Absence Of Direct Comparisons Research Articles

Network Meta-analysis of Chinese patent medicines in treatment of chronic pulmonary heart disease

Network Meta-analysis was performed to compare the efficacy and safety of Chinese patent medicines in treating chronic pulmonary heart disease. CNKI, VIP, Wanfang, SinoMed, PubMed, Web of Science, EMbase, and Cochrane Library were searched for randomized controlled trial(RCT) of treating chronic pulmonary heart disease with Chinese patent medicines with the time interval from inception to December 2023. The Cochrane risk-of-bias tool was used for quality assessment of the included articles. RevMan 5.4 and Stata 17.0 were employed to establish the risk of bias map and perform the network Meta-analysis, respectively. Ultimately, a total of 95 RCTs involving 8 787 cases and 11 different Chinese patent medicines were included. Network Meta-analysis yielded the following results based on the surface under the cumulative ranking curve(SUCRA).(1)In terms of cardiac function improves clinical total effective rate, SUCRA the top three were Wenxin Granules + conventional western medicine, Tongxinluo Capsules + conventional western medicine, and Qishen Yiqi Dropping Pills + conventional western medicine.(2)For improving forced expiratory volume in the first se-cond(FEV1), SUCRA the top three were Danting Feixin Granules + conventional western medicine, Tongxinluo Capsules + conventional western medicine, and Bufei Huoxue Capsules + conventional western medicine.(3)Regarding increasing the FEV1/forced vital capacity(FVC%) value, SUCRA the top three were Qili Qiangxin Capsules + conventional western medicine, Shexiang Baoxin Pills + conventional western medicine, and Qishen Yiqi Dropping Pills + conventional western medicine.(4)In terms of increasing the partial pressure of oxygen(PaO_2), SUCRA the top three were Qili Qiangxin Capsules + conventional western medicine, Qishen Yiqi Dropping Pills + conventional western medicine, and Shexiang Baoxin Pills + conventional western medicine.(5)In terms of reducing the partial pressure of carbon dioxide(PaCO_2), SUCRA the top three were Tongxinluo Capsules + conventional western medicine, Qishen Yiqi Dropping Pills + conventional western medicine, and Shexiang Baoxin Pills + conventional western medicine.(6)In terms of increasing left ventricular ejection fraction(LVEF), SUCRA the top three were Bufei Huoxue Capsules + conventional western medicine, Qishen Yiqi Dropping Pills + conventional western medicine, and Shexiang Baoxin Pills + conventional western medicine.(7)In terms of decreasing brain natriu-retic peptide(BNP), SUCRA the top three were Compound Danshen Dropping Pills + conventional western medicine, Qili Qiangxin Capsules + conventional western medicine, and Tongxinluo Capsules + conventional western medicine.(8)In terms of improving the hematocrit level, SUCRA the top three were Qishen Yiqi Dropping Pills + conventional western medicine, Compound Danshen Dropping Pills + conventional western medicine, and Tongxinluo Capsules + conventional western medicine. In terms of safety, 26 RCTs reported adverse reactions, which primarily involved the circulatory and digestive systems. The combination of Chinese patent medicines with conventional western medicine has demonstrated enhanced therapeutic effects on chronic pulmonary heart disease. However, due to the varying quality and sample sizes of included studies and the absence of direct comparisons between Chinese patent medicines, the conclusions should be further validated by multicenter studies with larger sample sizes and higher methodological rigor.

First-Line Treatments and Management of Metastatic Renal Cell Carcinoma Patients: An Italian Interdisciplinary Uro-Oncologic Group Algorithm.

The treatment landscape for metastatic renal cell carcinoma (mRCC) has undergone significant transformations in recent years. The introduction of novel combination therapies involving tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors has resulted in improved oncological outcomes compared to traditional TKI monotherapy. In this evolving paradigm, the pivotal role of the multidisciplinary tumor board is underscored, particularly in shaping the therapeutic trajectory for patients eligible for locoregional interventions like cytoreductive nephrectomy and metastasectomy. In cases where systemic treatment is deemed appropriate, the absence of direct comparisons among the various combination therapies complicates the selection of a first-line approach. The clinician is faced with the challenge of making decisions based on patient-specific factors such as performance status, risk classification according to the International Metastatic Renal Cell Carcinoma Database Consortium, comorbidities, and disease characteristics, including the number and location of metastases and tumor histology. Considering these concerns, we propose, as a member of a Tuscany Interdisciplinary Uro-Oncologic Group, an algorithm to streamline the decision-making process for mRCC patients, offering guidance to clinicians in their day-to-day clinical practice.

Comparative overall survival of CDK4/6 inhibitors in combination with endocrine therapy in advanced breast cancer

Individual trials of abemaciclib, palbociclib, and ribociclib show a similar impact on progression-free survival yet differing statistical significance for overall survival (OS). A robust comparative evaluation of OS, safety, and tolerability of the three drugs is warranted. A systematic literature search identified phase 3 randomized clinical trials reporting OS of CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy in ER-positive/HER2-negative advanced breast cancer. Trial-level data on OS and common and serious adverse events (AE) were extracted for each drug. In the absence of direct comparisons, a network meta-analysis was performed to evaluate pairwise comparative efficacy, safety, and tolerability of each of the CDK4/6i. Seven studies comprising of 4415 patients met the inclusion criteria. Median follow-up was 73.3 months (range: 48.7–97.2 months). There were no statistically significant differences in OS between any of the CDK4/6i. Compared to palbociclib, ribociclib and abemaciclib both showed significantly higher GI toxicity (grade 1–2 vomiting OR 1.87 [95% CI 1.37–2.56] and OR 2.27 [95% CI 1.59–3.23] respectively). Compared to palbociclib, abemaciclib was associated with more grade 3–4 diarrhea OR 118.06 [95% CI 7.28–1915.32]. In contrast, palbociclib was associated with significantly more neutropenia than ribociclib and abemaciclib but significantly lower risk of grade 3–4 infections. Abemaciclib had significantly less grade 3–4 transaminitis and grade 3–4 neutropenia than ribociclib. Treatment discontinuation and death due to AE were significantly higher with abemaciclib than palbociclib and ribociclib. There is no statistically significant difference in OS between CDK4/6i despite differing statistical significance levels of individual trials. Real-world data analyses may help to identify if there is a meaningful inter-drug difference in efficacy. Significant differences between CDK4/6i are observed for safety and tolerability outcomes.

The emerging therapies are reshaping the first-line treatment for advanced hepatocellular carcinoma: a systematic review and network meta-analysis.

Given the superior performance of various therapies over sorafenib in advanced hepatocellular carcinoma (HCC) and the absence of direct comparisons, it is crucial to explore the efficacy of these treatments in phase III randomized clinical trials. The goal is to identify which patients are most likely to benefit significantly from these emerging therapies, contributing to more personalized and informed clinical decision-making. Systematic review and network meta-analysis. PubMed, Embase, ClinicalTrials.gov, and international conference databases have been searched from 1 January 2010 to 1 December 2023. After screening, 17 phase III trials encompassing 18 treatments were included. In the whole-population network meta-analysis, the newly first-line tremelimumab plus durvalumab (Tre + Du) was found to be comparable with atezolizumab plus bevacizumab (Atezo + Beva) in providing the best overall survival (OS) benefit [hazard ratio (HR) 1.35, 95% confidence interval (CI): 0.93-1.92]. Concerning OS benefits, sintilimab plus bevacizumab biosimilar (Sint + Beva), camrelizumab plus rivoceranib (Camre + Rivo), and lenvatinib plus pembrolizumab (Lenva + Pemb) appear to exhibit similar effects to Tre + Du and Atezo + Beva. In the context of progression-free survival, Atezo + Beva seemed to outperform Tre + Du (HR: 0.66 CI: 0.49-0.87), while the effects are comparable to Sint + Beva, Camre + Rivo, and Lenva + Pemb. Upon comparison between Asia-Pacific and non-Asia-Pacific cohorts, as well as between hepatitis B virus (HBV)-infected and non-HBV-infected populations, immune checkpoint inhibitor (ICI)-based treatments seemed to exhibit heightened efficacy in the Asia-Pacific group and among individuals with HBV infection. However, combined ICI-based therapies did not show more effectiveness than molecular-targeted drugs in patients without macrovascular invasion and/or extrahepatic spread. As for grades 3-5 adverse events, combined therapies showed comparable safety to sorafenib and lenvatinib. Compared with sorafenib and lenvatinib, combination therapies based on ICIs significantly improved the prognosis of advanced HCC and demonstrated similar safety. At the same time, the optimal treatment approach should be tailored to individual patient characteristics, such as etiology, tumor staging, and serum alpha-fetoprotein levels. With lower incidence rates of treatment-related adverse events and non-inferior efficacy compared to sorafenib, ICI monotherapies should be prioritized as a first-line treatment approach for patients who are not suitable candidates for ICI-combined therapies. PROSPERO, CRD42022288172.

Comparative overall survival of patients in trials of CKD4/6 inhibitors in combination with endocrine therapy in advanced breast cancer.

1056 Background: CDK4/6i and endocrine therapy (ET) are an international gold standard therapy in estrogen receptor (ER) positive and HER2-negative advanced breast cancer (aBC). Individual trials of abemaciclib, palbociclib and ribociclib show similar impact on progression-free survival yet differing statistical significance for OS. A robust comparative evaluation of the efficacy, safety, and tolerability of the three drugs is warranted. Methods: We searched PubMed, ASCO, ESMO and SABCS proceedings to identify phase 3 randomized clinical trials reporting OS of CDK4/6i in combination with ET in ER-positive aBC in first or second line. A network meta-analysis using WinBUGS was performed to evaluate comparative efficacy, based on the ET partner, in the absence of direct comparisons. Trial level data on common and serious adverse events (AE) were extracted for each drug. The odds ratio (OR) for each AE was calculated comparing each CDK4/6i to the respective endocrine therapy backbone (aromatase inhibitor (AI) or fulvestrant) alone. Results: Seven studies comprising 4087 patients met the inclusion criteria. Median follow up was 70.2 months. Four studies paired a CDK4/6i with an AI or tamoxifen, 3 studies were paired with fulvestrant. There were no statistically significant differences in OS between any of the CDK4/6i with any ET backbone. Compared to palbociclib, ribociclib and abemaciclib showed significantly lower grade 1-2 fatigue/asthenia (ribociclib OR 0.69 [95% CI 0.58, 0.83]; abemaciclib OR 0.6 [95% CI 0.49, 0.74]) and abemaciclib showed significantly lower grade 1-2 alopecia (abemaciclib 0.76 [95% CI 0.6, 0.97]). Compared to palbociclib, ribociclib and abemaciclib showed significantly higher GI toxicity (ribociclib any grade vomiting OR 1.71 [95% CI 1.36, 2.15]; abemaciclib any grade vomiting OR 2.1 [95% CI 1.61, 2.62], any grade diarrhea 13.2 [95% CI 10.31, 16.78]). Treatment discontinuation was highest with abemaciclib. Conclusions: In this network meta-analysis, there was no statistically significant difference in OS between CDK4/6i despite differences in individual trials. Real-world data analyses may help to identify if a there is a meaningful inter-drug difference in efficacy. Significant differences between CDK4/6i are observed for safety and tolerability outcomes. [Table: see text]

Application of artificial intelligence for an early comparison of efficacy between new cancer drugs.

The clinical choice among recently approved cancer drugs is burdened by the absence of direct comparisons in terms of efficacy across these new agents. In this article we present the IPDfromKM method, an artificial intelligence (AI) application that aims to facilitate the analyses on efficacy based on secondary data. Seven therapeutic areas were selected in which at least three new agents were recently approved. Kaplan-Meier curves of related clinical trials were digitized. Then, the IPDfromKM method was employed to reconstruct patient-level survival data. This information allowed us to compare selected agents in each therapeutic area and to rank them in terms of efficacy. We identified the most effective treatment in each of the seven selected therapeutic areas. In two cases, immunotherapies, sharing similar mechanisms of actions, were compared highlighting the most effective one. In the remaining cases, our comparison included also the standard of care, which proved to be superior to new agents in patients with osteosarcoma. When randomized clinical trials are not available, indirect comparisons can be a valuable source of information. The experience described herein recommends the use of a new method endowed by two important advantages: remarkable speed of analysis and free access to computational tools. In assessing the place in therapy for newly developed agents, this approach can further promote the application of evidence-based principles.

Pharmacoeconomic aspects of the targeted drugs use in psoriatic arthritis in context of the Russian healthcare system

Objective: to study the clinical and economic aspects of the use of biological disease modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs), Janus kinase inhibitors (JAKi), for the treatment of psoriatic arthritis (PsA).Patients and methods. The study included adult patients (age ≥18) with active PsA, bionaive or previously treated with bDMARDs. Comparison technologies included: adalimumab (ADA), guselcumab, golimumab, ixekizumab, secukinumab (SEC), tofacitinib (TOFA), certolizumab pegol (CZP), upadacitinib (UPA), ustekinumab, etanercept. The efficacy and safety of the bDMARDs and tsDMARDs included in the study were evaluated based on the results of a systematic search and analysis of data on the comparative clinical efficacy and safety of their use. First of all, the results of phase III randomized controlled trials of drugs that are used to treat active PsA in adult patients as active treatment compared with placebo or with another active drug, or systematic reviews with meta-analysis (MA) and network MA based on them, were considered. The period from the 12th to the 24th week after the start of therapy was taken as the time point for assessing the clinical efficacy of drugs, and the frequency of achieving the ACR20/50/70 criteria was taken as the performance indicator. Cost per responder (СpR), calculated on the basis of the cost of PsA therapy by the time a response is achieved according to the ACR20/50/70 criteria, was used as a criterion for clinical and economic efficiency and to analyze the impact on the budget.Results and discussion. The data of the performed MA indicate a significantly greater effectiveness of the analyzed bDMARDs and JAKi compared to placebo in terms of the frequency of achieving a response according to the ACR20/50/70 criteria both in the group of bionaive patients and in the group of PsA patients, previously treated with bDMARDs. There were no differences between the drugs included in the study in terms of the frequency of achieving ACR20/50/70 response during the treatment of PsA. According to the study, by the 24th week of therapy, ADA, UPA and SEC 150 mg were characterized by the lowest costs to achieve the ACR20/50/70 criteria in bionaive patients and ACR20/50 in patients who were previously treated with bDMARDs. A low CpR value was determined in cases of ADA 40 mg and UPA 15 mg use for the treatment of patients with PsA who had not previously received bDMARDs. Among interleukin inhibitors, the lowest CpR value was registered for SEC 150 mg. By the 12th week of treatment, the CpR of TOFA 5 mg was higher compared to that of UPA 15 mg. CpR indicators for achieving ACR20/50 criteria in patients who were previously treated with bDMARDs were lower in UPA 15 mg and CZP compared to other drugs.Conclusion. The results of the study demonstrate the clinical and economic feasibility of introducing different bDMARDs and JAKi into real practice of PsA treatment. At the same time, the use of original drugs is not always associated with significant costs per 1 patient who responded to treatment. In the absence of direct comparisons, real clinical practice provides important information about the relative efficacy and safety of alternative therapies in the management of PsA patients.

Intrusive memories following disaster: Relationship with peritraumatic responses and later affect.

Cognitive theories of posttraumatic stress disorder (PTSD) suggest that intrusive memories result from disrupted information processing during traumatic memory encoding and are characterized by fear, helplessness, and horror at recall. Existing naturalistic studies are limited by the absence of direct comparisons between specific moments that do and do not correspond to intrusive memories. We tested predictions from cognitive theories of PTSD by comparing peritraumatic responses during moments experienced as intrusive memories versus distressing moments of the same traumatic event from the same individual not experienced as intrusive memories. A further comparison was with highly distressing moments experienced during the same event by individuals without intrusive memories. We utilized a psychometrically generated model to distinguish different peritraumatic reactions. Moments experienced as intrusive memories were characterized by higher peritraumatic distress, immobility, cognitive overload, and somatic dissociation when compared both to distressing moments from the same individual that did not intrude and to the most distressing memories of individuals without intrusions. Exploratory analyses indicated that at recall, intrusive memories were characterized by higher levels of primary traumatic emotions such as anxiety, fear, and helplessness in comparison with nonintrusive memories. Findings from this novel naturalistic design support predictions made by cognitive theories of PTSD and have implications for research and preventative interventions targeting intrusive memories. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

PRO92 Assessing the Acceptance of Population Adjustment Methods in Orphan Drug HTA Submissions in the EU5 and the Nordics

Orphan drugs are often approved based on single arms trials, resulting in challenges when estimating relative clinical efficacy. A traditional approach is to use naïve, unadjusted, indirect comparisons, to analyze the comparative effectiveness of interventions. Matching-adjusted indirect comparison (MAIC) is a relatively recently developed tool considered a better alternative to traditional unadjusted ITCs, as it allows for comparisons of different treatment outcomes in a population-matched setting. The aim of this research was to assess the use and acceptance of MAICs in reimbursement desicions of orphan drugs in the EU5 and the Nordics. Orphan drugs with a market authorization in 2017 onwards were included in this research targeting the EU5 countries and the Nordics. The reimbursement assessments reports of the identified orphan drugs were subsequently reviewed. Search was conducted for more than 33 orphan drugs from each of the reimbursement agencies websites. Only a small proportion of the submissions during the specified time period included a MAIC and in some cases the analysis was presented alongside a head-to-head analysis. MAIC is thus not commonly used and is not always accepted by HTA bodies (e.g. IQWiG). The main challenges associated with its use relate to how comprehensive the variables included should be, as well as to the precision of the results. Nevertheless, given the current landscape on drug development and the increase in single-arm trials, ITCs and MAIC will become more common, and as such, their advantages and challenges should be clearly stated and acknowledged. The current study found that even though it is a new method, the use of population adjusted methods in the absence of direct comparisons between treatments has been increasing across different therapeutic areas, and so has its acceptability by HTA bodies, although questions about its validity and correct application remain.

PGI27 Systematic Review and Network Meta-Analysis: Topical Corticosteroids for Inducing Histological Remission in Eosinophilic Oesophagitis

Topical corticosteroids, comprised mainly of fluticasone multi-dose inhaler content swallowed or budesonide viscous solution (BVS), are the foundation of treatment for eosinophilic oesophagitis (EoE). Recently, a budesonide orodispersible tablet (BOT) has been approved for the treatment of EoE. Given the absence of direct comparisons, we evaluated the relative efficacy of BOT with other topical corticosteroid formulations for inducing histological remission in patients with EoE by a network meta-analysis (NMA). A systematic literature review was performed using MEDLINE and Embase up to August 1, 2019. Eligible studies comprised randomised controlled trials (RCTs) which evaluated adult patients with a diagnosis of active EoE treated with a topical corticosteroid in comparison to placebo or another topical corticosteroid. The outcome of interest was the proportion of patients achieving induction of histological remission defined as a peak oesophageal eosinophil count of <5 eosinophils/high-power field. Direct comparisons were made using the Mantel-Haenszel method and an NMA was performed using a fixed effects Bayesian framework with Markov Chain Monte Carlo simulations. A total of 6 trials (n=447 patients) were included in the quantitative summary. The NMA determined that BOT was associated with a higher odds of histological remission compared to BVS (odds ratio [OR]=4.9 [95% credible interval [CrI]=1.4, 19.1]), fluticasone (7.4 [1.7, 34.5]), nebulised swallowed budesonide (NSB) (25.0 [2.9, 247.2]) and placebo (387.6 [97.5, 2,275.6]). Similar findings were observed for direct comparisons. This NMA of RCTs suggest that BOT is significantly more likely to achieve histological remission in adult patients with EoE compared to BVS, fluticasone, and NSB.

Understanding the challenge of comparative effectiveness research in focal epilepsy: A review of network meta‐analyses and real‐world evidence on antiepileptic drugs

ObjectiveHead‐to‐head randomized controlled trials (RCTs) are the gold standard for assessing comparative treatment effects. In the absence of direct comparisons between all possible antiepileptic drugs (AEDs), however, clinical decision‐making in focal (partial onset) epilepsy relies on alternative evidence borne from indirect comparisons including network meta‐analyses (NMAs) and from real‐world evidence (RWE) studies. We review NMAs and observational RWE studies comparing AEDs in the adjunctive setting to compare the robustness of these methods and to formulate recommendations for future evidence development.MethodsA literature review identified NMAs and RWE studies comparing AEDs for the adjunctive treatment of focal seizures published between January 2008 and October 2018. NMAs were evaluated for robustness using a framework based on guidelines from the National Institute for Health and Care Excellence Decision Support Unit and the International Society for Pharmacoeconomics and Outcomes Research. RWE studies were evaluated using the GRACE checklist.ResultsFrom a total of 1993 records, 11 NMAs and six RWE studies were eligible. Key limitations identified in the NMAs include nonsystematic selection of RCTs, unexplored heterogeneity between included RCTs in terms of study and patient characteristics, and selection of AEDs and AED doses or dosing strategies that are not reflective of clinical practice. The main limitations of RWE studies concern sample size, design, and analysis methods. Approximately 90% of comparisons between individual AEDs were nonsignificant in the NMAs. None of the RWE studies adjusted for baseline differences between comparator groups; therefore, they lack the validity to make comparative conclusions.SignificanceCurrent NMAs and RWE studies provide only nominal comparative evidence for AED treatments in focal epilepsy, and should be used with caution for decision‐making due to their methodological limitations. To overcome these hurdles, adherence to methodological guidelines and concerted efforts to collect relevant outcome data in the real world are needed.

Peculiarities of the treatment of venous thromboembolism with direct oral anticoagulants in challenging patients: senile age, renal failure, fragility

The paper is a narrative review of the literature on the use of direct oral anticoagulants (DOACs) for the VTE treatment in challenging patients: senile age (≥75 years), impaired renal function (estimated glomerular filtration rate ≤50 ml/min), fragility (one of the previous characteristics and/or bodyweight ≤50 kg). The paper discusses the studies of EINSTEIN DVT and PE (rivaroxaban), AMPLIFY (apixaban), HOKUSAI-VTE (edoxaban), RE-COVER I and II (dabigatran) in the focus of the secondary analysis in the pre-specified patient's subgroups, as well as their pooled analyzes and meta-analyzes. Based on the results of this review, it was concluded that in a subgroup of senile age patients, dabigatran increases the risk of major bleeding by 4.8 times and has no advantages over vitamin K antagonists (VKA); rivaroxaban and apixaban retain superiority over VKA on the safety outcomes and reduce the risk of major bleeding by 73% and 77%. In the subgroup of patients with impaired renal function, the use of apixaban and dabigatran is associated with an increase in the risk of major bleeding by 6.5 and 7.3 times, and these DOACs do not have advantages over VKA; rivaroxaban retains its superiority over VKA and reduces the risk of major bleeding by 78%. For fragile patients, a secondary analysis is available only for rivaroxaban, which remains superior to VKA on safety endpoints and reduces the risk of major bleeding by 73%. In the absence of direct comparisons between the available DOACs, the presented data can be used as a rational approach for the choice of appropriate treatment for VTE in challenging patients.

An indirect treatment comparison of the efficacy of patisiran and tafamidis for the treatment of hereditary transthyretin-mediated amyloidosis with polyneuropathy

ABSTRACTBackground: Hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) is a progressive, life-threatening disease. Until recently, tafamidis was the only approved pharmacotherapy. Patisiran significantly improved polyneuropathy and quality of life (QoL) in the phase III APOLLO trial. In the absence of direct comparisons, this analysis aimed to evaluate the comparative efficacy of tafamidis and patisiran in hATTR amyloidosis with polyneuropathy.Research design and methods: Randomized controlled trial evidence for tafamidis was identified by systematic literature review. Indirect treatment comparisons were performed using the standard pairwise Bucher method for endpoints used in both APOLLO and the tafamidis Fx-005 trial: change from baseline in Neuropathy Impairment Score-lower limbs (NIS-LL), Norfolk QoL-Diabetic Neuropathy questionnaire (QoL-DN), NIS-LL response, and mBMI vs. placebo. Inter-trial population differences were assessed by sensitivity analysis.Results: The base-case analysis (FAP Stage 1 APOLLO patients vs. intent-to-treat Fx-005 population) suggested patisiran had a greater treatment effect vs. tafamidis for all endpoints, with significant improvements in mean change in NIS-LL (–5.49) and QoL-DN (–13.10) from baseline to Month 18. Similar trends were observed in all sensitivity analyses.Conclusions: In the absence of direct comparisons, this analysis suggests patisiran has a greater treatment effect than tafamidis in patients with hATTR amyloidosis with polyneuropathy.

Comparative Effectiveness of Adalimumab versus Secukinumab for the Treatment of Psoriatic Arthritis: A Matching-Adjusted Indirect Comparison.

IntroductionThe Phase III FUTURE I and II trials demonstrated the clinical efficacy of secukinumab in active psoriatic arthritis (PsA). In the absence of head-to-head trials, this study compared the clinical efficacy and cost effectiveness of adalimumab 40 mg versus secukinumab 150 and 300 mg for the treatment of active PsA.MethodsA matching-adjusted indirect comparison was conducted using individual patient data from the ADEPT trial of adalimumab and published data from FUTURE I and II. To adjust for the cross-trial differences, individual patients in ADEPT were re-weighted so that the mean baseline characteristics (including age, weight, gender, race, baseline methotrexate use, psoriasis ≥3% body surface area, baseline PASI score, presence of dactylitis and enthesitis, and HAQ-DI) matched those in the FUTURE trials. Response rates relative to placebo and incremental costs per responder (CPR) over 24 weeks for ACR 20/50/70 and PASI 75/90 were compared between adalimumab and secukinumab 150 and 300 mg from the German social health insurance (SHI) perspective.ResultsAfter matching, mean baseline characteristics were balanced across the ADEPT and the FUTURE I and II populations. The mean differences between adalimumab and secukinumab 150 mg in relative ACR 20/50/70 and PASI 75/90 response rates were 9.5, 3.0, 6.0, 13.1, and 6.7%, respectively (p > 0.05 for all comparisons). Post-match relative ACR 20/50/70 and PASI 75 to placebo were also higher with adalimumab compared to secukinumab 300 mg. Adalimumab had lower incremental costs per responder over 24 weeks for all outcomes compared with secukinumab 150 and 300 mg.ConclusionsIn the absence of direct comparisons between adalimumab and secukinumab, this study provides valuable and reliable evidence for physicians and payers. After adjusting for cross-trial differences in baseline characteristics, adalimumab was associated with higher relative ACR and PASI rates and lower incremental CPRs compared with secukinumab 150 mg or 300 mg at week 24 among patients with active PsA.FundingAbbVie.

Treatment of idiopathic pulmonary fibrosis: a network meta-analysis.

BackgroundIdiopathic pulmonary fibrosis (IPF) is an interstitial lung disease associated with high morbidity and mortality. Effective treatments for IPF are limited. Several recent studies have investigated novel therapeutic agents for IPF, but very few have addressed their comparative benefits and harms.MethodsWe performed a Bayesian network meta-analysis (NMA) to assess the effects of different treatments for IPF on mortality and serious adverse events (SAEs). We searched MEDLINE and EMBASE for randomized controlled trials (RCTs) up to August 2015. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach served to assess the certainty in the evidence of direct and indirect estimates. We calculated the surface under the cumulative ranking curve (SUCRA) for each treatment.We included parallel group RCTs, including factorial designs, but excluded quasi-randomized and cross-over trials. Studies were only included if they involved adult (≥18 years of age) patients with IPF as defined by the 2011 criteria and examined one of the 10 interventions of interest (ambrisentan, bosentan, imatinib, macitentan, N-acetylcysteine, nintedanib, pirfenidone, sildenafil, prednisone/azathioprine/N-acetylcysteine triple therapy, and vitamin K antagonist).ResultsA total of 19 RCTs (5,694 patients) comparing 10 different interventions with placebo and an average follow-up period of 1 year fulfilled the inclusion criteria. SUCRA analysis suggests nintedanib, pirfenidone, and sildenafil are the three treatments with the highest probability of reducing mortality in IPF. Indirect comparison showed no significant difference in mortality between pirfenidone and nintedanib (NMA OR, 1.05; 95 % CrI, 0.45–2.78, moderate certainty of evidence), pirenidone and sildenafil (NMA OR, 2.26; 95 % CrI, 0.44–13.17, low certainty of evidence), or nintedanib and sildenafil (NMA OR 2.40; 95 % CrI, 0.47–14.66, low certainty of evidence). Sildenafil, pirfenidone, and nintedanib were ranked second, fourth, and sixth out of 10 for SAEs.ConclusionIn the absence of direct comparisons between treatment interventions, this NMA suggests that treatment with nintedanib, pirfenidone, and sildenafil extends survival in patients with IPF. The SAEs of these agents are similar to the other interventions and include mostly dermatologic and gastrointestinal manifestations. Head-to-head comparisons need to confirm these findings.

Sobre la equivalencia terapéutica y los nuevos anticoagulantes orales

In an attempt to minimize the economic impact due to the incorporation of innovative drugs, health authorities have promoted and supported the evaluation and market positioning of drugs, as equivalent therapeutic alternatives. This issue has recently gained importance, possibly due to the current economic crisis. The equivalent therapeutic alternatives are justified by the need to compete on price, and by the authorities recommendation to establish therapeutic equivalence, price and financing of medicinal products at the same time. The establishment of the new oral anticoagulants and the equivalent therapeutic alternatives is a problematic issue if it is based on the absence of direct comparisons between different drugs and the questionable methodology used in the current indirect comparisons. Currently, it is difficult to determine when a new oral anticoagulant is more recommendable than others, but efforts are being made in order to propose alternatives for the decision based on patient characteristics.

Net Clinical Benefit of Non-vitamin K Antagonist Oral Anticoagulants Versus Warfarin in Phase III Atrial Fibrillation Trials

ObjectivesThe evaluation of the “net clinical benefit” allows an integrated assessment of both the anti-ischemic and the prohemorrhagic effects of non-vitamin K antagonist oral anticoagulants compared with warfarin, and—in the absence of direct comparisons—may inform clinical decisions. We estimated the net clinical benefit of non-vitamin K antagonist oral anticoagulants versus warfarin across the 4 phase III clinical trials performed in patients with atrial fibrillation. MethodsWe considered various composites of the main ischemic and hemorrhagic events, estimating the rate ratio of all treatment groups versus warfarin for each composite outcome. Because the clinical relevance of the various ischemic or hemorrhagic events is not identical, we then attributed to each of them a weight, according to its impact on death, as derived from previous studies. We evaluated a weighed net clinical benefit of each non-vitamin K antagonist oral anticoagulant compared with warfarin in the 4 trials. ResultsThe composite outcome of ischemic + hemorrhagic stroke was reduced by dabigatran 150 mg and apixaban. The composite of disabling stroke + life-threatening bleeding was reduced by all non–vitamin K antagonist oral anticoagulants. The composite of ischemic stroke + systemic embolism + myocardial infarction + hemorrhagic stroke + major bleeding was reduced by apixaban and edoxaban at both doses. By attributing weights to these events according to their impact on mortality, all non-vitamin K antagonist oral anticoagulants featured a favorable net clinical benefit compared with warfarin, albeit to a quantitatively different extent. ConclusionsThe choice of the proper antithrombotic treatment in patients with atrial fibrillation has to consider the net clinical benefit of each drug. However, all non-vitamin K antagonist oral anticoagulants have a better efficacy/safety profile than warfarin in patients with atrial fibrillation.

Improving the care of patients who have treatment-resistant depression: the promise of the PCORnet Mood Network.

In this issue of JCP, Zhou and colleagues review and integrate placebo-controlled efficacy trials of medications for treatment-resistant depression (TRD) to compare efficacy in a meta-analysis. They conclude that, among 11 augmentation options for TRD, aripiprazole and quetiapine have the most robust evidence for efficacy, with the caveats that these treatments carry substantial risks of adverse events and no long-term data are available. In the absence of direct comparisons, this exercise highlights the formidable challenges that clinicians face when making decisions.

Photo(chemo)therapy in the management of atopic dermatitis: an updated systematic review with implications for practice and research

Photo(chemo)therapy is a common treatment modality in patients with atopic dermatitis (AD), but evidence on its effectiveness has not been recently systematically reviewed. To evaluate the effect of treatment with photo(chemo)therapy in patients with AD and to make treatment recommendations on basis of the evidence. We performed an electronic literature search in MEDLINE (OVID), EMBASE (OVID), the Cochrane Central Register of Controlled Trials (CENTRAL), Global Resource of EczemA Trials (GREAT) and prospective trial registers, complemented with a search of PubMed to find recent studies not yet available in OVID MEDLINE. All randomized controlled trials (RCTs) on phototherapy for the treatment of AD were considered for data extraction. Nineteen studies were included (905 participants). The identified RCTs were generally clinically and qualitatively heterogeneous. Therefore a formal meta-analysis was not feasible. Conclusions must be drawn carefully because of small sample sizes, varying study quality and sometimes the absence of direct comparisons, but on the basis of the included evidence, ultraviolet (UV) A1 and narrowband (NB)-UVB appeared the most effective treatment modalities for the reduction of clinical signs and symptoms. No difference between high-dose UVA1 and medium-dose UVA1 was seen. UVAB was shown to be more effective than UVA and broadband-UVB for the improvement of clinical symptoms, but not compared with UVA1. Other effective treatment options include full-spectrum light, psoralen plus UVA and balneophototherapy. No serious side-effects were reported. Phototherapy can be a valid therapeutic option for patients with AD. Based on the results of this review, preference is given to UVA1 and NB-UVB. Further well-designed, adequately powered RCTs are required.

Is surgery now the primary treatment for stress urinary incontinence in women?

Stress urinary incontinence, defined as the involuntary loss of urine during physical exertion, coughing or sneezing, is a common condition in women and is associated with an impaired quality of life. There are several treatment options, such as pelvic floor muscle training (PFMT) and synthetic midurethral sling (SMUS) operations. Until recently, the sequence of these two modalities (both tested in numerous randomized trials) was clear as, in the absence of direct comparisons, it seemed prudent to put weight on the conservative option as the primary treatment given its almost complete lack of risks. In the light of a newly published head-to-head randomized trial, the evidence for surgery versus physiotherapy as the primary treatment for stress urinary incontinence is reviewed, the data summarized and conclusions drawn for the future management of stress-incontinent women.