Comparative effectiveness and safety of 32 pharmacological interventions recommended by guidelines for coronavirus disease 2019: a systematic review and network meta-analysis combining 66 trials

Abstract

Background: The global pandemic coronavirus disease 2019 (COVID-19) has become a major public health problem and presents an unprecedented challenge. However, no specific drugs were currently proven. This study aimed to evaluate the comparative efficacy and safety of pharmacological interventions in patients with COVID-19. Methods: Medline, Embase, the Cochrane Library, and clinicaltrials.gov were searched for randomized controlled trials (RCTs) in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)/SARS-CoV. Random-effects network meta-analysis within the Bayesian framework was performed, followed by the Grading of Recommendations Assessment, Development, and Evaluation system assessing the quality of evidence. The primary outcome of interest includes mortality, cure, viral negative conversion, and overall adverse events (OAEs). Odds ratio (OR) with 95% confidence interval (CI) was calculated as the measure of effect size. Results: Sixty-six RCTs with 19,095 patients were included, involving standard of care (SOC), eight different antiviral agents, six different antibiotics, high and low dose chloroquine (CQ_HD, CQ_LD), traditional Chinese medicine (TCM), corticosteroids (COR), and other treatments. Compared with SOC, a significant reduction of mortality was observed for TCM (OR = 0.34, 95% CI: 0.20–0.56, moderate quality) and COR (OR = 0.84, 95% CI: 0.75–0.96, low quality) with improved cure rate (OR = 2.16, 95% CI: 1.60–2.91, low quality for TCM; OR = 1.17, 95% CI: 1.05–1.30, low quality for COR). However, an increased risk of mortality was found for CQ_HD vs . SOC (OR = 3.20, 95% CI: 1.18–8.73, low quality). TCM was associated with decreased risk of OAE (OR = 0.52, 95% CI: 0.38–0.70, very low quality) but CQ_HD (OR = 2.51, 95% CI: 1.20–5.24) and interferons (IFN) (OR = 2.69, 95% CI: 1.02–7.08) vs . SOC with very low quality were associated with an increased risk. Conclusions: COR and TCM may reduce mortality and increase cure rate with no increased risk of OAEs compared with standard care. CQ_HD might increase the risk of mortality. CQ, IFN, and other antiviral agents could increase the risk of OAEs. The current evidence is generally uncertain with low-quality and further high-quality trials are needed.

Efficacy and safety of current treatment interventions for patients with severe COVID‐19 infection: A network meta‐analysis of randomized controlled trials

“… 39 While no significant decrease in ACM was found between SOC and 14 other medications or placebo for severe COVID‐19 infection. This result seems to be inconsistent with prior NMA studies by Zhang et al, 40 Wu et al, 41 and Siemieniuk et al 42 They suggested that tocilizumab or corticosteroids might reduce the ACM compared with SOC for COVID‐19 infection. A possible explanation for this was that we compared the ACM of SOC, which existed the bias due to the differential SOC of every country (i.e., the SOC is not standardized) except for the reasons given above.…”

“…This finding was consistent with a previous report of NMA. 41 Comparison of the findings with those of other studies 17 , 48 , 49 confirmed most medications of COVID‐19 might be acceptable in TEAEs. It was worth noting that clinicians might need to select treatment regimens based on the rank of safety (i.e., SUCRA) in treating severe COVID‐19.…”

Prescription Patterns of Drugs Given to Hospitalized COVID-19 Patients: A Cross-Sectional Study in Colombia

“…In the midst of the need to find an effective treatment for COVID-19, antiviral drugs, antibiotics, antimalarials, immunosuppressants, immunomodulators, and corticosteroids, among others, have been chosen as therapeutic measures that help reduce the mortality of mechanical ventilation, severe acute respiratory syndrome (SARS), and other complications caused by the virus [7,8]. Many of the proposed drugs have a possible mechanism of action on SARS-CoV-2 or on the pathophysiology of the disease [9,10].…”

“…Many of the proposed drugs have a possible mechanism of action on SARS-CoV-2 or on the pathophysiology of the disease [9,10]. However, most drugs have not demonstrated efficacy through clinical studies, and others still do not have enough evidence to be recommended [7,8]. Even so, they are used in the general population, bringing the risk of drug interactions and adverse drug reactions [11,12].…”

Meta-Analyses Do Not Establish Improved Mortality With Ivermectin Use in COVID-19

“…13 We have identified 17 metaanalyses concluding HCQ/CQ increased mortality in COVID-19, potentially worsening control outcomes, and overstating ivermectin's efficacy. [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] Only 3 metaanalyses indicated reduced mortality with HCQ/CQ, potentially favoring control outcomes. [41][42][43] Importantly, the Food and Drug Administration and European Medicines Agency recommend using active controls that are standard of care and already approved for the studied indication which is not the case for HCQ/CQ.…”