Prospective reporting of statistical analysis plans for randomised controlled trials

In 2017, JAMA published a statistical analysis plan (SAP) guidance document for randomised clinical trials (RCTs). This guidance is part of the EQUATOR Network of reporting resources and includes a checklist of minimum items for reporting details of statistical analysis of RCTs [1]. While the clinical trial protocol should describe the principal features of the statistical analysis, a separate detailed SAP containing sufficient information to support replication by an independent statistician may be needed [2,3,4]

Five-year outcomes of chronic total occlusion treatment with a biolimus A9-eluting biodegradable polymer stent versus a sirolimus-eluting permanent polymer stent in the LEADERS all-comers trial

Background: Few data are available on long-term follow-up of drug-eluting stents in the treatment of chronic total occlusion (CTO). The LEADERS CTO sub-study compared the long-term results in CTO and non-CTO lesions of a Biolimus A9™-eluting stent (BES) with a sirolimus-eluting stent (SES).Methods: Among 1,707 patients enrolled in the prospective, multi-center, all-comers LEADERS trial, 81 with CTOs were treated with either a BES (n = 45) or a SES (n = 36). The primary endpoint was the occurrence of major adverse cardiac events (MACE): cardiac death, myocardial infarction (MI) and clinically-indicated target vessel revascularization (TVR).Results: At 5 years, the rate of MACE was numerically higher in the CTO group than in the non-CTO group (29.6% vs. 23.3%; p = 0.173), with a significant increase in the incidence of target lesion revascularization (TLR) (21.0 vs. 12.6; p = 0.033), but no difference in stent thrombosis (ST). Patients with CTO receiving a BES demonstrated a lower incidence of MACE (22.2% vs. 38.9%; p = 0.147) with a significant reduction in TLR compared to patients receiving a SES (11.1% vs. 33.3%, p = 0.0214) with an incidence similar to that observed in the non-CTO group treated with BES (11.6%). Definite ST at 5 years nearly halved in the BES group (4.4% vs. 8.3%, p = 0.478) with no ST in the BES group after the first year (0% vs. 8.3%, p for interaction = 0.009).Conclusions: The use of a BES showed a reduction in MACE, TVR, TLR, and ST over time in the CTO subset with similar outcome as for non-CTO lesions

Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study

Objective: To examine whether the association of inadequate or unclear allocation concealment and lack of blinding with biased estimates of intervention effects varies with the nature of the intervention or outcome. Design: Combined analysis of data from three metaepidemiological studies based on collections of metaanalyses. Data sources 146 meta-analyses including 1346 trials examining a wide range of interventions and outcomes. Main outcome measures Ratios of odds ratios quantifying the degree of bias associated with inadequate or unclear allocation concealment, and lack of blinding, for trials with different types of intervention and outcome. A ratio of odds ratios <1 implies that inadequately concealed or nonblinded trials exaggerate intervention effect estimates. Results: In trials with subjective outcomes effect estimates were exaggerated when there was inadequate or unclear allocation concealment (ratio of odds ratios 0.69 (95% CI 0.59 to 0.82)) or lack of blinding (0.75 (0.61 to 0.93)). In contrast, there was little evidence of bias in trials with objective outcomes: ratios of odds ratios 0.91 (0.80 to 1.03) for inadequate or unclear allocation concealment and 1.01 (0.92 to 1.10) for lack of blinding. There was little evidence for a difference between trials of drug and nondrug interventions. Except for trials with all cause mortality as the outcome, the magnitude of bias varied between meta-analyses. Conclusions: The average bias associated with defects in the conduct of randomised trials varies with the type of outcome. Systematic reviewers should routinely assess the risk of bias in the results of trials, and should report meta-analyses restricted to trials at low risk of bias either as the primary analysis or in conjunction with less restrictive analyses

Revascularisation versus medical treatment in patients with stable coronary artery disease: network meta-analysis.

peer reviewedOBJECTIVE: To investigate whether revascularisation improves prognosis compared with medical treatment among patients with stable coronary artery disease. DESIGN: Bayesian network meta-analyses to combine direct within trial comparisons between treatments with indirect evidence from other trials while maintaining randomisation. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: A strategy of initial medical treatment compared with revascularisation by coronary artery bypass grafting or Food and Drug Administration approved techniques for percutaneous revascularization: balloon angioplasty, bare metal stent, early generation paclitaxel eluting stent, sirolimus eluting stent, and zotarolimus eluting (Endeavor) stent, and new generation everolimus eluting stent, and zotarolimus eluting (Resolute) stent among patients with stable coronary artery disease. DATA SOURCES: Medline and Embase from 1980 to 2013 for randomised trials comparing medical treatment with revascularisation. MAIN OUTCOME MEASURE: All cause mortality. RESULTS: 100 trials in 93,553 patients with 262,090 patient years of follow-up were included. Coronary artery bypass grafting was associated with a survival benefit (rate ratio 0.80, 95% credibility interval 0.70 to 0.91) compared with medical treatment. New generation drug eluting stents (everolimus: 0.75, 0.59 to 0.96; zotarolimus (Resolute): 0.65, 0.42 to 1.00) but not balloon angioplasty (0.85, 0.68 to 1.04), bare metal stents (0.92, 0.79 to 1.05), or early generation drug eluting stents (paclitaxel: 0.92, 0.75 to 1.12; sirolimus: 0.91, 0.75 to 1.10; zotarolimus (Endeavor): 0.88, 0.69 to 1.10) were associated with improved survival compared with medical treatment. Coronary artery bypass grafting reduced the risk of myocardial infarction compared with medical treatment (0.79, 0.63 to 0.99), and everolimus eluting stents showed a trend towards a reduced risk of myocardial infarction (0.75, 0.55 to 1.01). The risk of subsequent revascularisation was noticeably reduced by coronary artery bypass grafting (0.16, 0.13 to 0.20) followed by new generation drug eluting stents (zotarolimus (Resolute): 0.26, 0.17 to 0.40; everolimus: 0.27, 0.21 to 0.35), early generation drug eluting stents (zotarolimus (Endeavor): 0.37, 0.28 to 0.50; sirolimus: 0.29, 0.24 to 0.36; paclitaxel: 0.44, 0.35 to 0.54), and bare metal stents (0.69, 0.59 to 0.81) compared with medical treatment. CONCLUSION: Among patients with stable coronary artery disease, coronary artery bypass grafting reduces the risk of death, myocardial infarction, and subsequent revascularisation compared with medical treatment. All stent based coronary revascularisation technologies reduce the need for revascularisation to a variable degree. Our results provide evidence for improved survival with new generation drug eluting stents but no other percutaneous revascularisation technology compared with medical treatment

Impact of proton pump inhibitors on efficacy of antiplatelet strategies with ticagrelor or aspirin after percutaneous coronary intervention:Insights from the GLOBAL LEADERS trial

BACKGROUND Several studies have suggested that proton pump inhibitors (PPIs) may reduce the antiplatelet effects of clopidogrel and/or aspirin, possibly leading to cardiovascular events. AIMS We aimed to investigate the association between PPI and clinical outcomes in patients treated with ticagrelor monotherapy or conventional antiplatelet therapy after percutaneous coronary intervention (PCI). METHODS This is a subanalysis of the randomized GLOBAL LEADERS trial, comparing the experimental antiplatelet arm (23-month ticagrelor monotherapy following 1-month dual antiplatelet therapy [DAPT]) with the reference arm (12-month aspirin monotherapy following 12-month DAPT) after PCI. Patient-oriented composite endpoints (POCEs: all-cause mortality, myocardial infarction, stroke, or repeat revascularization) and its components were assessed stratified by PPI use as a time-dependent covariate in patients with the experiment or reference antiplatelet arm. RESULTS Among 15,839 patients, 2115 patients (13.5%) experienced POCE at 2 years. In the reference arm, the use of PPIs was independently associated with POCE (hazard ratio [HR]: 1.27; 95% confidence interval [CI]: 1.12-1.44) and its individual components, whereas it was not in the experimental arm (HR: 1.04; 95% CI: 0.92-1.19; pinteraction  = 0.035). During the second-year follow-up, patients taking aspirin with PPIs had a significantly higher risk of POCE compared to those on aspirin without PPIs (HR: 1.57; 95% CI: 1.27-1.94), whereas the risk did not differ significantly irrespective of PPI in ticagrelor monotherapy group (HR: 1.03; 95% CI: 0.83-1.28; pinteraction  = 0.008). CONCLUSIONS In contrast to conventional antiplatelet strategy, there were no evidence suggesting the interaction between ticagrelor monotherapy and PPIs on increased cardiovascular events, which should be confirmed in further studies. CLINICAL TRIAL REGISTRATION URL: https://clinicaltrials.gov

A MAFG-lncRNA axis links systemic nutrient abundance to hepatic glucose metabolism

Obesity and type 2 diabetes mellitus are global emergencies and long noncoding RNAs (lncRNAs) are regulatory transcripts with elusive functions in metabolism. Here we show that a high fraction of lncRNAs, but not protein-coding mRNAs, are repressed during diet-induced obesity (DIO) and refeeding, whilst nutrient deprivation induced lncRNAs in mouse liver. Similarly, lncRNAs are lost in diabetic humans. LncRNA promoter analyses, global cistrome and gain-of-function analyses confirm that increased MAFG signaling during DIO curbs lncRNA expression. Silencing Mafg in mouse hepatocytes and obese mice elicits a fasting-like gene expression profile, improves glucose metabolism, de-represses lncRNAs and impairs mammalian target of rapamycin (mTOR) activation. We find that obesity-repressed LincIRS2 is controlled by MAFG and observe that genetic and RNAi-mediated LincIRS2 loss causes elevated blood glucose, insulin resistance and aberrant glucose output in lean mice. Taken together, we identify a MAFG-lncRNA axis controlling hepatic glucose metabolism in health and metabolic disease

A MAFG-lncRNA axis links systemic nutrient abundance to hepatic glucose metabolism

Obesity and type 2 diabetes mellitus are global emergencies and long noncoding RNAs (lncRNAs) are regulatory transcripts with elusive functions in metabolism. Here we show that a high fraction of lncRNAs, but not protein-coding mRNAs, are repressed during diet-induced obesity (DIO) and refeeding, whilst nutrient deprivation induced lncRNAs in mouse liver. Similarly, lncRNAs are lost in diabetic humans. LncRNA promoter analyses, global cistrome and gain-of-function analyses confirm that increased MAFG signaling during DIO curbs lncRNA expression. Silencing Mafg in mouse hepatocytes and obese mice elicits a fasting-like gene expression profile, improves glucose metabolism, de-represses lncRNAs and impairs mammalian target of rapamycin (mTOR) activation. We find that obesity-repressed LincIRS2 is controlled by MAFG and observe that genetic and RNAi-mediated LincIRS2 loss causes elevated blood glucose, insulin resistance and aberrant glucose output in lean mice. Taken together, we identify a MAFG-lncRNA axis controlling hepatic glucose metabolism in health and metabolic disease

Investigating the effect of independent blinded digital image assessment on the STOP GAP trial

Background Blinding is the process of keeping treatment assignment hidden and is used to minimise the possibility of bias. Trials at high risk of bias have been shown to report larger treatment effects than low risk studies. In dermatology, one popular method of blinding is to have independent outcome assessors who are unaware of treatment allocation assessing the end point using digital photographs. However, this can be complex, expensive and time-consuming. The objective of this study was to compare the effect of blinded and unblinded outcome assessment on the results of the STOP GAP trial. Methods The STOP GAP trial compared prednisolone to ciclosporin in treating pyoderma gangrenosum. Participants’ lesions were measured at baseline and 6 weeks to calculate the primary outcome, speed of healing. Independent blinded assessors obtained measurements from digital photographs using specialist software. In addition, unblinded treating clinicians estimated lesion area by measuring length and width. The primary outcome was determined using blinded measurements where available, otherwise unblinded measurements were used (method referred to as trial measurements). In this study, agreement between the trial and unblinded measurements was determined using the intraclass correlation coefficient (ICC). The STOP GAP primary analysis was repeated using unblinded measurements only. We introduced differential and non-differential error in unblinded measurements and investigated the effect on the STOP GAP primary analysis. Results 86 (80%) of the 108 patients were assessed using digital images. Agreement between trial and unblinded measurements was excellent (ICC=0.92 at baseline; 0.83 at 6 weeks). There was no evidence that the results of the trial primary analysis differed according to how the primary outcome was assessed (p-value for homogeneity = 1.00). Conclusions Blinded digital image assessment in STOP GAP did not meaningfully alter trial conclusions compared with unblinded assessment. However, as the process brought added accuracy and credibility to the trial it was considered worthwhile. These findings question the usefulness of digital image assessment in a trial with an objective outcome and where bias is not expected to be excessive. Further research should investigate if there are alternative, less complex ways of incorporating blinding in clinical trials

Pragmatic randomized controlled trials: strengthening the concept through a robust international collaborative network: PRIME-9-pragmatic research and innovation through multinational experimentation.

In an era focused on value-based healthcare, the quality of healthcare and resource allocation should be underpinned by empirical evidence. Pragmatic clinical trials (pRCTs) are essential in this endeavor, providing randomized controlled trial (RCT) insights that encapsulate real-world effects of interventions. The rising popularity of pRCTs can be attributed to their ability to mirror real-world practices, accommodate larger sample sizes, and provide cost advantages over traditional RCTs. By harmonizing efficacy with effectiveness, pRCTs assist decision-makers in prioritizing interventions that have a substantial public health impact and align with the tenets of value-based health care. An international network for pRCT provides several advantages, including larger and diverse patient populations, access to a broader range of healthcare settings, sharing knowledge and expertise, and overcoming ethical and regulatory barriers. The hypothesis and study design of pRCT answers the decision-maker's questions. pRCT compares clinically relevant alternative interventions, recruits participants from diverse practice settings, and collects data on various health outcomes. They are scarce because the medical products industry typically does not fund pRCT. Prioritizing these studies by expanding the infrastructure to conduct clinical research within the healthcare delivery system and increasing public and private funding for these studies will be necessary to facilitate pRCTs. These changes require more clinical and health policy decision-makers in clinical research priority setting, infrastructure development, and funding. This paper presents a comprehensive overview of pRCTs, emphasizing their importance in evidence-based medicine and the advantages of an international collaborative network for their execution. It details the development of PRIME-9, an international initiative across nine countries to advance pRCTs, and explores various statistical approaches for these trials. The paper underscores the need to overcome current challenges, such as funding limitations and infrastructural constraints, to leverage the full potential of pRCTs in optimizing healthcare quality and resource utilization

Osteoarthritis: 119. The Effectiveness of Exercise Therapy with and without Manual Therapy for Hip Osteoarthritis: A Multicentre Randomised Controlled Trial

Background: Current evidence indicates that exercise therapy (ET) has a short and medium-term benefit for hip osteoarthritis (OA), but evidence is inconclusive regarding the effect of manual therapy (MT). The primary aim of this randomised controlled trial was to determine the effectiveness of ET with and without MT on clinical outcomes for individuals with hip OA. A secondary aim was to ascertain the effect of an 8-week waiting period on outcomes. Methods: 131 men and women with hip OA recruited in four hospitals were initially randomised to one of three groups: ET (n = 45), a combination of ET and MT (n = 43) and wait-list control (n = 43). The two intervention groups underwent individualised ET or ET/MT for 8 weeks. Patients in the control group waited 8 weeks and were randomised to receive either ET or ET/MT after 9 week follow-up, and pooled with original treatment group data: ET (n = 66) and ET/ MT (n = 65). All participants were followed up at 9 and 18 weeks and the control group was reassessed at 27 weeks (18 weeks post-treatment) by the same blinded assessor. The primary outcome measure was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Other outcomes included sit-to-stand, 50-foot walk test, pain severity, hip range of motion (ROM), anxiety, depression, quality of life (QOL), analgesic usage, physical activity, patient-perceived change and patient satisfaction. Intention-to-treat analysis was performed to determine within-group change and between-group differences for the three groups at baseline and 9 weeks, and the two treatment groups at baseline, 9 and 18 weeks. Results: Eight patients (6.1%) were lost to follow-up at 9 weeks and 19 (14.5%) were lost to follow-up by 18 weeks. Both ET (n = 66) and ET/MT groups (n = 65) showed significant within-group improvements in WOMAC, pain severity, sit-to-stand and HROM measures at 9 weeks, which were still evident at 18 weeks. There was no significant within-group change in anxiety, depression, QOL, analgesic usage, 50-foot walk test or physical activity. There was no significant difference between the two intervention groups for any of the outcomes. Regarding the results of the original ET, ET/MT and control group allocation, there was a significant improvement in one or both ET and ET/MT groups compared with the control group in the same outcomes, as well as patient perceived improvement at 9 weeks. There was no significant difference between the three groups in analgesic usage, WOMAC stiffness subscale, sit-to-stand and 50 foot walk tests, QOL and physical activity. There was an overall deterioration in anxiety and depression scores. Conclusions: The addition of MT to an 8 week programme of ET for hip OA resulted in similar improvements in pain, function and ROM at 9 and 18 weeks. The significant improvement which occurred in the same outcomes in the two treatment groups compared with a wait-list control of 8 weeks has implications for waiting list management Disclosure statement: The authors have declared no conflicts of interes