinical outcome. Our meta-analysis revealed an implication cardiometabolic syndrome (e.g. cardiovascular disease, cerebrovascular disease, hypertension, and diabetes), chronic kidney disease and chronic obstructive pulmonary disease as main co-morbidities associated with worsen the clinical outcomes including mortality (risk difference RD 0.12, 95 %-CI 0.05-0.19, p = 0.001), admission to ICU (RD 0.10, 95 %-CI 0.04-0.16, p = 0.001) and severe infection (RD 0.05, 95 %-CI 0.01-0.09, p = 0.01) in COVID-19 patients. Potential DDI on pharmacokinetic level were identified between the antiviral agents atazanavir and lopinavir/ritonavir and some drugs, used in the treatment of cardiovascular diseases such as antiarrhythmics and anti-coagulants possibly affecting the clinical outcome including cardiac injury or arrest because of QTc-time prolongation or bleeding. Concluding, DDI occurring in the course of anti-Covid-19 treatment and co-morbidities could lead to ADRs, increasing the risk of hospitalization, prolonged time to recovery or death on extreme cases. COVID-19 patients with cardiometabolic diseases, chronic kidney disease and chronic obstructive pulmonary disease should be subjected to particular carefully clinical monitoring of adverse events with a possibility of dose adjustment when necessary.

Keywords: COVID-19; Comorbidity; Drug-drug interaction; SARS-CoV-2; Side-effect.

Graphical abstract

Fig. 1

Flow diagram indicating publications on clinical COVID-19 studies excluded and included in the meta-analysis.

Fig. 2

Meta-analysis of comorbidities in COVID-19 patients and typical related drugs. Cardiometabolic syndrome (cardiovascular disease, hypertension, and diabetes) was associated with worse clinical outcome of COVID-19 in affected patients. Drugs used for management or treatment of comorbidities: antihypertensives, antiarrhythmics, lipid lowering drugs (statins) listed could increase poor clinical outcome in comorbid patients by potential interaction with drugs used in the course of COVID-19. *indication for both pulmonary hypertension and erectile dysfunction.

Fig. 3

Heatmap of potential DDI between drugs used in the course of COVID-19 and co-medications. The co-medications are putatively used for treatment of identified comorbidities (hypertension, cerebrovascular, cardiovascular, diabetes and COPD) based on results of the meta-analysis. Anti-viral drugs LPV/r and AZM interact with drugs prescribed for cardiometabolic syndrome. Potential interactions were predicting using www.covid19-druginteractions.org database. Abbreviations: atazanavir (ATV), azithromycin (AZM) darunavir/cobicistat (DRV/c), lopinavir/ritonavir (LPV/r), remdesivir/GS-5734 (RDV), favipiravir (FAVI), chloroquine (CLQ), hydroxychloroquine (HCLQ), nitazoxanide (NITA), ribavirin (RBV), tocilizumab (TCZ), interferon β-1a (IFN-β-1a) and oseltamivir (OSV).