Risk of Venous Thromboembolism by Cancer Type: A Network Meta-Analysis.

Patients with cancer have an increased risk of venous thromboembolism (VTE). Comparing tumor-specific VTE risk is complicated by factors such as surgery, disease stage, and chemotherapy. Network meta-analysis (NMA) using cancer types as network nodes enabled us to estimate VTE rates by leveraging comparisons across cancer types while adjusting for baseline VTE risk in individual studies. This study was conducted to estimate the risk of VTE by cancer type and factors influencing VTE risk. The Embase, MEDLINE, and Cochrane Library repositories were systematically searched to identify clinical trials and observational studies published from 2005 to 2022 that assessed the risk of primary cancer-related VTE among two or more distinct cancer types. Studies with similar cancer populations and study methods reporting VTE occurring within 1 year of diagnosis were included in the NMA. Relative VTE rates across cancer types were estimated with random-effects Bayesian NMAs. Absolute VTE rates were calculated from these estimates using the average VTE incidence in lung cancer (the most frequently reported type) as the "anchor." From 2,603 records reviewed, 30 studies were included in this NMA. The general network described 3,948,752 patients and 18 cancer types: 3.1% experienced VTE within 1 year of diagnosis, with cancer-specific rates ranging from 0.7 to 7.4%. Consistent with existing VTE risk prediction tools, pancreatic cancer was associated with higher-than-average VTE risk. Other cancer types with high VTE risk were brain and ovarian cancers. The relative rankings of VTE risk for certain cancers changed based on disease stage and/or receipt of chemotherapy or surgery.

Indirect comparisons of brigatinib and alectinib for front-line ALK-positive non-small-cell lung cancer.

Aim: To conduct an indirect treatment comparison (ITC) of the relative efficacy of brigatinib and alectinib for progression-free survival in people with tyrosine kinase inhibitor (TKI)-naive ALK-positive non-small-cell lung cancer (NSCLC). Methods: Final aggregate and patient-level data from the ALTA-1L trial comparing brigatinib to crizotinib and published aggregate data from ALEX (comparing alectinib to crizotinib) were contrasted using Bucher ITC and matching-adjusted indirect comparisons (MAICs). Results: No statistically significant differences were identified between brigatinib and alectinib in reducing the risk of disease progression overall and in patients with baseline central nervous system metastases. Conclusion: Brigatinib appeared similar to alectinib in reducing risk of disease progression for people with TKI-naive ALK-positive NSCLC.

Patients with advanced non-small-cell lung cancer (NSCLC) who have a genetic marker called rearrangement in the anaplastic lymphoma kinase, or ALK-positive disease, are treated with targeted medications taken by mouth. Two medications, alectinib and brigatinib, are both considered first-line treatment for these patients but have not been compared head-to-head. Recently, updated clinical trial results were published for these medications. The present study utilized these updated results and advanced statistical tests to indirectly compare the effectiveness of the two treatments to help guide clinical treatment choices. Results showed brigatinib and alectinib have a similar magnitude of effect in decreasing the risk of a patient with ALK-positive NSCLC developing worsening disease.

A comparative evaluation of gemtuzumab ozogamicin + daunorubicin-cytarabine and other treatments for newly diagnosed acute myeloid leukemia.

AIM: To evaluate the comparative efficacy and safety of gemtuzumab ozogamicin + daunorubicin-cytarabine (GO + DA) versus common induction therapies for newly diagnosed acute myeloid leukemia. Materials & methods: A network meta-analysis following a systematic literature review. RESULTS: In base-case analyses, GO + DA was associated with significantly greater overall survival and relapse-free survival versus most comparators, and similar rates of complete remission versus all evaluated comparators. Similar findings were seen in the subgroup analyses. Grade 3+ bleeding and hepatic events were higher with GO + DA versus some comparators, consistent with GO's profile. No differences were found for other evaluated outcomes. CONCLUSION: GO + DA provides significant overall survival and relapse-free survival benefit versus evaluated induction regimens for newly diagnosed acute myeloid leukemia.

Safety and effectiveness of classical and alternative sunitinib dosing schedules for metastatic renal cell carcinoma: a meta-analysis.

The optimal dosing schedule to maintain the effectiveness of sunitinib for metastatic renal cell carcinoma - while reducing toxicity - remains an important clinical question. A meta-analysis of randomized trials and observational studies assessed the relative treatment effects of 4/2, 2/1 and transitional-2/1 schedules on outcomes and adverse events using Bayesian network meta-analysis methods. Treatment with 2/1 reduced the risk of disease progression or death by 25% and had lower odds of hand-and-foot syndrome compared with the 4/2. A numerical but not 'statistical' benefit in progression-free survival was observed with the transitional-2/1 compared with 4/2. Alternative schedules with the 2/1 and transitional-2/1 may be more clinically beneficial in metastatic renal cell carcinoma than the 4/2 schedule.

A systematic review of the association between delayed appropriate therapy and mortality among patients hospitalized with infections due to Klebsiella pneumoniae or Escherichia coli: how long is too long?

BACKGROUND: Temporal relationships between the time to appropriate antibiotic therapy and outcomes are not well described. METHODS: A systematic literature review and meta-analysis was performed to examine this relationship in patients hospitalized with Klebsiella pneumoniae or Escherichia coli infections. RESULTS: Twenty identified studies contained data for patients who received delayed appropriate therapy (DAT) versus appropriate antibiotic therapy for these pathogens. Of the 20 included studies, the majority (19/20) focused on patients with bloodstream infections, and only 1 study evaluated patients with pneumonia. When all DAT results were combined (any delay > 24 h from culture collection or any delay after culture and susceptibility reporting [C& SR]), there was an increased risk of mortality (odds ratio [OR], 1.60 [95% CI, 1.25-2.50]). The risk of mortality was greater when DAT > 48 h from culture collection or DAT > C&SR results were combined (OR, 1.76 [95% CI, 1.27-2.44]). CONCLUSIONS: Our findings suggest there is a need to shift current treatment practices away from antibiotic escalation strategies that contribute to delayed appropriate therapy and toward early, relatively aggressive and comprehensive, antibiotic therapy, especially among patients with bloodstream infections due to K. pneumoniae or E. coli.

The association of lung function and St. George's respiratory questionnaire with exacerbations in COPD: a systematic literature review and regression analysis.

BACKGROUND: This study investigated the relationship between changes in lung function (as measured by forced expiratory volume in one second [FEV1]) and the St. George's Respiratory Questionnaire (SGRQ) and economically significant outcomes of exacerbations and health resource utilization, with an aim to provide insight into whether the effects of COPD treatment on lung function and health status relate to a reduced risk for exacerbations. METHODS: A systematic literature review was conducted in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials to identify randomized controlled trials of adult COPD patients published in English since 2002 in order to relate mean change in FEV1 and SGRQ total score to exacerbations and hospitalizations. These predictor/outcome pairs were analyzed using sample-size weighted regression analyses, which estimated a regression slope relating the two treatment effects, as well as a confidence interval and a test of statistical significance. RESULTS: Sixty-seven trials were included in the analysis. Significant relationships were seen between: FEV1 and any exacerbation (time to first exacerbation or patients with at least one exacerbation, p = 0.001); between FEV1 and moderate-to-severe exacerbations (time to first exacerbation, patients with at least one exacerbation, or annualized rate, p = 0.045); between SGRQ score and any exacerbation (time to first exacerbation or patients with at least one exacerbation, p = 0.0002) and between SGRQ score and moderate-to-severe exacerbations (time to first exacerbation or patients with at least one exacerbation, p = 0.0279; annualized rate, p = 0.0024). Relationships between FEV1 or SGRQ score and annualized exacerbation rate for any exacerbation or hospitalized exacerbations were not significant. CONCLUSIONS: The regression analysis demonstrated a significant association between improvements in FEV1 and SGRQ score and lower risk for COPD exacerbations. Even in cases of non-significant relationships, results were in the expected direction with few exceptions. The results of this analysis offer health care providers and payers a broader picture of the relationship between exacerbations and mean change in FEV1 as well as SGRQ score, and will help inform clinical and formulary-making decisions while stimulating new research questions for future prospective studies.

Nintedanib plus docetaxel as second-line therapy in patients with non-small-cell lung cancer: a network meta-analysis.

BACKGROUND: Nintedanib plus docetaxel has proven an overall survival benefit over docetaxel monotherapy in second-line treatment of non-small-cell lung cancer of adenocarcinoma histology in the LUME-Lung 1 pivotal trial. No published trials have previously compared nintedanib plus docetaxel with agents ­ other than docetaxel ­ that are approved second-line treatments for non-small-cell lung cancer. METHODS: The relative efficacy of nintedanib plus docetaxel versus second-line agents was evaluated by conducting a network meta-analysis of progression-free survival and overall survival. RESULTS: Nine suitable studies were identified. The estimated probability of nintedanib plus docetaxel being the best treatment with regard to overall survival was 70% (versus 16% for pemetrexed, 10% for docetaxel and 3% for erlotinib). Results for progression-free survival were similar. CONCLUSION: In patients with advanced non-small-cell lung cancer of adenocarcinoma histology, results suggest that nintedanib plus docetaxel offers clinical benefit compared with docetaxel alone, when used as second-line treatment, and suggests that this combination may also add clinical benefit compared with erlotinib in this patient group.

Relating relapse and T2 lesion changes to disability progression in multiple sclerosis: a systematic literature review and regression analysis.

BACKGROUND: In the treatment of multiple sclerosis (MS), the most important therapeutic aim of disease-modifying treatments (DMTs) is to prevent or postpone long-term disability. Given the typically slow progression observed in the majority of relapsing-remitting MS (RRMS) patients, the primary endpoint for most randomized clinical trials (RCTs) is a reduction in relapse rate. It is widely assumed that reducing relapse rate will slow disability progression. Similarly, MRI studies suggest that reducing T2 lesions will be associated with slowing long-term disability in MS. The objective of this study was to evaluate the relationship between treatment effects on relapse rates and active T2 lesions to differences in disease progression (as measured by the Expanded Disability Status Scale [EDSS]) in trials evaluating patients with clinically isolated syndrome (CIS), RRMS, and secondary progressive MS (SPMS). METHODS: A systematic literature review was conducted in Medline, Embase, CENTRAL, and PsycINFO to identify randomized trials published in English from January 1, 1993-June 3, 2013 evaluating DMTs in adult MS patients using keywords for CIS, RRMS, and SPMS combined with keywords for relapse and recurrence. Eligible studies were required to report outcomes of relapse and T2 lesion changes or disease progression in CIS, RRMS, or SPMS patients receiving DMTs and have a follow-up duration of at least 22 months. Ultimately, 40 studies satisfied these criteria for inclusion. Regression analyses were conducted on RCTs to relate differences between the effect of treatments on relapse rates and on active T2 lesions to differences between the effects of treatments on disease progression (as measured by EDSS). RESULTS: Regression analysis determined there is a substantive clinically and statistically significant association between concurrent treatment effects in relapse rate and EDSS; p < 0.01. Lower treatment effects were associated with higher relative rates of disease progression. Significant associations between T2 lesion measures and EDSS measures also were found (p < 0.05), with some suggestion that the strength of the association may differ for older versus newer DMTs. CONCLUSIONS: Treatment differences in relapse reduction and T2 lesions are positively related to differences in disease progression over the first two years of treatment.

Efficacy of abobotulinumtoxinA versus onabotulinumtoxinA for the treatment of refractory neurogenic detrusor overactivity: a systematic review and indirect treatment comparison.

AIMS: To compare the efficacy and safety of abobotulinumtoxinA (aboBoNT-A) and onabotulinumtoxinA (onaBoNT-A) for the treatment of refractory neurogenic detrusor overactivity (NDO), using an indirect treatment comparison (ITC). MATERIALS AND METHODS: A systematic literature review was used to identify randomized controlled trials (RCTs) that evaluated botulinum toxin type A for the treatment of refractory NDO. Treatments were compared using a Bucher ITC approach. Efficacy outcomes were reduction in number of weekly urinary incontinence (UI) episodes at 6, 12, and 24 weeks of follow-up. The safety outcome was the proportion of patients with treatment-emergent urinary tract infections (TE-UTIs) during follow-up. Subgroup/sensitivity analyses were performed to investigate the impact of heterogeneity. RESULTS: Fifteen studies of botulinum toxin type A were identified. Among these, onaBoNT-A 200 U was the only botulinum toxin type A considered an appropriate comparator for aboBoNT-A 600 U and 800 U. As such, six RCTs that evaluated onaBoNT-A or aboBoNT-A were included in the ITC. In base-case analyses, there were no statistically significant differences between aboBoNT-A and onaBoNT-A in terms of UI episodes or TE-UTIs. Numerically, the trend favored aboBoNT-A (either dose) for all endpoints and time points. At 12 and 24 weeks, the difference in reduction of UI episodes per week was considered clinically relevant when comparing aboBoNT-A 800 U with onaBoNT-A 200 U, but not when comparing the lower dose of aboBoNT-A (600 U) with onaBoNT-A 200 U. Results from subgroup/sensitivity analyses were consistent with the base case. LIMITATIONS: Heterogeneity across studies was observed; however, strong consistency of trends across analyses suggests the impact of heterogeneity is low. CONCLUSIONS: There may be potential advantages of aboBoNT-A over onaBoNT-A, in terms of UI reduction, in patients with refractory NDO. More confirmatory studies are needed owing to the sparsity of current evidence.

Neurogenic detrusor overactivity (NDO) is a condition in which the bladder muscle wall is overactive and does not function normally. This can lead to urinary incontinence (i.e. accidental leakage of urine). NDO may also cause urinary tract infections and upper urinary tract damage if it is left untreated or if treatment does not work (i.e. refractory NDO).Botulinum toxin is a treatment that relaxes muscles in patients with refractory NDO, so they have less chance of experiencing urinary incontinence. This study used results from clinical trials to compare two types of botulinum toxin ­ abobotulinumtoxinA (aboBoNT-A) and onabotulinumtoxinA (onaBoNT-A) ­ to see if one works better than the other.Clinical trials are experiments to assess how well treatments work by giving different treatments to different patients and observing the results. When there is no clinical trial that compares the two treatments you are interested in, it is possible to combine results from a number of different clinical trials instead. This is known as an indirect treatment comparison.We used an indirect treatment comparison to compare aboBoNT-A and onaBoNT-A for the treatment of refractory NDO. Results showed that aboBoNT-A may be more effective than onaBoNT-A in reducing the frequency of urinary incontinence episodes. On average, patients treated with aboBoNT-A had at least three fewer episodes of urinary incontinence per week than those treated with onaBoNT-A. These results suggest that patients treated with aboBoNT-A could have a better quality of life than those treated with onaBoNT-A.

Risk of Adverse Events Associated with Domperidone and Metoclopramide in Gastroparesis: Systematic Review and Meta-analysis.

BACKGROUND: Dopamine antagonists are the main pharmacological options to treat gastroparesis. The aim of this study was to conduct a systematic literature review (SLR) to evaluate the profile of adverse events (AEs) of dopamine antagonists used in the treatment of children and adults with gastroparesis. METHODS: We searched EMBASE and MEDLINE up to March 25, 2021, for relevant clinical trials and observational studies. We conducted a proportional meta-analysis to estimate the pooled occurrence of AEs (%), with 95% confidence interval (CI), from arm-level data across studies and the comparative occurrence of AEs from placebo-controlled clinical trials (odds ratio [OR] with 95% CI). RESULTS: We identified 28 studies assessing AEs experienced by patients treated for gastroparesis with domperidone and metoclopramide; 22 studies contributed data to the meta-analyses. Cardiovascular, neurological, and endocrine AEs were commonly observed, with point incidences varying from 1 to > 50%. Clinically important AEs, such as QTc prolongation, occurred in 5% of patients treated with domperidone (95% CI: 3.32-8.62). Restlessness, an extrapyramidal AE, occurred in 15% of patients (95% CI: 7.48-26.61) treated with metoclopramide, with a 7-fold increase compared with patients receiving placebo (OR: 7.72; 95% CI: 1.27-47.05). Variation in terminology to describe extrapyramidal events precluded further pooled analyses. Additional meta-analyses were not feasible due to discrepancies in the assessment and reporting of the AEs. CONCLUSIONS: The evidence confirms concerns of cardiovascular, extrapyramidal, and endocrine AEs in patients with gastroparesis treated with domperidone and metoclopramide. Imprecise AE reporting limits firm interpretation and conclusions. REGISTRATION: PROSPERO international prospective register of systematic reviews (registration number: CRD42021248888).

Handling related publications reporting real-world evidence in network meta-analysis: a case study in multiple sclerosis.

Aim: The presence of two or more publications that report on overlapping patient cohorts poses a challenge for quantitatively synthesizing real-world evidence (RWE) studies. Thus, we evaluated eight approaches for handling such related publications in network meta-analyses (NMA) of RWE studies. Methods: Bayesian NMAs were conducted to estimate the annualized relapse rate (ARR) of disease-modifying therapies in multiple sclerosis. The NMA explored the impact of hierarchically selecting one pivotal study from related publications versus including all of them while adjusting for correlations. Results: When selecting one pivotal study from related publications, the ARR ratios were mostly similar regardless of the pivotal study selected. When including all related publications, there were shifts in the point estimates and the statistical significance. Conclusion: An a priori hierarchy should guide the selection among related publications in NMAs of RWE. Sensitivity analyses modifying the hierarchy should be considered for networks with few or small studies.

Comparative Efficacy of Biologic Disease-Modifying Anti-Rheumatic Drugs for Non-Radiographic Axial Spondyloarthritis: A Systematic Literature Review and Bucher Indirect Comparisons.

INTRODUCTION: Biologic disease-modifying anti-rheumatic drugs (bDMARDs), including certolizumab pegol (CZP), are effective treatment options for the management of non-radiographic spondyloarthritis (nr-axSpA). In the absence of head-to-head comparisons in nr-axSpA, we conducted a systematic literature review (SLR) and indirect treatment comparison (ITC) to better understand the comparative efficacy of CZP vs. other bDMARDs. METHODS: Literature searches were conducted in October 2020 in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials to identify randomized controlled trials in patients with nr-axSpA who had failed at least one non-steroidal anti-inflammatory drug and were treated with bDMARDs. Outcomes of interest included the Assessment of Spondyloarthritis international Society (ASAS), Ankylosing Spondylitis Disease Activity Score (ASDAS), Bath Ankylosing Spondylitis Functional Index (BASFI) and Disease Activity Index (BASDAI), and spinal pain score. Comparative efficacy was examined using a series of Bucher ITCs in subgroups matched by prior exposure to bDMARDs, disease duration, baseline C-reactive protein (CRP) levels/magnetic resonance imaging (MRI) status, and timepoints, to ensure comparability between studies. RESULTS: At 12-16 weeks, treatment with CZP was significantly more likely to achieve ASAS20/40 response and ASDAS-inactive disease status vs. etanercept (ETN), ixekizumab (IXE), and secukinumab (SEC). CZP showed statistically significant improvement in BASDAI, BASFI, and total spine pain score over adalimumab (ADA), ETN, and IXE, and in BASFI over SEC. Among patients with objective signs of inflammation (OSI; elevated CRP levels and/or inflammation on MRI at baseline), CZP had a statistically significant advantage over ETN and SEC (with or without loading dose) in achieving ASAS40, whereas the comparisons with other bDMARDs did not show any statistically significant differences. CONCLUSION: In the overall matched population, CZP performed significantly better than most comparators in improving the clinical outcomes. Among patients with OSI, CZP was found to be superior to SEC (in the MRI-/CRP + and MRI + /CRP- subgroups) and ETN (in the MRI + /CRP- subgroup) and it was comparable to golimumab and IXE across the different OSI subgroups.

SABAs as Reliever Medications in Asthma Management: Evidence-Based Science.

The role of as-needed inhaled short-acting ß2-agonists (SABAs) in the management of asthma has become a subject of debate due to differing opinions in the professional community relating to the use of SABAs. In this article, we summarize the current position of SABAs when used as reliever medications and examine the challenges to appropriate use including a critique of the data that have led to the condemnation of SABA used as a reliever. We consider the evidence for the appropriate use of SABA as a reliever together with practical solutions to ensure such use, including identifying patients at risk of misusing their SABA relievers and managing issues of inhaler technique and treatment adherence. We conclude that inhaled corticosteroid (ICS)-based maintenance treatment with SABA used as-needed as a reliever is an effective and safe treatment for patients with asthma, with no scientific evidence of a causal link between SABA use as a reliever and mortality or serious adverse events (including exacerbations). Increased SABA use warns of a deterioration in asthma control, and patients at risk of misusing their ICS and SABA medication should be rapidly identified to ensure they are receiving adequate ICS-based controller therapy. Appropriate use of ICS-based controller therapy and as-needed SABA should be encouraged and promoted with educational activities.

Systematic review and meta-analysis of the efficacy of cardioversion by vernakalant and comparators in patients with atrial fibrillation.

PURPOSE: Rate and rhythm control are two well established treatment objectives for atrial fibrillation (AF) patients. While symptom reduction is a primary treatment goal, therapeutic practice related to cardioversion varies by region and patient, with several precautions associated with the use of current therapies. No comprehensive literature review on the relative efficacy of existing cardioversion approaches compared to newly available therapies has been conducted. METHODS AND RESULTS: A systematic literature review and meta-analysis were undertaken to evaluate the efficacy of pharmacologic therapies in eliciting cardioversion within 2 and 8-24 h among patients with recent-onset, short duration AF. Eligible studies included randomized controlled trials in which cardioversion rates were evaluated in at least 2 treatment groups. Bayesian mixed-treatment comparisons estimated odds ratios (95% credible intervals) for successful cardioversion. Results within 2 h showed vernakalant IV, propafenone IV and flecainide (IV and oral) were more efficacious in pair-wise comparisons to placebo. Results were mixed in analyses comparing efficacy rates between 8 and 24 h. Few adverse events were reported, with the most common being bradycardia and hypotension. CONCLUSIONS: In pair-wise comparisons of active treatment arms to one another, results suggest vernakalant IV, propafenone IV and flecainide appear to be effective in achieving rapid cardioversion in patients with short duration AF compared to other agents. Application of these findings to clinical practice need to account for the variable comorbidity profiles of patients, important determinants in the selection of appropriate therapy for individual patients. Though best practice methods were used, further research comparing treatments through direct head-to-head comparisons may be warranted to confirm these findings and further inform clinical practice.

Meta-Regression of Herpes Zoster Incidence Worldwide.

INTRODUCTION: Many studies have been conducted worldwide to estimate herpes zoster (HZ) incidence rates. We synthesized studies of HZ incidence rates in the general population using meta-analysis models. METHODS: A random effects meta-analysis was conducted to estimate HZ incidence from a published worldwide systematic literature review (SLR) including only individuals aged 50 years and older. Meta-regression was used to explore whether variability in incidence rates could be explained by a combination of study-specific characteristics including age, gender, continent and year of study data. The impact of adding additional covariates-case detection method (general practitioner surveillance, healthcare database, sentinel network, etc.), case definition (medical record-based, self-reported), study design (retrospective passive surveillance, retrospective active surveillance, etc.), incidence type (cumulative incidence/1000 persons or incidence rate/1000 person-years), patient type (outpatients or in- and out-patients) and latitude to the base model-was also assessed. RESULTS: Sixty-one records from 59 studies were included in the analysis: 25, 20, 11 and 5 from Europe, North America, Asia and Oceania, respectively. There was variation in study methodology and outcomes. Heterogeneity of incidence rates was greatest among studies conducted in Asia. Meta-analysis showed that incidence increased with age, was lower in males compared to females, tended to be lower in Europe and North America compared to Asia and Oceania and increased with year of study data. The data-driven meta-regression model included continent, year of study data, gender, age and an age × gender interaction term. The difference in incidence between males and females was greater in younger ages (e.g., 50-59) compared to older age groups (e.g., 80+). None of the additional covariates contributed significantly to the model. CONCLUSION: Incidence rates were shown to vary by age, gender, continent and year of study data.

Comparative efficacy of non-statin lipid-lowering therapies in patients with hypercholesterolemia at increased cardiovascular risk: a network meta-analysis.

OBJECTIVE: Network meta-analysis was used to derive estimates of the relative efficacy of inclisiran, evolocumab, alirocumab, bempedoic acid, and ezetimibe in patients with hypercholesterolemia and/or at increased cardiovascular risk due to elevated low-density lipoprotein cholesterol taking maximum tolerated dose statins. METHODS: Clinical trials published through February 2021 comparing percent change from baseline in low-density lipoprotein cholesterol were identified via a systematic review. Bayesian network meta-analyses were performed for patients with atherosclerotic cardiovascular disease and/or high cardiovascular risk on maximally tolerated statins in the base case, which included 23 trials. RESULTS: Results from the base-case analyses demonstrated that inclisiran, evolocumab, and alirocumab provide superior efficacy over placebo, bempedoic acid, and ezetimibe in terms of reduction in low-density lipoprotein cholesterol. Inclisiran was also comparable to alirocumab (mean difference: 0.78% [95% CrI: -8.35, 9.88]) and evolocumab (8.16%, [95% CrI: -1.82, 18.49]). Findings of a scenario which also included trials conducted in patients with heterozygous familial hypercholesterolemia were consistent with the base case. There was evidence of statistical heterogeneity across the included trials, roughly equivalent to variation of 5-10% change in low-density lipoprotein cholesterol, suggesting that any differences between treatments that were greater than 5-10% are generalizable. CONCLUSIONS: This study provides insight regarding the comparative efficacy of drugs for which no head-to-head trials exist and suggests that inclisiran, alirocumab, and evolocumab are expected to provide similar clinically meaningful improvements in low-density lipoprotein cholesterol in patients with hypercholesterolemia on maximally tolerated statins who are at increased cardiovascular risk.

AbobotulinumtoxinA Doses in Upper and Lower Limb Spasticity: A Systematic Literature Review.

Disabling limb spasticity can result from stroke, traumatic brain injury or other disorders causing upper motor neuron lesions such as multiple sclerosis. Clinical studies have shown that abobotulinumtoxinA (AboBoNT-A) therapy reduces upper and lower limb spasticity in adults. However, physicians may administer potentially inadequate doses, given the lack of consensus on adjusting dose according to muscle volume, the wide dose ranges in the summary of product characteristics or cited in the published literature, and/or the high quantity of toxin available for injection. Against this background, a systematic literature review based on searches of MEDLINE and Embase (via Ovid SP) and three relevant conferences (2018 to 2020) was conducted in November 2020 to examine AboBoNT-A doses given to adults for upper or lower limb muscles affected by spasticity of any etiology in clinical and real-world evidence studies. From the 1781 unique records identified from the electronic databases and conference proceedings screened, 49 unique studies represented across 56 publications (53 full-text articles, 3 conference abstracts) were eligible for inclusion. Evidence from these studies suggested that AboBoNT-A dose given per muscle in clinical practice varies considerably, with only a slight trend toward a relationship between dose and muscle volume. Expert-based consensus is needed to inform recommendations for standardizing AboBoNT-A treatment initiation doses based on muscle volume.

Efficacy of Bimekizumab and Other Biologics in Moderate to Severe Plaque Psoriasis: A Systematic Literature Review and a Network Meta-Analysis.

INTRODUCTION: Biologic treatments are increasingly being used in the management of moderate to severe plaque psoriasis (PSO). Bimekizumab is a selective inhibitor of both interleukin (IL)-17A and IL-17F approved for the treatment of moderate to severe PSO. Although bimekizumab trials provide comparisons to secukinumab, adalimumab and ustekinumab, there are no further head-to-head comparisons of bimekizumab to other biologics. This network meta-analysis (NMA) aimed to compare the short-term efficacy of bimekizumab versus other biologic systemic therapies for moderate to severe PSO. METHODS: A systematic literature review was conducted to identify randomised controlled trials (RCTs) in patients with moderate to severe PSO. MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and the Database of Systematic Reviews and PsycINFO were searched on July 1, 2020. An enhanced multinomial Bayesian NMA model was used to evaluate the comparative efficacy in 50%, 75%, 90% and 100% improvement from baseline Psoriasis Area and Severity Index (PASI 50/75/90/100) at 10-16 weeks. The model was also adjusted for baseline risk, given the variable placebo responses across the trials. RESULTS: Eighty-six RCTs (including 34,476 patients) were included in the NMA. IL-17 and IL-23 inhibitors were the most effective treatments across all PASI levels. At 10-16 weeks, bimekizumab had the highest probability of achieving PASI 75 (92.3%), PASI 90 (84.0%) and PASI 100 (57.8%). Bimekizumab demonstrated statistical superiority over all biologics in achieving PASI 90 and PASI 100 thresholds. For PASI 75, the benefit of bimekizumab was statistically significant compared to all other treatments except risankizumab and ixekizumab. CONCLUSION: This analysis demonstrated that IL-17 and IL-23 inhibitors were highly effective in achieving short-term improvement among patients with moderate to severe PSO. Patients receiving bimekizumab were significantly more likely to achieve PASI 90 or PASI 100 within 10-16 weeks of the first injection than all other biologics.

Real-world evidence comparing oral anticoagulants in non-valvular atrial fibrillation: a systematic review and network meta-analysis.

Aim: To compare real-world effectiveness/safety of non-vitamin K antagonist oral anticoagulants and vitamin K antagonists among patients with non-valvular atrial fibrillation. Materials & methods: A systematic review of electronic databases yielded 7661 citations published from January 2013 to January 2020. Fifty-five studies were included in Bayesian network meta-analyses of hazard ratios. Results & conclusion: In comparison with vitamin K antagonists, apixaban, dabigatran and rivaroxaban were associated with a reduced risk of stroke or systemic embolism, ischemic stroke, intracranial hemorrhage and all-cause mortality. Apixaban, dabigatran and edoxaban, but not rivaroxaban, were associated with a reduced risk of major bleeding. This study confirmed the effectiveness and safety of non-vitamin K antagonist oral anticoagulants for the treatment of non-valvular atrial fibrillation in real-world settings, consistent with clinical trial evidence.

This study aimed to compare real-world effectiveness/safety of non-vitamin K antagonist oral anticoagulants and vitamin K antagonists among patients with non-valvular atrial fibrillation. A systematic review was conducted from January 2013 to January 2020, and a total of 7661 references were assessed for relevance. Fifty-five studies were combined in the analysis; in comparison with vitamin K antagonists, apixaban, dabigatran and rivaroxaban were associated with a reduced risk of stroke or systemic embolism, ischemic stroke, intracranial hemorrhage and all-cause mortality. Apixaban, dabigatran and edoxaban, but not rivaroxaban, were associated with a reduced risk of major bleeding. This study confirmed the effectiveness and safety of non-vitamin K antagonist oral anticoagulants for the treatment of non-valvular atrial fibrillation in real-world settings, consistent with clinical trial evidence.

Cancer risk with tumor necrosis factor alpha (TNF) inhibitors: meta-analysis of randomized controlled trials of adalimumab, etanercept, and infliximab using patient level data.

PURPOSE: Uncertain short- and long-term cancer risks with anti-TNF therapies is a concern, and led to a recent black box warning. This meta-analysis, requested by the European Medicines Agency, aimed at better assessing short-term risks by using meta-analytic techniques based on individual patient data from all corporate-sponsored randomized controlled trials (RCTs) of adalimumab, etanercept, and infliximab. METHODS: All 74 RCTs of TNF inhibitors of at least 4 weeks duration were provided to independent investigators, including case narratives for events occurring between trial start until 30 days after planned end of treatment and indicating a possible cancer. Relative risks were estimated using Bayesian piecewise exponential models. RESULTS: One hundred thirty (0.84%) of 15,418 individuals randomized to anti-TNF therapy were diagnosed with cancer, compared to 48 (0.64%) of 7486 individuals randomized to comparators. The relative risks associated with all anti-TNF were 0.99 (95%CI 0.61-1.68) for cancers excluding non-melanoma skin cancer (NMSC), and 2.02 (95%CI 1.11-3.95) for NMSC. There were indications of differences in the relative risks for the three anti-TNF drugs, but also of differences across the cancer rates in the three comparator arms for adalimumab, etanercept, and infliximab. CONCLUSIONS: Despite a reassuring overall short-term risk, we could neither refute nor verify that individual anti-TNF therapies affect the short-term clinical emergence of cancer. Despite representing the best available evidence, statistical precision, and differences in baseline cancer risk and reporting detail between trials of adilumumab, etanercept, and infliximab hampered distinction of drug-specific from trial effects, illustrating the challenges in safety-assessments using RCT meta-analyses. Long-term risk assessment requires observational studies.