Individual Patient Data Network Meta-analysis Research Articles

Role of chemotherapy in patients with nasopharynx carcinoma treated with radiotherapy (MAC-NPC): an updated individual patient data network meta-analysis.

The meta-analysis of chemotherapy for nasopharynx carcinoma (MAC-NPC) collaborative group previously showed that the addition of adjuvant chemotherapy to concomitant chemoradiotherapy had the highest survival benefit of the studied treatment regimens in nasopharyngeal carcinoma. Due to the publication of new trials on induction chemotherapy, we updated the network meta-analysis. For this individual patient data network meta-analysis, trials of radiotherapy with or without chemotherapy in patients with non-metastatic nasopharyngeal carcinoma that completed accrual before Dec 31, 2016, were identified and updated individual patient data were obtained. Both general databases (eg, PubMed and Web of Science) and Chinese medical literature databases were searched. Overall survival was the primary endpoint. A frequentist network meta-analysis approach with a two-step random effect stratified by trial based on hazard ratio Peto estimator was used. Global Cochran Q statistic was used to assess homogeneity and consistency, and p score to rank treatments, with higher scores indicating higher benefit therapies. Treatments were grouped into the following categories: radiotherapy alone, induction chemotherapy followed by radiotherapy, induction chemotherapy without taxanes followed by chemoradiotherapy, induction chemotherapy with taxanes followed by chemoradiotherapy, chemoradiotherapy, chemoradiotherapy followed by adjuvant chemotherapy, and radiotherapy followed by adjuvant chemotherapy. This study is registered with PROSPERO, CRD42016042524. The network comprised 28 trials and included 8214 patients (6133 [74·7%] were men, 2073 [25·2%] were women, and eight [0·1%] had missing data) enrolled between Jan 1, 1988, and Dec 31, 2016. Median follow-up was 7·6 years (IQR 6·2-13·3). There was no evidence of heterogeneity (p=0·18), and inconsistency was borderline (p=0·10). The three treatments with the highest benefit for overall survival were induction chemotherapy with taxanes followed by chemoradiotherapy (hazard ratio 0·75; 95% CI 0·59-0·96; p score 92%), induction chemotherapy without taxanes followed by chemoradiotherapy (0·81; 0·69-0·95; p score 87%), and chemoradiotherapy followed by adjuvant chemotherapy (0·88; 0·75-1·04; p score 72%), compared with concomitant chemoradiotherapy (p score 46%). The inclusion of new trials modified the conclusion of the previous network meta-analysis. In this updated network meta-analysis, the addition of either induction chemotherapy or adjuvant chemotherapy to chemoradiotherapy improved overall survival over chemoradiotherapy alone in nasopharyngeal carcinoma. Institut National du Cancer and Ligue Nationale Contre le Cancer.

Completion, safety, and efficacy of tuberculosis preventive treatment regimens containing rifampicin or rifapentine: an individual patient data network meta-analysis

3 months of weekly rifapentine plus isoniazid (3HP) and 4 months of daily rifampicin (4R) are recommended for tuberculosis preventive treatment. As these regimens have not been compared directly, we used individual patient data and network meta-analysis methods to compare completion, safety, and efficacy between 3HP and 4R. We conducted a network meta-analysis of individual patient data by searching PubMed for randomised controlled trials (RCTs) published between Jan 1, 2000, and Mar 1, 2019. Eligible studies compared 3HP or 4R to 6 months or 9 months of isoniazid and reported treatment completion, adverse events, or incidence of tuberculosis disease. Deidentified individual patient data from eligible studies were provided by study investigators and outcomes were harmonised. Methods for network meta-analysis were used to generate indirect adjusted risk ratios (aRRs) and risk differences (aRDs) with their 95% CIs. We included 17 572 participants from 14 countries in six trials. In the network meta-analysis, treatment completion was higher for people on 3HP than for those on 4R (aRR 1·06 [95% CI 1·02-1·10]; aRD 0·05 [95% CI 0·02-0·07]). For treatment-related adverse events leading to drug discontinuation, risks were higher for 3HP than for 4R for adverse events of any severity (aRR 2·86 [2·12-4·21]; aRD 0·03 [0·02-0·05]) and for grade 3-4 adverse events (aRR 3·46 [2·09-6·17]; aRD 0·02 [0·01-0·03]). Similar increased risks with 3HP were observed with other definitions of adverse events and were consistent across age groups. No difference in the incidence of tuberculosis disease between 3HP and 4R was found. In the absence of RCTs, our individual patient data network meta-analysis indicates that 3HP provided an increase in treatment completion over 4R, but was associated with a higher risk of adverse events. Although findings should be confirmed, the trade-off between completion and safety must be considered when selecting a regimen for tuberculosis preventive treatment. None. For the French and Spanish translations of the abstract see Supplementary Materials section.

Comparative efficacy and complications of long-acting and intermediate-acting insulin regimens for adults with type 1 diabetes: an individual patient data network meta-analysis

ObjectiveTo examine the comparative efficacy and complications of long-acting and intermediate-acting insulin for different patient characteristics for type 1 diabetes mellitus (T1DM).DesignSystematic review and individual patient data (IPD) network meta-analysis...

High-dose Radiotherapy or Androgen Deprivation Therapy (HEAT) as Treatment Intensification for Localized Prostate Cancer: An Individual Patient–data Network Meta-analysis from the MARCAP Consortium

BackgroundThe relative benefits of radiotherapy (RT) dose escalation and the addition of short-term or long-term androgen deprivation therapy (STADT or LTADT) in the treatment of prostate cancer are unknown. ObjectiveTo perform a network meta-analysis (NMA) of relevant randomized trials to compare the relative benefits of RT dose escalation ± STADT or LTADT. Design, setting, and participantsAn NMA of individual patient data from 13 multicenter randomized trials was carried out for a total of 11862 patients. Patients received one of the six permutations of low-dose RT (64 to <74 Gy) ± STADT or LTADT, high-dose RT (≥74 Gy), or high-dose RT ± STADT or LTADT. Outcome measurements and statistical analysesMetastasis-free survival (MFS) was the primary endpoint. Frequentist and Bayesian NMAs were performed to rank the various treatment strategies by MFS and biochemical recurrence–free survival (BCRFS). Results and limitationsMedian follow-up was 8.8 yr (interquartile range 5.7–11.5). The greatest relative improvement in outcomes was seen for addition of LTADT, irrespective of RT dose, followed by addition of STADT, irrespective of RT dose. RT dose escalation did not improve MFS either in the absence of ADT (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.80–1.18) or with STADT (HR 0.99, 95% CI 0.8–1.23) or LTADT (HR 0.94, 95% CI 0.65–1.37). According to P-score ranking and rankogram analysis, high-dose RT + LTADT was the optimal treatment strategy for both BCRFS and longer-term outcomes. ConclusionsConventionally escalated RT up to 79.2 Gy, alone or in the presence of ADT, does not improve MFS, while addition of STADT or LTADT to RT alone, regardless of RT dose, consistently improves MFS. RT dose escalation does provide a high probability of improving BCRFS and, provided it can be delivered without compromising quality of life, may represent the optimal treatment strategy when used in conjunction with ADT. Patient summaryUsing a higher radiotherapy dose when treating prostate cancer does not reduce the chance of developing metastases or death, but it does reduce the chance of having a rise in prostate-specific antigen (PSA) signifying recurrence of cancer. Androgen deprivation therapy improves all outcomes. A safe increase in radiotherapy dose in conjunction with androgen deprivation therapy may be the optimal treatment.

Comparative safety and efficacy of cognitive enhancers for Alzheimer’s dementia: a systematic review with individual patient data network meta-analysis

ObjectiveTo examine the comparative efficacy and safety of cognitive enhancers by patient characteristics for managing Alzheimer’s dementia (AD).DesignSystematic review and individual patient data (IPD) network meta-analysis (NMA) based on our...

Penalized Poisson model for network meta-analysis of individual patient time-to-event data.

Network meta-analysis (NMA) allows the combination of direct and indirect evidence from a set of randomized clinical trials. Performing NMA using individual patient data (IPD) is considered as a "gold standard" approach as it provides several advantages over NMA based on aggregate data. For example, it allows to perform advanced modeling of covariates or covariate-treatment interactions. An important issue in IPD NMA is the selection of influential parameters among terms that account for inconsistency, covariates, covariate-by-treatment interactions or nonproportionality of treatments effect for time to event data. This issue has not been deeply studied in the literature yet and in particular not for time-to-event data. A major difficulty is to jointly account for between-trial heterogeneity which could have a major influence on the selection process. The use of penalized generalized mixed effect model is a solution, but existing implementations have several shortcomings and an important computational cost that precludes their use for complex IPD NMA. In this article, we propose a penalized Poisson regression model to perform IPD NMA of time-to-event data. It is based only on fixed effect parameters which improve its computational cost over the use of random effects. It could be easily implemented using existing penalized regression package. Computer code is shared for implementation. The methods were applied on simulated data to illustrate the importance to take into account between trial heterogeneity during the selection procedure. Finally, it was applied to an IPD NMA of overall survival of chemotherapy and radiotherapy in nasopharyngeal carcinoma.

Comparative effectiveness and safety of antiviral agents for patients with COVID-19: Protocol for a systematic review and individual-patient data network meta-analysis.

BackgroundA recent cluster of pneumonia cases in Wuhan, China, has been caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We propose the protocol described below to perform an individual-patient data (IPD) network meta-analysis (NMA) in order to evaluate the efficacies of different antiviral drugs to treat patients with coronavirus disease 2019 (COVID-19).Materials and methodsWe will search the Medline, EMBASE, Cochrane Library, SinoMed, CNKI and VIP databases from their inceptions through July 2020. There will be no restrictions on language, publication year, or publication type. Randomized clinical trials (RCTs) and prospective cohort studies with antiviral treatments for COVID-19 will be considered. Two reviewers will independently select studies and collect data. Risk-of-bias assessments will be completed using the Cochrane risk-of-bias scale. Primary outcome will be the COVID-19 recovery rate. We will combine aggregated data from IPD with the NMA in a single model, compare the effects of different antiviral drugs on patient-relevant efficacy, and rank the results to decide which is the most effective.Trial registrationPROSPERO registration number: CRD42020167038.

Fixed vs adjusted-dose benznidazole for adults with chronic Chagas disease without cardiomyopathy: A systematic review and meta-analysis.

Chagas disease is a neglected disease that remains a public health threat, particularly in Latin America. The most important treatment options are nitroimidazole derivatives, such as nifurtimox and benznidazole (BZN). Some studies suggest that for adults seropositive to T. cruzi but without clinically evident chronic Chagas cardiomyopathy (CCC), a simple fixed-dose scheme of BZN could be equivalent to a weight-adjusted dose. We compared the efficacy and safety of a fixed dose of BZN with an adjusted dose for T. cruzi seropositive adults without CCC. We used the Cochrane methods, and reported according to the PRISMA statement. We included randomized controlled trials (RCTs) allocating participants to fixed and/or adjusted doses of BZN for T. cruzi seropositive adults without CCC. We searched (December 2019) Cochrane, MEDLINE, EMBASE, LILACS, Clinicaltrials.gov, and International Clinical Trials Registry Platform (ICTRP), and contacted Chagas experts. Selection, data extraction, and risk of bias assessment, using the Cochrane tool, were performed independently by pairs of reviewers. Discrepancies were solved by consensus within the team. Primary outcomes were parasite-related outcomes and efficacy or patient-related safety outcomes. We conducted a meta-analysis using RevMan 5.3 software and used GRADE summary of finding tables to present the certainty of evidence by outcome. We identified 655 records through our search strategy and 10 studies (four of them ongoing) met our inclusion criteria. We did not find any study directly comparing fixed vs adjusted doses of BZN, however, some outcomes allowed subgroup comparisons between fixed and adjusted doses of BZN against placebo. Moderate-certainty evidence suggests no important subgroup differences for positive PCR at one year and for three safety outcomes (drug discontinuation, peripheral neuropathy, and mild rash). The same effect was observed for any serious adverse events (low-certainty evidence). All subgroups showed similar effects (I2 0% for all these subgroup comparisons but 32% for peripheral neuropathy), supporting the equivalence of BZN schemes. We conclude that there is no direct evidence comparing fixed and adjusted doses of BZN. Based on low to very low certainty of evidence for critical clinical outcomes and moderate certainty of evidence for important outcomes, fixed and adjusted doses may be equivalent in terms of safety and efficacy. An individual patient data network meta-analysis could better address this issue.

Network-meta-analysis of chemotherapy in nasopharyngeal carcinoma (MAC-NPC): An update on 8,221 patients.

6523 Background: Based on an individual patient data (IPD) network meta-analysis (NMA) of 20 randomized trials and 5,144 patients (pts), the MAC-NPC collaborative group has shown that the addition of adjuvant chemotherapy (AC) to chemo-radiotherapy (CRT) achieved the highest survival benefit in nasopharyngeal carcinoma (NPC; Ribassin-Majed JCO 2017). Here, we updated the meta-analysis with the addition of 8 trials. Methods: Trials of Radiotherapy (RT) with or without chemotherapy (CT) in patients with non-metastatic NPC were identified and updated IPD obtained. Both Western and Chinese medical literatures were searched. Overall Survival (OS) was the main endpoint. Fixed and random-effects frequentist NMA models were applied, network heterogeneity and consistency were evaluated. P-score was used to rank the treatments. R software - netmeta package was used to perform the analyses. Treatments were grouped in the following categories: RT alone (RT), induction chemotherapy followed by RT (IC-RT), induction chemotherapy without taxanes followed by concomitant chemoradiotherapy (ICtax(-)-CRT), induction chemotherapy with taxanes followed by concomitant chemoradiotherapy (ICtax(+)-CRT), concomitant chemoradiotherapy (CRT), concomitant chemoradiotherapy followed by adjuvant chemotherapy (CRT-AC) and RT followed by adjuvant chemotherapy (RT-AC). Results: Overall 28 trials and 8,214 pts were included. Median follow-up was 7.2 years. There was no heterogeneity in the NMA. There was inconsistency in the main analysis, which disappeared after the exclusion of 2 outlier trials. ICtax(+)-CRT ranked the best treatment for OS with a P-Score of 91%. Hazard ratio [HR, 95% Confidence Interval] for ICtax(+)-CRT was 0.75 [0.59-0.96] compared to CRT and 0.92 [0.69-1.24] compared to CRT-AC (second best treatment in raking with a P-Score of 85%; see league table below). When the 2 types of IC were merged, CRT-AC ranked the first followed by IC-CRT with P-Scores of 93% and 86% respectively, with a HR of 0.97 [0.84-1.14] for CRT-AC vs. IC-CRT. Conclusions: This IPD NMA of the treatment of locally advanced NPC demonstrates that the addition of IC or AC to CRT improves disease control probability and survival over CRT alone. Data on progression-free survival, locoregional and distant control will be presented at the meeting. [Table: see text]

Efficacy and Safety of Stents in ST-Segment Elevation Myocardial Infarction

BackgroundTo date, no specific drug-eluting stent (DES) has fully proven its superiority over others in patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention. ObjectivesThe purpose of this study was to compare the safety and efficacy of coronary artery stents in STEMI patients in a patient-level network meta-analysis. MethodsEligible studies were dedicated randomized controlled trials comparing different stents in STEMI patients undergoing percutaneous coronary intervention with at least 12 months of clinical follow-up. Of 19 studies identified from the published data, individual patient data were collected in 15 studies with 10,979 patients representing 87.7% of patients in the overall network of evidence. The primary endpoint was the composite of cardiac death, reinfarction, or target lesion revascularization. ResultsOverall, 8,487 (77.3%) of 10,979 STEMI patients were male and the mean age was 60.7 years. At a median follow-up of 3 years, compared with bare-metal stents (BMS), patients treated with paclitaxel-, sirolimus-, everolimus-, or biolimus-eluting stents had a significantly lower risk of the primary endpoint (adjusted hazard ratios [HRs]: 0.74 [95% confidence interval (CI): 0.63 to 0.88], 0.65 [95% CI: 0.49 to 0.85], 0.70 [95% CI: 0.53 to 0.91], and 0.66 [95% CI: 0.49 to 0.88], respectively). The risk of primary endpoint was not different between patients treated with BMS and zotarolimus-eluting stents (adjusted HR: 0.83 [95% CI: 0.51 to 1.38]). Among patients treated with DES, no significant difference in the risk of the primary outcome was demonstrated. Treatment with second-generation DES was associated with significantly lower risk of definite or probable stent thrombosis compared with BMS (adjusted HR: 0.61 [95% CI: 0.42 to 0.89]) and first-generation DES (adjusted HR: 0.56 [95% CI: 0.36 to 0.88]). ConclusionsIn STEMI patients, DES were superior to BMS with respect to long-term efficacy. No difference in long-term efficacy and safety was observed among specific DES. Second-generation were superior to first-generation DES in reducing stent thrombosis. (Clinical Outcomes After Primary Percutaneous Coronary Intervention [PCI] Using Contemporary Drug-Eluting Stent [DES]: Evidence From the Individual Patient Data Network Meta-Analysis; CRD42018104053)

P3589New generation stents for primary percutaneous coronary intervention in patients with acute myocardial infarction: evidence from an individual patient data network meta-analysis of randomized clinical

Abstract Background Drug-eluting stents have shown their superiority in primary percutaneous intervention in patients with ST-segment elevation myocardial infarction (STEMI). No specific stent type has fully proven its superiority over others. Purpose We sought to compare the safety and efficacy of coronary artery stents in STEMI patients undergoing primary PCI through comprehensive network meta-analysis (NMA). Methods We performed an individual patient data (IPD) NMA of dedicated randomized trials in STEMI patients treated with coronary stents. The primary endpoint of interest was the composite outcome of cardiac death, any myocardial infarction (MI) or target lesion revascularization (TLR). Secondary outcomes were the individual component of the primary endpoint and definite or probable stent thrombosis. Outcomes were analyzed at the longest available follow-up. The primary analysis was performed using a one-stage random-effects meta-analysis. Results IPD from 15 randomized trials in STEMI patients were obtained including a total of 10,979 patients. Six different stent types were studied including bare metal stents (BMS), durable-polymer paclitaxel-eluting stents (DP-PES), durable-polymer sirolimus-eluting stents (DP-SES), durable-polymer zotarolimus-eluting stents (DP-ZES), durable-polymer everolimus-eluting stents (DP-EES) and biodegradable-polymer biolimus-eluting stent (BP-BES). Mean patient age was 60.7±11.9 years; 22.7% were female and 16.1% were diabetic. Median symptom onset to balloon time was 210 min. At a median follow-up of 3 years (interquartile range 2–4.9 years), patients treated with second-generation (DP-EES and BP-BES) or first-generation DES (DP-PES, DP-SES and DP-ZES) had significantly lower risk of the primary endpoint than patients treated with BMS (BMS vs. second-generation DES; HR 0.69, 95% CI 0.57–0.82, BMS vs. first-generation DES; HR 0.70, 95% CI 0.61–0.80). The differences were driven by the significant reduction of TLR associated with first- and second-generation DES compared with BMS. A trend towards lower risk of MI with second-generation DES compared with BMS or first-generation DES was observed (BMS vs. second-generation DES; HR 0.79, 95% CI 0.58–1.06, first- vs. second-generation DES; HR 0.75, 95% CI 0.54–1.03). Second-generation DES was associated with a significantly lower risk of definite or probable stent thrombosis compared with BMS (HR 0.62, 95% 0.40–0.97) and first-generation DES (HR 0.55, 95% CI 0.34–0.91). DP-EES and BP-BES had a similar risk of the primary endpoint, individual components of the primary endpoint, and definite or probable stent thrombosis. Conclusions In this larger-scale IPD NMA in STEMI patients, second-generation DES were superior to BMS with respect to long-term efficacy and safety outcomes. Second-generation DES were associated with a significant reduction of stent thrombosis compared with BMS and first-generation DES. Similar long-term outcomes were observed between DP-EES and BP-BES. Acknowledgement/Funding This study was funded by Biosensors International

Individual patient data network meta-analysis using either restricted mean survival time difference or hazard ratios: is there a difference? A case study on locoregionally advanced nasopharyngeal carcinomas

BackgroundThis study aimed at applying the restricted mean survival time difference (rmstD) as an absolute outcome measure in a network meta-analysis and comparing the results with those obtained using hazard ratios (HR) from the individual patient data (IPD) network meta-analysis (NMA) on the role of chemotherapy for nasopharyngeal carcinoma (NPC) recently published by the MAC-NPC collaborative group (Meta-Analysis of Chemotherapy [CT] in NPC).Patients and methodsTwenty trials (5144 patients) comparing radiotherapy (RT) with or without CT in non-metastatic NPC were included. Treatments were grouped in seven categories: RT alone (RT), induction CT followed by RT (IC-RT), RT followed by adjuvant CT (RT-AC), IC followed by RT followed by AC (IC-RT-AC), concomitant chemoradiotherapy (CRT), IC followed by CRT (IC-CRT), and CRT followed by AC (CRT-AC). The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival and locoregional control. The rmstD was estimated at t* = 10 years in each trial. Random-effect frequentist NMA models were applied. P score was used to rank treatments. Heterogeneity and inconsistency were evaluated.ResultsThe three treatments that had the highest effect on OS with rmstD were CRT-AC, IC-CRT, and CRT (respective P scores of 92%, 72%, and 64%) compared to CRT-AC, CRT, and IC-CRT when using HR (respective P scores of 96%, 71%, and 63%). Of the 32 HR and rmstD analyzed, 5 had a different interpretation, 3 with a direction change (different direction of treatment effect) and 2 with a change in significance (same direction but a change in statistical significance). Results for secondary endpoints were overall in agreement.ConclusionThe use of either HR or rmstD impacts the results of NMA. Given the sensitivity of HR to non-proportional hazards, this finding could have implications in terms of meta-analysis methodology.

What is the most effective treatment for head and neck squamous cell carcinoma? An individual patient data network meta-analysis from the MACH-NC and MARCH collaborative groups

What is the most effective treatment for head and neck squamous cell carcinoma? : An individual patient data network meta-analysis from the MACH-NC and MARCH collaborative groups

Comparative safety and effectiveness of cognitive enhancers for Alzheimer's dementia: protocol for a systematic review and individual patient data network meta-analysis

IntroductionAlzheimer's dementia (AD) is the most common cause of dementia, and several organisations, such as the National Institute for Health and Care Excellence, suggest that management of patients with AD...

Safety and effectiveness of long-acting versus intermediate-acting insulin for patients with type 1 diabetes: protocol for a systematic review and individual patient data network meta-analysis

IntroductionThe choice of a basal insulin regimen to manage type 1 diabetes mellitus (T1DM) may have different risks of adverse events and effectiveness, due to the difference in the effectiveness...

Individual patient data network meta-analysis of mortality effects of implantable cardiac devices

ObjectiveImplantable cardioverter defibrillators (ICD), cardiac resynchronisation therapy pacemakers (CRT-P) and the combination therapy (CRT-D) have been shown to reduce all-cause mortality compared with medical therapy alone in patients with heart...

PIN113 - Adherence Interventions to Improve Adherence to Antiretroviral Therapy in Low Income Settings: An Individual Patient Data Network Meta-Analysis

PIN113 - Adherence Interventions to Improve Adherence to Antiretroviral Therapy in Low Income Settings: An Individual Patient Data Network Meta-Analysis