Impact of suspected adverse drug reactions on mortality and length of hospital stay in the hospitalised patients: a meta-analysis.

PURPOSE: To estimate the risk of mortality and length of stay in hospitalised patients who have experienced suspected adverse drug reactions (ADRs) as compared to patients who did not experience suspected ADRs. METHODS: A systematic literature search was conducted on databases for observational and randomised controlled studies conducted in any inpatient setting that reported deaths and/or length of hospital stay in patients who had suspected ADRs and did not have suspected ADRs during hospitalisation. PRISMA guidelines were strictly followed during the review. The methodological quality of included studies was assessed using a tool designed by Smyth et al. for the studies of adverse drug reactions. The meta-analytic summary of all-cause mortality was estimated using odds ratio-OR (95% CI) and length of stay using mean difference-MD (95% CI). Both outcomes were pooled using a random effect model (DerSimonian and Laird method). Subgroup and meta-regression were performed based on study variables: study design, age group, study ward, study region, types of suspected ADRs (ADRAd-suspected ADRs that lead to hospitalisation and ADRIn-suspected ADRs that occur following hospitalisation), study duration, sample size and study period. The statistical analysis was conducted through the 'Review manager software version 5.4.1 and JASP (Version 0.14.1)'. RESULTS: After screening 475 relevant articles, 55 studies were included in this meta-analysis. Patients having suspected ADRs had reported significantly higher odds of all-cause mortality [OR: 1.50 (95% CI: 1.21-1.86; I2 = 100%) than those patients who did not have suspected ADRs during hospitalisation. Study wards, types of suspected ADRs and sample size were observed as significant predictors of all-cause mortality (p < 0.05). Patients having suspected ADRs had reported significantly higher mean difference in hospital stay [MD: 3.98 (95% CI: 2.91, 5.05; I2 = 99%) than those patients who did not have suspected ADRs during hospitalisation. Types of suspected ADRs and study periods were observed as significant predictors of length of stay (p < 0.05). CONCLUSION: Suspected ADRs significantly increase the risk of mortality and length of stay in hospitalised patients. SYSTEMATIC REVIEW REGISTRATION: CRD42020176320.

Drug-related deaths among inpatients: a meta-analysis.

PURPOSE: To estimate the prevalence of drug-related deaths with regard to total hospital mortality and to explore the heterogeneity in its estimation through subgroup analysis, univariate and multivariate analysis. METHODS: Two investigators independently searched the PubMed and Google Scholar databases with appropriate key terms to identify observational and randomised studies assessing drug-related problems. The prevalence of drug-related deaths was estimated using a double arcsine method. The heterogeneity was explored through subgroup and univariate analysis for the following study characteristics: study design, age group, study ward, study region, types of drug-related problems, study duration, sample size and study period. The study variables showing significant effects were further explored through a multivariable regression model. The percentage of preventable drug-related deaths was explored as a secondary objective. RESULTS: Of the 480 full-text articles assessed, 23 studies satisfying the selection criteria were included. The mean percentage of drug-related deaths was 5.6% (95% CI: 3.8-7.6%; I2 = 96%). The univariable analysis showed study design (regression coefficient: 4.31) and study wards (regression coefficient: - 6.37) as heterogeneity modifiers. In the multivariable model, only the study ward was considered a significant predictor of drug-related deaths (regression coefficient: - 5.78; p = 0.04). The mean percentage of preventable drug-related deaths was 45.2% (95% CI: 33.6-57.0%; I2 = 60%). CONCLUSION: Drug-related problems are an important cause of mortality. The variability in its estimation could be explained by admission wards.

A Phase 3, randomized, non-inferiority study of a heterologous booster dose of SARS CoV-2 recombinant spike protein vaccine in adults.

Due to waning immunity following primary immunization with COVID-19 vaccines, booster doses may be required. The present study assessed a heterologous booster of SII-NVX-CoV2373 (spike protein vaccine) in adults primed with viral vector and inactivated vaccines. In this Phase 3, observer-blind, randomized, active controlled study, a total of 372 adults primed with two doses of ChAdOx1 nCoV-19 (n = 186) or BBV152 (n = 186) at least six months ago, were randomized to receive a booster of SII-NVX-CoV2373 or control vaccine (homologous booster of ChAdOx1 nCoV-19 or BBV152). Anti-S IgG and neutralizing antibodies (nAbs) were assessed at days 1, 29, and 181. Non-inferiority (NI) of SII-NVX-CoV2373 to the control vaccine was assessed based on the ratio of geometric mean ELISA units (GMEU) of anti-S IgG and geometric mean titers (GMT) of nAbs (NI margin > 0.67) as well as seroresponse (≥ 2 fold-rise in titers) (NI margin -10%) at day 29. Safety was assessed throughout the study period. In both the ChAdOx1 nCoV-19 prime and BBV152 prime cohorts, 186 participants each received the study vaccines. In the ChAdOx1 nCoV-19 prime cohort, the GMEU ratio was 2.05 (95% CI 1.73, 2.43) and the GMT ratio was 1.89 (95% CI 1.55, 2.32) whereas the difference in the proportion of seroresponse was 49.32% (95% CI 36.49, 60.45) for anti-S IgG and 15% (95% CI 5.65, 25.05) for nAbs on day 29. In the BBV152 prime cohort, the GMEU ratio was 5.12 (95% CI 4.20, 6.24) and the GMT ratio was 4.80 (95% CI 3.76, 6.12) whereas the difference in the proportion of seroresponse was 74.08% (95% CI 63.24, 82.17) for anti-S IgG and 24.71% (95% CI 16.26, 34.62) for nAbs on day 29. The non-inferiority of SII-NVX-CoV2373 booster to the control vaccine for each prime cohort was met. SII-NVX-CoV2373 booster showed significantly higher immune responses than BBV152 homologous booster. On day 181, seroresponse rates were ≥ 70% in all the groups for both nAbs and anti-S IgG. Solicited adverse events reported were transient and mostly mild in severity in all the groups. No causally related SAE was reported. SII-NVX-CoV2373 as a heterologous booster induced non-inferior immune responses as compared to homologous boosters in adults primed with ChAdOx1 nCoV-19 and BBV152. SII-NVX-CoV2373 showed a numerically higher boosting effect than homologous boosters. The vaccine was also safe and well tolerated.

Safety and immunogenicity of SII-NVX-CoV2373 (COVID-19 vaccine) in adults in a phase 2/3, observer-blind, randomised, controlled study.

Background: NVX-CoV2373, a Covid-19 vaccine was developed in the USA with ∼90% efficacy. The same vaccine is manufactured in India after technology transfer (called as SII-NVX-CoV2373), was evaluated in this phase 2/3 immuno-bridging study. Methods: This was an observer-blind, randomised, phase 2/3 study in 1600 adults. In phase 2, 200 participants were randomized 3:1 to SII-NVX-CoV2373 or placebo. In phase 3, 1400 participants were randomized 3:1 to SII-NVX-CoV2373 or NVX-CoV2373 (940 safety cohort and 460 immunogenicity cohort). Two doses of study products (SII-NVX-CoV2373, NVX-CoV2373 or placebo) were given 3 weeks apart. Primary objectives were to demonstrate non-inferiority of SII-NVX-CoV2373 to NVX-CoV2373 in terms of geometric mean ELISA units (GMEU) ratio of anti-S IgG antibodies 14 days after the second dose (day 36) and to determine the incidence of causally related serious adverse events (SAEs) through 180 days after the first dose. Anti-S IgG response was assessed using an Enzyme-Linked Immunosorbent Assay (ELISA) and neutralizing antibodies (nAb) were assessed by a microneutralization assay using wild type SARS CoV-2 in participants from the immunogenicity cohort at baseline, day 22, day 36 and day 180. Cell mediated immune (CMI) response was assessed in a subset of 28 participants from immunogenicity cohort by ELISpot assay at baseline, day 36 and day 180. The total follow-up was for 6 months. Trial registration: CTRI/2021/02/031554. Findings: Total 1596 participants (200 in Phase 2 and 1396 in Phase 3) received the first dose. SII-NVX-CoV2373 was found non-inferior to NVX-CoV2373 (anti-S IgG antibodies GMEU ratio 0.91; 95% CI: 0.79, 1.06). At day 36, there was more than 58-fold rise in anti-S IgG and nAb titers compared to baseline in both the groups. On day 180 visit, these antibody titers declined to levels slightly lower than those after the first dose (13-22 fold-rise above baseline). Incidence of unsolicited and solicited AEs was similar between the SII-NVX-CoV2373 and NVX-CoV2373 groups. No adverse event of special interest (AESI) was reported. No causally related SAE was reported. Interpretation: SII-NVX-CoV2373 induced a non-inferior immune response compared to NVX-CoV2373 and has acceptable safety profile. Funding: SIIPL, Indian Council of Medical Research, Novavax.

Efficacy and safety of lopinavir-ritonavir in COVID-19: A systematic review of randomized controlled trials.

BACKGROUND: Lopinavir-ritonavir is a repurposed drug for coronavirus disease-2019 (COVID-19). In this study, a pooled effect of lopinavir-ritonavir on mortality, virological cure, radiological improvement and safety profile in COVID-19 patients has been evaluated. METHODS: The databases were searched for comparative randomized controlled studies evaluating the efficacy and/or safety of lopinavir-ritonavir in COVID-19 patients. The mortality outcome was pooled as a risk difference (RD) with 95% CI. The virological cure, radiological improvement and adverse events were pooled as risk ratio (RR) with 95% CI. All outcomes were pooled using the Mantle-Hanzle method random effect model. The heterogeneity was assessed using the I2 test. RESULTS: Out of 82 full text assessed, seven studies were included in the analysis. The included studies had five different control interventions: supportive care (n=4), umifenovir (arbidol) (n=2), navaferon (recombinant anti-tumour and anti-virus protein) (n=1), lopinavir-ritonavir+novaferon (n=1) and lopinavir-ritonavir+interferon beta 1b+ribavirin (n=1). Lopinavir-ritonavir group did not show significant difference in mortality [RD: 0.00 (95% CI: -0.01, 0.02), I2=0], virological cure [RR: 1.06 (95% CI: 0.85, 1.31), I2=0%], radiological improvement [RR: 0.81 (95% CI: 0.62, 1.05)] and adverse events [RR: 2.59 (95% CI: 0.17, 38.90), I2=75%] than supportive care. Similarly, no difference was observed for any efficacy outcomes between lopinavir-ritonavir and other control interventions. We observed significantly high risk of adverse events with lopinavir-ritonavir as compared to umifenovir [RR: 2.96 (95% CI: 1.42-6.18); I2=0%]. CONCLUSION: There is no benefit of the addition of lopinavir-ritonavir to the standard care in COVID-19 patients.

Does Adding of Hydroxychloroquine to the Standard Care Provide any Benefit in Reducing the Mortality among COVID-19 Patients?: a Systematic Review.

Hydroxychloroquine has been promoted for its use in treatment of COVID-19 patients based on in-vitro evidences. We searched the databases to include randomized and observational studies evaluating the effect of Hydroxychloroquine on mortality in COVID-19 patients. The outcome was summarized as odds ratios (OR) with a 95% confidence interval (CI).We used the inverse-variance method with a random effect model and assessed the heterogeneity using I2 test. We used ROBINS-I tool to assess methodological quality of the included studies. We performed the meta-analysis using 'Review manager software version 5.3'. We identified 6 observationalstudies satisfying the selection criteria. In all studies, Hydroxychloroquine was given as add on to the standard care and effect was compared with the standard care alone. A pooled analysis observed 251 deaths in 1331 participants of the Hydroxychloroquine arm and 363 deaths in 1577 participants of the control arm. There was no difference in odds of mortality events amongst Hydroxychloroquine and supportive care arm [1.25 (95% CI: 0.65, 2.38); I2 = 80%]. A similar trend was observed with moderate risk of bias studies [0.95 (95% CI: 0.44, 2.06); I2 = 85%]. The odds of mortality were significantly higher in patients treated with Hydroxychloroquine + Azithromycin than supportive care alone [2.34 (95% CI: 1.63, 3.34); I2 = 0%]. A pooled analysis of recently published studies suggests no additional benefit for reducing mortality in COVID-19 patients when Hydroxychloroquine is given as add-on to the standard care. Graphical Abstract.