Effectiveness and safety of intra-articular interventions for knee and hip osteoarthritis based on large randomized trials: A systematic review and network meta-analysis.

OBJECTIVE: To quantify the effectiveness and safety of intra-articular interventions for knee and hip osteoarthritis (OA) through a systematic review and Bayesian random-effects network meta-analysis. DESIGN: We searched CENTRAL and regulatory agency websites (inception-2023) for large, English-language, randomized controlled trials (RCTs) (≥100 patients/group) examining any intra-articular intervention. PRIMARY OUTCOME: pain intensity. SECONDARY OUTCOMES: physical function and safety outcomes. Pain and function outcomes were analyzed at 2, 6, 12, 24, and 52 weeks post-randomization, and presented as standardized mean differences (SMDs) (95% credible intervals, 95% CrI). The prespecified minimal clinically important between-group difference (MID) was -0.37 SMD. Safety outcomes were presented as odds ratios (OR) (95% CrI). FINDINGS: Among 57 RCTs (22,795 participants) examining 18 intra-articular interventions, usual care or placebo, treatment effects were larger in 35 high-risk-of-bias trials than in 22 low/unclear-risk-of-bias trials. In the main analysis (excluding high-risk-of-bias trials), triamcinolone had the highest probabilities of reaching the MID at weeks 2 and 6 (75.3% and 90%, respectively) with corresponding SMDs of -0.48 (95% CrI,-0.85 to -0.10) and -0.53 (95% CrI,-0.79 to -0.27) compared to placebo (1 trial). The complex homeopathic products Tr14/Ze14 showed therapeutic potential at week 6 compared to placebo (SMD:-0.42, 95% CrI,-0.71 to -0.11, 63.5% probability of reaching the MID, 1 trial). Hyaluronic acid had no effect on pain (SMD:-0.04, 95% CrI,-0.19 to 0.11, 11 trials) but a higher risk of dropouts due to adverse events (OR: 2.01, 95% CrI,1.08 to 3.77) and serious adverse events (OR: 1.86, 95% CrI, 1.16 to 3.03) than placebo. CONCLUSION: Triamcinolone had the highest probabilities to have a treatment effect beyond the MID at weeks 2-6. Large RCTs with lower risk of bias indicate that the effects of 16 intra-articular interventions in knee or hip OA were smaller than the MID, and that most were consistent with placebo effects. Lack of evidence of long-term effectiveness underscores the need for further research beyond 24 weeks.

Evidence-based hierarchy of pain outcome measures for osteoarthritis clinical trials and meta-analyses.

OBJECTIVE: To rank commonly used patient-reported outcome measures (PROMs) for assessing pain in osteoarthritis trials according to their assay sensitivity, defined as the ability of a PROM to distinguish an effective from a less effective intervention or placebo, proposing a hierarchy for PROM selection in trials and data-extraction in meta-analyses. DESIGN: Analysis of trials with placebo, sham, or non-intervention control that included ≥100 patients per arm with knee/hip osteoarthritis, reporting treatment effects on ≥2 pain PROMs. Treatment effects from all PROMs were standardized on a 0-100 scale. Negative mean differences indicated a larger effect of the experimental treatment compared to control. We ranked PROMs by assay sensitivity using a Bayesian multi-outcome synthesis random-effects model. RESULTS: 135 trials comprising 57,141 participants were included. The ranking of PROMs from highest to lowest assay sensitivity was as follows: pain overall, pain on stairs, pain at night, pain on walking, pain at rest, WOMAC pain, WOMAC global, Lequesne index. Pain overall, the highest-ranked PROM, had a pooled mean difference of -6.96 (95%CrI -7.94, -6.02), while WOMAC pain, the most reported PROM in our study, had a pooled mean difference of -4.90 (95%CrI -5.55, -4.26). The pooled ratio of mean differences between pain overall and WOMAC pain was 1.42 (95%CrI 1.30, 1.55), representing a 42% larger effect size with pain overall. CONCLUSIONS: Pain overall has better assay sensitivity than other pain PROMs. Investigators should consider the hierarchy proposed in this study to guide PROM selection in osteoarthritis clinical trials and data extraction in osteoarthritis meta-analyses.

Complication Rates of Central Venous Catheters: A Systematic Review and Meta-Analysis.

Importance: Central venous catheters (CVCs) are commonly used but are associated with complications. Quantifying complication rates is essential for guiding CVC utilization decisions. Objective: To summarize current rates of CVC-associated complications. Data Sources: MEDLINE, Embase, CINAHL, and CENTRAL databases were searched for observational studies and randomized clinical trials published between 2015 to 2023. Study Selection: This study included English-language observational studies and randomized clinical trials of adult patients that reported complication rates of short-term centrally inserted CVCs and data for 1 or more outcomes of interest. Studies that evaluated long-term intravascular devices, focused on dialysis catheters not typically used for medication administration, or studied catheters placed by radiologists were excluded. Data Extraction and Synthesis: Two reviewers independently extracted data and assessed risk of bias. Bayesian random-effects meta-analysis was applied to summarize event rates. Rates of placement complications (events/1000 catheters with 95% credible interval [CrI]) and use complications (events/1000 catheter-days with 95% CrI) were estimated. Main Outcomes and Measures: Ten prespecified complications associated with CVC placement (placement failure, arterial puncture, arterial cannulation, pneumothorax, bleeding events requiring action, nerve injury, arteriovenous fistula, cardiac tamponade, arrhythmia, and delay of ≥1 hour in vasopressor administration) and 5 prespecified complications associated with CVC use (malfunction, infection, deep vein thrombosis [DVT], thrombophlebitis, and venous stenosis) were assessed. The composite of 4 serious complications (arterial cannulation, pneumothorax, infection, or DVT) after CVC exposure for 3 days was also assessed. Results: Of 11 722 screened studies, 130 were included in the analyses. Seven of 15 prespecified complications were meta-analyzed. Placement failure occurred at 20.4 (95% CrI, 10.9-34.4) events per 1000 catheters placed. Other rates of CVC placement complications (per 1000 catheters) were arterial canulation (2.8; 95% CrI, 0.1-10), arterial puncture (16.2; 95% CrI, 11.5-22), and pneumothorax (4.4; 95% CrI, 2.7-6.5). Rates of CVC use complications (per 1000 catheter-days) were malfunction (5.5; 95% CrI, 0.6-38), infection (4.8; 95% CrI, 3.4-6.6), and DVT (2.7; 95% CrI, 1.0-6.2). It was estimated that 30.2 (95% CrI, 21.8-43.0) in 1000 patients with a CVC for 3 days would develop 1 or more serious complication (arterial cannulation, pneumothorax, infection, or DVT). Use of ultrasonography was associated with lower rates of arterial puncture (risk ratio [RR], 0.20; 95% CrI, 0.09-0.44; 13.5 events vs 68.8 events/1000 catheters) and pneumothorax (RR, 0.25; 95% CrI, 0.08-0.80; 2.4 events vs 9.9 events/1000 catheters). Conclusions and Relevance: Approximately 3% of CVC placements were associated with major complications. Use of ultrasonography guidance may reduce specific risks including arterial puncture and pneumothorax.

Which Remote Rehabilitation Interventions Work Best for Chronic Musculoskeletal Pain and Depression? A Bayesian Network Meta-Analysis.

OBJECTIVE: To evaluate the effectiveness of remote rehabilitation interventions for people living with chronic musculoskeletal pain and depression. DESIGN: A systematic review with network meta-analysis (NMA) of randomized controlled trials. LITERATURE SEARCH: We searched the Cochrane Central Register of Controlled Trials, CINAHL, EMBASE, LILACS MEDLINE, PSYNDEX, and PsycINFO databases from inception to May 2023. STUDY SELECTION CRITERIA: Randomized controlled trials that evaluated the effectiveness of remote rehabilitation interventions in people with chronic musculoskeletal pain and depression. DATA SYNTHESIS: We used Bayesian random-effects models for the NMA. Effect estimates were comparisons between rehabilitation interventions and waitlist. We performed a sensitivity analysis based on bias in the randomization process, large trials (>100 patients per arm) and musculoskeletal condition. RESULTS: Fifty-eight randomized controlled trials involving 10 278 participants (median sample size: 137; interquartile range [IQR]: 77-236) were included. Interactive voice response cognitive behavioral therapy (CBT; standardized mean difference [SMD] -0.66, 95% credible interval [CrI] -1.17 to -0.16), CBT in person (SMD -0.50, 95% CrI -0.97 to -0.04), and mobile app CBT plus exercise (SMD -0.37, 95% CrI -0.69 to -0.02) were superior to waitlist at 12-week follow-up for reducing pain (> 98% probability of superiority). For depression outcomes, Internet-delivered CBT and telecare were superior to waitlist at 12-week follow-up (SMD -0.51, 95% CrI -0.87 to -0.13) (> 99% probability of superiority). For pain outcomes, the certainty of evidence ranged from low to moderate. For depression outcomes, the certainty of evidence ranged from very low to moderate. The proportion of dropouts attributed to adverse events was unclear. No intervention was associated with higher odds of dropout. CONCLUSION: Interactive voice response CBT and mobile app CBT plus exercise showed similar treatment effects with in-person CBT on pain reduction among people living with chronic musculoskeletal pain and depression had over 98% probability of superiority than waitlist control at 12-week follow-up. Internet-delivered CBT and telecare had over 99% probability of superiority than waitlist control for improving depression outcomes at 12-week follow-up. J Orthop Sports Phys Ther 2024;54(6):1-16. Epub 26 February 2024. doi:10.2519/jospt.2024.12216.

Effectiveness of Fludrocortisone Plus Hydrocortisone versus Hydrocortisone Alone in Septic Shock: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

Rationale: The use of hydrocortisone in adult patients with septic shock is controversial, and the effectiveness of adding fludrocortisone to hydrocortisone remains uncertain. Objectives: To assess the comparative effectiveness and safety of fludrocortisone plus hydrocortisone, hydrocortisone alone, and placebo or usual care in adults with septic shock. Methods: A systematic review and a Bayesian network meta-analysis of peer-reviewed randomized trials were conducted. The primary outcome was all-cause mortality at last follow-up. Treatment effects are presented as relative risks (RRs) with 95% credible intervals (CrIs). Placebo or usual care was the reference treatment. Measurements and Main Results: Among 7,553 references, we included 17 trials (7,688 patients). All-cause mortality at last follow-up was lowest with fludrocortisone plus hydrocortisone (RR, 0.85; 95% CrI, 0.72-0.99; 98.3% probability of superiority, moderate-certainty evidence), followed by hydrocortisone alone (RR, 0.97; 95% CrI, 0.87-1.07; 73.1% probability of superiority, low-certainty evidence). The comparison of fludrocortisone plus hydrocortisone versus hydrocortisone alone was based primarily on indirect evidence (only two trials with direct evidence). Fludrocortisone plus hydrocortisone was associated with a 12% lower risk of all-cause mortality compared with hydrocortisone alone (RR, 0.88; 95% CrI, 0.74-1.03; 94.2% probability of superiority, moderate-certainty evidence). Conclusions: In adult patients with septic shock, fludrocortisone plus hydrocortisone was associated with lower risk of all-cause mortality at last follow-up than placebo and hydrocortisone alone. The scarcity of head-to-head trials comparing fludrocortisone plus hydrocortisone versus hydrocortisone alone led our network meta-analysis to rely primarily on indirect evidence for this comparison. Although we undertook several sensitivity analyses and assessments, these findings should be considered while also acknowledging the heterogeneity of included trials.

Rehabilitation Interventions for Physical Capacity and Quality of Life in Adults With Post-COVID-19 Condition: A Systematic Review and Meta-Analysis.

Importance: Current rehabilitation guidelines for patients with post-COVID-19 condition (PCC) are primarily based on expert opinions and observational data, and there is an urgent need for evidence-based rehabilitation interventions to support patients with PCC. Objective: To synthesize the findings of existing studies that report on physical capacity (including functional exercise capacity, muscle function, dyspnea, and respiratory function) and quality of life outcomes following rehabilitation interventions in patients with PCC. Data Sources: A systematic electronic search was performed from January 2020 until February 2023, in MEDLINE, Scopus, CINAHL, and the Clinical Trials Registry. Key terms that were used to identify potentially relevant studies included long-covid, post-covid, sequelae, exercise therapy, rehabilitation, physical activity, physical therapy, and randomized controlled trial. Study Selection: This study included randomized clinical trials that compared respiratory training and exercise-based rehabilitation interventions with either placebo, usual care, waiting list, or control in patients with PCC. Data Extraction and Synthesis: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. A pairwise bayesian random-effects meta-analysis was performed using vague prior distributions. Risk of bias was assessed using the Cochrane risk of bias tool version 2, and the certainty of evidence was evaluated using the GRADE system by 2 independent researchers. Main Outcomes and Measures: The primary outcome was functional exercise capacity, measured at the closest postintervention time point by the 6-minute walking test. Secondary outcomes were fatigue, lower limb muscle function, dyspnea, respiratory function, and quality of life. All outcomes were defined a priori. Continuous outcomes were reported as standardized mean differences (SMDs) with 95% credible intervals (CrIs) and binary outcomes were summarized as odds ratios with 95% CrIs. The between-trial heterogeneity was quantified using the between-study variance, τ2, and 95% CrIs. Results: Of 1834 identified records, 1193 were screened, and 14 trials (1244 patients; 45% female participants; median [IQR] age, 50 [47 to 56] years) were included in the analyses. Rehabilitation interventions were associated with improvements in functional exercise capacity (SMD, -0.56; 95% CrI, -0.87 to -0.22) with moderate certainty in 7 trials (389 participants). These improvements had a 99% posterior probability of superiority when compared with current standard care. The value of τ2 (0.04; 95% CrI, 0.00 to 0.60) indicated low statistical heterogeneity. However, there was significant uncertainty and imprecision regarding the probability of experiencing exercise-induced adverse events (odds ratio, 1.68; 95% CrI, 0.32 to 9.94). Conclusions and Relevance: The findings of this systematic review and meta-analysis suggest that rehabilitation interventions are associated with improvements in functional exercise capacity, dyspnea, and quality of life, with a high probability of improvement compared with the current standard care; the certainty of evidence was moderate for functional exercise capacity and quality of life and low for other outcomes. Given the uncertainty surrounding the safety outcomes, additional trials with enhanced monitoring of adverse events are necessary.

The evidence base of US Food and Drug Administration approvals of novel cancer therapies from 2000 to 2020.

Concerns have been raised that regulatory programs to accelerate approval of cancer drugs in cancer may increase uncertainty about benefits and harms for survival and quality of life (QoL). We analyzed all pivotal clinical trials and all non-pivotal randomized controlled trials (RCTs) for all cancer drugs approved for the first time by the FDA between 2000 and 2020. We report regulatory and trial characteristics. Effects on overall survival (OS), progression-free survival and tumor response were summarized in meta-analyses. Effects on QoL were qualitatively summarized. Between 2000 and 2020, the FDA approved 145 novel cancer drugs for 156 indications based on 190 clinical trials. Half of indications (49%) were approved without RCT evidence; 82% had a single clinical trial only. OS was primary endpoint in 14% of trials and QoL data were available from 25%. The median OS benefit was 2.55 months (IQR, 1.33-4.28) with a mean hazard ratio for OS of 0.75 (95%CI, 0.72-0.79, I2  = 42). Improvement for QoL was reported for 7 (4%) of 156 indications. Over time, priority review was used increasingly and the mean number of trials per indication decreased from 1.45 to 1.12. More trials reported results on QoL (19% in 2000-2005; 41% in 2016-2020). For 21 years, novel cancer drugs have typically been approved based on one single, often uncontrolled, clinical trial, measuring surrogate endpoints. This leaves cancer patients without solid evidence that novel drugs improve their survival or QoL and there is no indication towards improvement.

Robustness of reported postacute health outcomes in children with SARS-CoV-2 infection: a systematic review.

OBJECTIVE: To systematically assess the robustness of reported postacute SARS-CoV-2 infection health outcomes in children. METHODS: A search on PubMed and Web of Science was conducted to identify studies published up to 22 January 2022 that reported on postacute SARS-CoV-2 infection health outcomes in children (<18 years) with follow-up of ≥2 months since detection of infection or ≥1 month since recovery from acute illness. We assessed the consideration of confounding bias and causality, as well as the risk of bias. RESULTS: 21 studies including 81 896 children reported up to 97 symptoms with follow-up periods of 2.0-11.5 months. Fifteen studies had no control group. The reported proportion of children with post-COVID syndrome was between 0% and 66.5% in children with SARS-CoV-2 infection (n=16 986) and between 2.0% and 53.3% in children without SARS-CoV-2 infection (n=64 910). Only two studies made a clear causal interpretation of an association between SARS-CoV-2 infection and the main outcome of 'post-COVID syndrome' and provided recommendations regarding prevention measures. The robustness of all 21 studies was seriously limited due to an overall critical risk of bias. CONCLUSIONS: The robustness of reported postacute SARS-CoV-2 infection health outcomes in children is seriously limited, at least in all the published articles we could identify. None of the studies provided evidence with reasonable certainty on whether SARS-CoV-2 infection has an impact on postacute health outcomes, let alone to what extent. Children and their families urgently need much more reliable and methodologically robust evidence to address their concerns and improve care.

Viscosupplementation for knee osteoarthritis: systematic review and meta-analysis.

OBJECTIVE: To evaluate the effectiveness and safety of viscosupplementation for pain and function in patients with knee osteoarthritis. DESIGN: Systematic review and meta-analysis of randomised trials. DATA SOURCES: Searches were conducted of Medline, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases from inception to 11 September 2021. Unpublished trials were identified from the grey literature and trial registries. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Randomised trials comparing viscosupplementation with placebo or no intervention for knee osteoarthritis treatment. MAIN OUTCOME MEASURES: The prespecified primary outcome was pain intensity. Secondary outcomes were function and serious adverse events. Pain and function were analysed as standardised mean differences (SMDs). The prespecified minimal clinically important between group difference was -0.37 SMD. Serious adverse events were analysed as relative risks. METHODS: Two reviewers independently extracted relevant data and assessed the risk of bias of trials using the Cochrane risk of bias tool. The predefined main analysis was based only on large, placebo controlled trials with ≥100 participants per group. Summary results were obtained through a random effects meta-analysis model. Cumulative meta-analysis and trial sequential analysis under a random effects model were also performed. RESULTS: 169 trials provided data on 21 163 randomised participants. Evidence of small study effects and publication biases was observed for pain and function (Egger's tests with P<0.001 and asymmetric funnel plots). Twenty four large, placebo controlled trials (8997 randomised participants) included in the main analysis of pain indicated that viscosupplementation was associated with a small reduction in pain intensity compared with placebo (SMD -0.08, 95% confidence interval -0.15 to -0.02), with the lower bound of the 95% confidence interval excluding the minimal clinically important between group difference. This effect corresponds to a difference in pain scores of -2.0 mm (95% confidence interval -3.8 to -0.5 mm) on a 100 mm visual analogue scale. Trial sequential analysis for pain indicated that since 2009 there has been conclusive evidence of clinical equivalence between viscosupplementation and placebo. Similar conclusions were obtained for function. Based on 15 large, placebo controlled trials on 6462 randomised participants, viscosupplementation was associated with a statistically significant higher risk of serious adverse events than placebo (relative risk 1.49, 95% confidence interval 1.12 to 1.98). CONCLUSION: Strong conclusive evidence indicates that viscosupplementation leads to a small reduction in knee osteoarthritis pain compared with placebo, but the difference is less than the minimal clinically important between group difference. Strong conclusive evidence indicates that viscosupplementation is also associated with an increased risk of serious adverse events compared with placebo. The findings do not support broad use of viscosupplementation for the treatment of knee osteoarthritis. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021236894.

Diagnostic accuracy of prenatal imaging for the diagnosis of congenital Zika syndrome: Systematic review and meta-analysis.

Objective: The aim of this study was to assess the accuracy of prenatal imaging for the diagnosis of congenital Zika syndrome. Data sources: Medline (via Pubmed), PubMed, Scopus, Web of Science, and Google Scholar from inception to March 2022. Two researchers independently screened study titles and abstracts for eligibility. Study eligibility criteria: Observational studies with Zika virus-infected pregnant women were included. The index tests included ultrasound and/or magnetic resonance imaging. The reference standard included (1) Zika infection-related perinatal death, stillbirth, and neonatal death within the first 48 h of birth, (2) neonatal intensive care unit admission, and (3) clinically defined adverse perinatal outcomes. Synthesis methods: We extracted 2 × 2 contingency tables. Pooled sensitivity and specificity were estimated using the random-effects bivariate model and assessed the summary receiver operating characteristic (ROC) curve. Risk of bias was assessed using QUADAS 2 tool. The certainty of the evidence was evaluated with grading of recommendations. Results: We screened 1,459 references and included 18 studies (2359 pregnant women, 347 fetuses with confirmed Zika virus infection). Twelve studies (67%) were prospective cohorts/case series, and six (37%) were retrospective cohort/case series investigations. Fourteen studies (78%) were performed in endemic regions. Ten studies (56%) used prenatal ultrasound only, six (33%) employed ultrasound and fetal MRI, and two studies (11%) used prenatal ultrasound and postnatal fetal MRI. A total of six studies (ultrasound only) encompassing 780 pregnant women (122 fetuses with confirmed Zika virus infection) reported relevant data for meta-analysis (gestation age at which ultrasound imagining was captured ranged from 16 to 34 weeks). There was large heterogeneity across studies regarding sensitivity (range: 12 to 100%) and specificity (range: 50 to 100%). Under a random-effects model, the summary sensitivity of ultrasound was 82% (95% CI, 19 to 99%), and the summary specificity was 97% (71 to 100%). The area under the ROC curve was 97% (95% CI, 72 to 100%), and the summary diagnostic odds ratio was 140 (95% CI, 3 to 7564, P < 0.001). The overall certainty of the evidence was "very low". Conclusion: Ultrasound may be useful in improving the diagnostic accuracy of Zika virus infection in pregnancy. However, the evidence is still substantially uncertain due to the methodological limitations of the available studies. Larger, properly conducted diagnostic accuracy studies of prenatal imaging for the diagnosis of congenital Zika syndrome are warranted. Systematic review registration: Identifier [CRD42020162914].

Feasibility and efficacy of transcatheter interatrial shunt devices for chronic heart failure: a systematic review and meta-analysis.

AIMS: To assess the feasibility and efficacy of interatrial shunt devices (IASD) for the treatment of chronic heart failure (CHF). METHODS AND RESULTS: MEDLINE and the Cochrane Central Register of Controlled Trials from inception until April 2021 were searched for prospective studies investigating dedicated transcatheter IASD for the treatment of CHF. Standardised mean differences were calculated for the within-group changes before and after implantation of the IASD. The pre-defined primary outcome was change in 6-min walking distance (6MWD) from baseline to 12 months. Other outcomes were change in New York Heart Association class, health-related quality of life (HRQoL), echocardiographic and haemodynamic data, device performance and safety. Subgroup analyses were crude univariable meta-regression analyses. Six studies (five single-arm open-label studies, one sham-controlled trial) were included. In these, 226 patients underwent IASD implantation using four different devices. From baseline to 12 months, 6MWD increased by 28.1 m [95% confidence interval (CI) 10.9-45.3] with no evidence for a difference between devices (P for interaction = 0.66) and patients with left ventricular ejection fraction (LVEF) >40% or ≤40% (P for interaction = 0.21). At 12 months, HRQoL improved by 17.7 points (95% CI 10.8-24.6) and pulmonary capillary wedge pressure (PCWP) decreased by 2.0 mmHg (95% CI -3.6 to -0.4). There were no changes in LVEF or N-terminal pro brain natriuretic peptide during follow-up. Shunt patency ranged from 50% for the first-generation v-Wave to 100% for the Corvia IASD II and the second-generation v-Wave system, respectively. The summary risk of serious adverse device-related effects was 8% (95% CI 1-20) at 12 months. CONCLUSIONS: Interatrial shunt device implantation in CHF is feasible and associates with improved submaximal exercise capacity (measured by 6MWD) and HRQoL, and reductions in PCWP.

Effectiveness and safety of non-steroidal anti-inflammatory drugs and opioid treatment for knee and hip osteoarthritis: network meta-analysis.

OBJECTIVE: To assess the effectiveness and safety of different preparations and doses of non-steroidal anti-inflammatory drugs (NSAIDs), opioids, and paracetamol for knee and hip osteoarthritis pain and physical function to enable effective and safe use of these drugs at their lowest possible dose. DESIGN: Systematic review and network meta-analysis of randomised trials. DATA SOURCES: Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, regulatory agency websites, and ClinicalTrials.gov from inception to 28 June 2021. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised trials published in English with ≥100 patients per group that evaluated NSAIDs, opioids, or paracetamol (acetaminophen) to treat osteoarthritis. OUTCOMES AND MEASURES: The prespecified primary outcome was pain. Physical function and safety outcomes were also assessed. REVIEW METHODS: Two reviewers independently extracted outcomes data and evaluated the risk of bias of included trials. Bayesian random effects models were used for network meta-analysis of all analyses. Effect estimates are comparisons between active treatments and oral placebo. RESULTS: 192 trials comprising 102 829 participants examined 90 different active preparations or doses (68 for NSAIDs, 19 for opioids, and three for paracetamol). Five oral preparations (diclofenac 150 mg/day, etoricoxib 60 and 90 mg/day, and rofecoxib 25 and 50 mg/day) had ≥99% probability of more pronounced treatment effects than the minimal clinically relevant reduction in pain. Topical diclofenac (70-81 and 140-160 mg/day) had ≥92.3% probability, and all opioids had ≤53% probability of more pronounced treatment effects than the minimal clinically relevant reduction in pain. 18.5%, 0%, and 83.3% of the oral NSAIDs, topical NSAIDs, and opioids, respectively, had an increased risk of dropouts due to adverse events. 29.8%, 0%, and 89.5% of oral NSAIDs, topical NSAIDs, and opioids, respectively, had an increased risk of any adverse event. Oxymorphone 80 mg/day had the highest risk of dropouts due to adverse events (51%) and any adverse event (88%). CONCLUSIONS: Etoricoxib 60 mg/day and diclofenac 150 mg/day seem to be the most effective oral NSAIDs for pain and function in patients with osteoarthritis. However, these treatments are probably not appropriate for patients with comorbidities or for long term use because of the slight increase in the risk of adverse events. Additionally, an increased risk of dropping out due to adverse events was found for diclofenac 150 mg/day. Topical diclofenac 70-81 mg/day seems to be effective and generally safer because of reduced systemic exposure and lower dose, and should be considered as first line pharmacological treatment for knee osteoarthritis. The clinical benefit of opioid treatment, regardless of preparation or dose, does not outweigh the harm it might cause in patients with osteoarthritis. SYSTEMATIC REVIEW REGISTRATION: PROSPERO number CRD42020213656.

Sodium-Glucose Cotransporter 2 Inhibitors, All-Cause Mortality, and Cardiovascular Outcomes in Adults with Type 2 Diabetes: A Bayesian Meta-Analysis and Meta-Regression.

Background This study aimed to assess the effectiveness of sodium-glucose cotransporter 2 inhibitors in reducing the incidence of mortality and cardiovascular outcomes in adults with type 2 diabetes. Methods and Results We conducted a Bayesian meta-analysis of randomized controlled trials comparing sodium-glucose cotransporter 2 inhibitors with placebo. We used meta-regression to examine the association between treatment effects and control group event rates as measures of cardiovascular baseline risk. Fifty-three randomized controlled trials were included in our synthesis. Empagliflozin, canagliflozin, and dapagliflozin reduced the incidence of all-cause mortality (empagliflozin: rate ratio [RR], 0.79; 95% credibility interval [CrI], 0.63-0.97; canagliflozin: RR, 0.86; 95% CrI, 0.69-1.05; dapagliflozin: RR, 0.86; 95% CrI, 0.72-1.01) and cardiovascular mortality (empagliflozin: RR, 0.78; 95% CrI, 0.61-1.00; canagliflozin: RR, 0.83; 95% CrI, 0.63-1.05; dapagliflozin: RR, 0.88; 95% CrI, 0.71-1.08), with a 90.1% to 98.7% probability for the true RR to be <1.00 for both outcomes. There was little evidence for ertugliflozin and sotagliflozin versus placebo for reducing all-cause and cardiovascular mortality. There was no association between treatment effects for all-cause and cardiovascular mortality and the control group event rates. There was evidence for a reduction in the incidence of heart failure for empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin versus placebo (probability RR <1.00 of ≥99.3%) and weaker, albeit positive, evidence for acute myocardial infarction for the first 3 agents (probability RR <1.00 of 89.0%-95.2%). There was little evidence of any agent except canagliflozin for reducing the incidence of stroke. Conclusions Empagliflozin, canagliflozin, and dapagliflozin reduced the incidence of all-cause and cardiovascular mortality versus placebo. Treatment effects of sodium-glucose cotransporter 2 inhibitors versus placebo do not vary by baseline risk.

Equivalence and switching between biosimilars and reference molecules in rheumatoid arthritis: protocol for a systematic review and meta-analysis.

BACKGROUND: Biologic drugs such as adalimumab, etanercept, and infliximab represent major first-line and second-line treatments for rheumatoid arthritis (RA) patients. However, their high cost poses a massive burden on healthcare systems worldwide. The expiration of patents for these biologics has driven the production of biosimilar drugs, which are potentially less costly and remarkably similar, albeit not identical to the reference molecules. This paper aims to outline the protocol of a systematic review that will investigate the efficacy and safety profile of biosimilars compared to biologics (objective 1) and the impact of switching between biosimilar drugs and reference biologics on the management of RA patients (objective 2). METHODS: We will investigate the effects of any biosimilars of adalimumab, etanercept, and infliximab on RA patients. We will include randomized controlled trials (RCTs) or quasi-RCTs to assess efficacy and safety outcomes and RCTs with two- or multiple-part designs to evaluate the consequences of switching from reference biologics to biosimilar drugs (and vice-versa). Electronic searches will be performed through MEDLINE (via PubMed), EMBASE, LILACS, and CENTRAL (from inception to April 2021). Two independent reviewers will screen studies, extract data, and evaluate the risk of bias. The latter will be carried out considering specific domains from equivalence trials and switching studies. Random-effects models will be fitted to obtain summary estimates using either relative risk or standardized mean difference as a metric. The primary outcome will be the rate of treatment success according to the American College of Rheumatology 20 (ACR20), and the co-primary outcome will be the Health Assessment Questionnaire-Disability Index (HAQ-DI). Conclusions will be based on equivalence hypothesis testing using predefined margins of equivalence elicited from a group of experienced rheumatologists and prior studies. The overall certainty of the evidence will be assessed based on the GRADE system. DISCUSSION: The present investigation proposes a comprehensive, clinician-oriented approach to assess the equivalence and the impact of switching between biosimilars and biologics on the management of patients with RA. Our results will elucidate the efficacy, safety, immunogenicity of biosimilars, and the clinical consequences of substituting biologics with biosimilars in the management of RA. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019137152 and CRD42019137155.

Clinical Trial Evidence Supporting US Food and Drug Administration Approval of Novel Cancer Therapies Between 2000 and 2016.

Importance: Clinical trial evidence used to support drug approval is typically the only information on benefits and harms that patients and clinicians can use for decision-making when novel cancer therapies become available. Various evaluations have raised concern about the uncertainty surrounding these data, and a systematic investigation of the available information on treatment outcomes for cancer drugs approved by the US Food and Drug Administration (FDA) is warranted. Objective: To describe the clinical trial data available on treatment outcomes at the time of FDA approval of all novel cancer drugs approved for the first time between 2000 and 2016. Design, Setting, and Participants: This comparative effectiveness study analyzed randomized clinical trials and single-arm clinical trials of novel drugs approved for the first time to treat any type of cancer. Approval packages were obtained from drugs@FDA, a publicly available database containing information on drug and biologic products approved for human use in the US. Data from January 2000 to December 2016 were included in this study. Main Outcomes and Measures: Regulatory and clinical trial characteristics were described. For randomized clinical trials, summary treatment outcomes for overall survival, progression-free survival, and tumor response across all therapies were calculated, and median absolute survival increases were estimated. Tumor types and regulatory characteristics were assessed separately. Results: Between 2000 and 2016, 92 novel cancer drugs were approved by the FDA for 100 indications based on data from 127 clinical trials. The 127 clinical trials included a median of 191 participants (interquartile range [IQR], 106-448 participants). Overall, 65 clinical trials (51.2%) were randomized, and 95 clinical trials (74.8%) were open label. Of 100 indications, 44 indications underwent accelerated approval, 42 indications were for hematological cancers, and 58 indications were for solid tumors. Novel drugs had mean hazard ratios of 0.77 (95% CI, 0.73-0.81; I2 = 46%) for overall survival and 0.52 (95% CI, 0.47-0.57; I2 = 88%) for progression-free survival. The median tumor response, expressed as relative risk, was 2.37 (95% CI, 2.00-2.80; I2 = 91%). The median absolute survival benefit was 2.40 months (IQR, 1.25-3.89 months). Conclusions and Relevance: In this study, data available at the time of FDA drug approval indicated that novel cancer therapies were associated with substantial tumor responses but with prolonging median overall survival by only 2.40 months. Approval data from 17 years of clinical trials suggested that patients and clinicians typically had limited information available regarding the benefits of novel cancer treatments at market entry.

Single pivotal trials with few corroborating characteristics were used for FDA approval of cancer therapies.

BACKGROUND AND OBJECTIVE: Novel cancer therapies are often approved with evidence from a single pivotal trial alone. There are concerns about the credibility of this evidence. Higher validity may be indicated by five methodological and statistical characteristics of pivotal trial evidence that were described by the U.S. Food and Drug Administration (FDA), which may corroborate the reliance on a single trial alone for approval decisions. STUDY DESIGN: We did a metaepidemiologic evaluation of all single pivotal trials supporting FDA approval of novel drugs and therapeutic biologicals for cancers between 2000 and 2016. For each trial, we determined the presence of these five characteristics, which we operationalized as (1) large and multicenter trial (≥200 patients; more than one center); consistent treatment benefits across (2) multiple patient subgroups (in view of FDA reviewers), (3) multiple endpoints (including overall survival, progression-free survival, response rate, health related quality of life), and (4) multiple treatment comparisons (e.g., multi-arm studies); and (5) "statistically very persuasive" results (P-values <0.00125). RESULTS: Thirty-five of 100 approvals were based on evidence from a single pivotal trial without any further supporting evidence on beneficial effects (20 randomized controlled trials and 15 single-arm trials). The number increased substantially from one approval before 2006 to 23 after 2011. Sixty-six percent (23/35) of the trials were large multicenter trials (median 301 patients and 63 centers). Consistent effects were demonstrated across subgroups in 66% (23/35), across endpoints in 43% (15/35), and across multiple comparisons in 3% (1/35). Very low P-values for the primary endpoint were seen in 34% (12/35). At least one of the corroborating characteristics was present in 94% (33/35) of all approvals, two or more were present in 54% (19/35), and none had all characteristics. CONCLUSIONS: Single pivotal trials typically have some of the corroborating characteristics, but often only one or two. These characteristics need to be better operationalized, defined, and reported and whether single trials with such characteristics provide similar evidence about benefits and harms of novel treatments as multiple trials would do needs to be shown.

Restrictive compared with liberal red cell transfusion strategies in cardiac surgery: a meta-analysis.

AIMS: To determine whether a restrictive strategy of red blood cell (RBC) transfusion at lower haemoglobin concentrations is inferior to a liberal strategy of RBC transfusion at higher haemoglobin concentrations in patients undergoing cardiac surgery. METHODS AND RESULTS: We conducted a systematic review, meta-analysis, and trial sequential analysis of randomized controlled trials of the effect of restrictive and liberal RBC transfusion strategies on mortality within 30 days of surgery as the primary outcome. Secondary outcomes were those potentially resulting from anaemia-induced tissue hypoxia and transfusion outcomes. We searched the electronic databases MEDLINE, EMBASE, and the Cochrane Library until 17 November 2017. Thirteen trials were included. The risk ratio (RR) of mortality derived from 4545 patients assigned to a restrictive strategy when compared with 4547 transfused according to a liberal strategy was 0.96 [95% confidence interval (CI) 0.76-1.21, I2 = 0]. A restrictive strategy did not have a statistically significant effect on the risk of myocardial infarction (RR 1.01, 95% CI 0.81-1.26; I2=0), stroke (RR 0.93, 95% CI 0.68-1.27, I2 = 0), renal failure (RR 0.96, 95% CI 0.76-1.20, I2 = 0), or infection (RR 1.12, 95% CI 0.98-1.29, I2 = 0). Subgroup analysis of adult and paediatric trials did not show a significant interaction. At approximately 70% of the critical information size, the meta-analysis of mortality crossed the futility boundary for inferiority of the restrictive strategy. CONCLUSION: The current evidence does not support the notion that restrictive RBC transfusion strategies are inferior to liberal RBC strategies in patients undergoing cardiac surgery.