Anti-Vascular Endothelial Growth Factor Drugs Compared With Panretinal Photocoagulation for the Treatment of Proliferative Diabetic Retinopathy: A Cost-Effectiveness Analysis.

OBJECTIVES: This study aimed to evaluate the cost-effectiveness of anti-vascular endothelial growth factor drugs (anti-VEGFs) compared with panretinal photocoagulation (PRP) for treating proliferative diabetic retinopathy (PDR) in the United Kingdom. METHODS: A discrete event simulation model was developed, informed by individual participant data meta-analysis. The model captures treatment effects on best corrected visual acuity in both eyes, and the occurrence of diabetic macular edema and vitreous hemorrhage. The model also estimates the value of undertaking further research to resolve decision uncertainty. RESULTS: Anti-VEGFs are unlikely to generate clinically meaningful benefits over PRP. The model predicted anti-VEGFs be more costly and similarly effective as PRP, generating 0.029 fewer quality-adjusted life-years at an additional cost of £3688, with a net health benefit of -0.214 at a £20 000 willingness-to-pay threshold. Scenario analysis results suggest that only under very select conditions may anti-VEGFs offer potential for cost-effective treatment of PDR. The consequences of loss to follow-up were an important driver of model outcomes. CONCLUSIONS: Anti-VEGFs are unlikely to be a cost-effective treatment for early PDR compared with PRP. Anti-VEGFs are generally associated with higher costs and similar health outcomes across various scenarios. Although anti-VEGFs were associated with lower diabetic macular edema rates, the number of cases avoided is insufficient to offset the additional treatment costs. Key uncertainties relate to the long-term comparative effectiveness of anti-VEGFs, particularly considering the real-world rates and consequences of treatment nonadherence. Further research on long-term visual acuity and rates of vision-threatening complications may be beneficial in resolving uncertainties.

Ablative and non-surgical therapies for early and very early hepatocellular carcinoma: a systematic review and network meta-analysis.

Background: A wide range of ablative and non-surgical therapies are available for treating small hepatocellular carcinoma in patients with very early or early-stage disease and preserved liver function. Objective: To review and compare the effectiveness of all current ablative and non-surgical therapies for patients with small hepatocellular carcinoma (≤ 3 cm). Design: Systematic review and network meta-analysis. Data sources: Nine databases (March 2021), two trial registries (April 2021) and reference lists of relevant systematic reviews. Review methods: Eligible studies were randomised controlled trials of ablative and non-surgical therapies, versus any comparator, for small hepatocellular carcinoma. Randomised controlled trials were quality assessed using the Cochrane Risk of Bias 2 tool and mapped. The comparative effectiveness of therapies was assessed using network meta-analysis. A threshold analysis was used to identify which comparisons were sensitive to potential changes in the evidence. Where comparisons based on randomised controlled trial evidence were not robust or no randomised controlled trials were identified, a targeted systematic review of non-randomised, prospective comparative studies provided additional data for repeat network meta-analysis and threshold analysis. The feasibility of undertaking economic modelling was explored. A workshop with patients and clinicians was held to discuss the findings and identify key priorities for future research. Results: Thirty-seven randomised controlled trials (with over 3700 relevant patients) were included in the review. The majority were conducted in China or Japan and most had a high risk of bias or some risk of bias concerns. The results of the network meta-analysis were uncertain for most comparisons. There was evidence that percutaneous ethanol injection is inferior to radiofrequency ablation for overall survival (hazard ratio 1.45, 95% credible interval 1.16 to 1.82), progression-free survival (hazard ratio 1.36, 95% credible interval 1.11 to 1.67), overall recurrence (relative risk 1.19, 95% credible interval 1.02 to 1.39) and local recurrence (relative risk 1.80, 95% credible interval 1.19 to 2.71). Percutaneous acid injection was also inferior to radiofrequency ablation for progression-free survival (hazard ratio 1.63, 95% credible interval 1.05 to 2.51). Threshold analysis showed that further evidence could plausibly change the result for some comparisons. Fourteen eligible non-randomised studies were identified (n ≥ 2316); twelve had a high risk of bias so were not included in updated network meta-analyses. Additional non-randomised data, made available by a clinical advisor, were also included (n = 303). There remained a high level of uncertainty in treatment rankings after the network meta-analyses were updated. However, the updated analyses suggested that microwave ablation and resection are superior to percutaneous ethanol injection and percutaneous acid injection for some outcomes. Further research on stereotactic ablative radiotherapy was recommended at the workshop, although it is only appropriate for certain patient subgroups, limiting opportunities for adequately powered trials. Limitations: Many studies were small and of poor quality. No comparative studies were found for some therapies. Conclusions: The existing evidence base has limitations; the uptake of specific ablative therapies in the United Kingdom appears to be based more on technological advancements and ease of use than strong evidence of clinical effectiveness. However, there is evidence that percutaneous ethanol injection and percutaneous acid injection are inferior to radiofrequency ablation, microwave ablation and resection. Study registration: PROSPERO CRD42020221357. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment (HTA) programme (NIHR award ref: NIHR131224) and is published in full in Health Technology Assessment; Vol. 27, No. 29. See the NIHR Funding and Awards website for further award information.

Hepatocellular carcinoma is the most common type of primary liver cancer. There are a range of different treatments available for patients with early hepatocellular carcinoma. We looked for clinical trials in patients with small tumours (up to 3 cm) that compared different treatments. We brought together and analysed the results of these trials to see which treatments were most effective in terms of survival, progression, side effects and quality of life. Overall, the evidence has limitations; many trials had few patients and were of poor quality. Most were from China or Japan, where the common causes of liver disease and treatments available differ from those in the United Kingdom. The results of our analyses were very uncertain so we cannot be sure which treatment is the best overall. We did find that three treatments ­ radiofrequency ablation, microwave ablation and surgery ­ were generally more effective than percutaneous ethanol injection and percutaneous acid injection. There was not enough evidence to be certain which treatment was better when radiofrequency ablation was compared with laser ablation, microwave ablation, proton beam therapy or surgery. We found only poor-quality, non-randomised trials on high-intensity focused ultrasound, cryoablation and irreversible electroporation. There was very little evidence on treatments that combined radiofrequency ablation with other therapies. We found no studies that compared electrochemotherapy, histotripsy, stereotactic ablative radiotherapy or wider radiotherapy techniques with other treatments. Only two studies reported data on quality of life or patient satisfaction. We discussed the findings with patients and clinical experts. Stereotactic ablative radiotherapy was highlighted as a treatment that requires further research; however, it is only appropriate for certain subgroups of patients. Feasibility studies could inform future clinical trials by exploring issues such as whether patients are willing to take part in a trial or find the treatments acceptable.

The effectiveness of ablative and non-surgical therapies for early hepatocellular carcinoma: Systematic review and network meta-analysis of randomised controlled trials.

BACKGROUND & AIMS: Non-surgical therapies are frequently used for patients with early or very early hepatocellular carcinoma (HCC). The aim of this systematic review and network meta-analysis (NMA) was to evaluate and compare the effectiveness of ablative and non-surgical therapies for patients with small HCC. METHODS: Nine databases were searched (March 2021) along with clinical trial registries. Randomised controlled trials (RCTs) of any ablative or non-surgical therapy versus any comparator in patients with HCC ≤3 cm were eligible. Risk of bias (RoB) was assessed using the Cochrane RoB 2 tool. The effectiveness of therapies was compared using NMA. Threshold analysis was undertaken to identify which NMA results had less robust evidence. RESULTS: Thirty-seven eligible RCTs were included (including over 3700 patients). Most were from China (n = 17) or Japan (n = 7). Sample sizes ranged from 30 to 308 patients. The majority had a high RoB or some RoB concerns. No RCTs were identified for some therapies and no RCTs reported quality of life outcomes. The results of the NMA and treatment effectiveness rankings were very uncertain. However, the evidence demonstrated that percutaneous ethanol injection was worse than radiofrequency ablation for overall survival (hazard ratio [HR]: 1.45, 95% credible interval [CrI]: 1.16-1.82), progression-free survival (HR: 1.36, 95% CrI: 1.11-1.67), overall recurrence (relative risk [RR]: 1.19, 95% CrI: 1.02-1.39) and local recurrence (RR: 1.80, 95% CrI: 1.19-2.71). The threshold analysis suggested that robust evidence was lacking for some comparisons. CONCLUSIONS: It is unclear which treatment is most effective for patients with small HCC because of limitations in the evidence base. It is also not known how these treatments would impact on quality of life. Further high quality RCTs are needed to provide robust evidence but may be difficult to undertake.

EarlyCDT Lung blood test for risk classification of solid pulmonary nodules: systematic review and economic evaluation.

BACKGROUND: EarlyCDT Lung (Oncimmune Holdings plc, Nottingham, UK) is a blood test to assess malignancy risk in people with solid pulmonary nodules. It measures the presence of seven lung cancer-associated autoantibodies. Elevated levels of these autoantibodies may indicate malignant disease. The results of the test might be used to modify the risk of malignancy estimated by existing risk calculators, including the Brock and Herder models. OBJECTIVES: The objectives were to determine the diagnostic accuracy, clinical effectiveness and cost-effectiveness of EarlyCDT Lung; and to develop a conceptual model and identify evidence requirements for a robust cost-effectiveness analysis. DATA SOURCES: MEDLINE (including Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE Daily and Ovid MEDLINE), EMBASE, Cochrane Central Register of Controlled Trials, Science Citation Index, EconLit, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Health Technology Assessment database, NHS Economic Evaluation Database ( NHS EED ) and the international Health Technology Assessment database were searched on 8 March 2021. REVIEW METHODS: A systematic review was performed of evidence on EarlyCDT Lung, including diagnostic accuracy, clinical effectiveness and cost-effectiveness. Study quality was assessed with the quality assessment of diagnostic accuracy studies-2 tool. Evidence on other components of the pulmonary nodule diagnostic pathway (computerised tomography surveillance, Brock risk, Herder risk, positron emission tomography-computerised tomography and biopsy) was also reviewed. When feasible, bivariate meta-analyses of diagnostic accuracy were performed. Clinical outcomes were synthesised narratively. A simulation study investigated the clinical impact of using EarlyCDT Lung. Additional reviews of cost-effectiveness studies evaluated (1) other diagnostic strategies for lung cancer and (2) screening approaches for lung cancer. A conceptual model was developed. RESULTS: A total of 47 clinical publications on EarlyCDT Lung were identified, but only five cohorts (695 patients) reported diagnostic accuracy data on patients with pulmonary nodules. All cohorts were small or at high risk of bias. EarlyCDT Lung on its own was found to have poor diagnostic accuracy, with a summary sensitivity of 20.2% (95% confidence interval 10.5% to 35.5%) and specificity of 92.2% (95% confidence interval 86.2% to 95.8%). This sensitivity was substantially lower than that estimated by the manufacturer (41.3%). No evidence on the clinical impact of EarlyCDT Lung was identified. The simulation study suggested that EarlyCDT Lung might potentially have some benefit when considering intermediate risk nodules (10-70% risk) after Herder risk analysis. Two cost-effectiveness studies on EarlyCDT Lung for pulmonary nodules were identified; none was considered suitable to inform the current decision problem. The conceptualisation process identified three core components for a future cost-effectiveness assessment of EarlyCDT Lung: (1) the features of the subpopulations and relevant heterogeneity, (2) the way EarlyCDT Lung test results affect subsequent clinical management decisions and (3) how changes in these decisions can affect outcomes. All reviewed studies linked earlier diagnosis to stage progression and stage shift to final outcomes, but evidence on these components was sparse. LIMITATIONS: The evidence on EarlyCDT Lung among patients with pulmonary nodules was very limited, preventing meta-analyses and economic analyses. CONCLUSIONS: The evidence on EarlyCDT Lung among patients with pulmonary nodules is insufficient to draw any firm conclusions as to its diagnostic accuracy or clinical or economic value. FUTURE WORK: Prospective cohort studies, in which EarlyCDT Lung is used among patients with identified pulmonary nodules, are required to support a future assessment of the clinical and economic value of this test. Studies should investigate the diagnostic accuracy and clinical impact of EarlyCDT Lung in combination with Brock and Herder risk assessments. A well-designed cost-effectiveness study is also required, integrating emerging relevant evidence with the recommendations in this report. STUDY REGISTRATION: This study is registered as PROSPERO CRD42021242248. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 49. See the NIHR Journals Library website for further project information.

People at risk of lung cancer sometimes undergo computerised tomography ( CT ) scans of their lungs. These scans may identify lung nodules that could be cancerous. Currently, CT scans of the lung nodules, or sometimes further positron emission tomography­computerised tomography ( PET-CT ) scans, are used to predict the risk that a nodule is cancerous. EarlyCDT Lung is a blood test that detects substances, called autoantibodies, associated with having cancer. If the autoantibodies are detected, the chance of a lung nodule being cancerous may be substantially increased. This test could help doctors make decisions about whether to treat immediately, carry out further tests or monitor the nodule over time to see if it grows or changes shape. This project examined the evidence on the clinical value of the EarlyCDT Lung test. We reviewed all published studies of EarlyCDT Lung and reanalysed the reported data. We found that there has been little research on EarlyCDT Lung among people with lung nodules (only five studies comprising 695 patients). This makes it difficult to draw any firm conclusions. The evidence suggests that EarlyCDT Lung may not be particularly effective at determining which lung nodules are cancerous, and may not improve diagnosis when compared with using CT and PET - CT scans. However, this is uncertain because the evidence is so limited. This project also looked for evidence on the value for money of the EarlyCDT Lung test in detecting lung cancer, and found no relevant evidence. This means that the value for money of EarlyCDT Lung is largely unknown, and there is currently no good evidence to support further analyses on this. We therefore sought to summarise the information and analyses that would be needed to support a future assessment of the value for money of EarlyCDT Lung.

Diagnostic coronary angiography and percutaneous coronary intervention practices in New Zealand: The All New Zealand Acute Coronary Syndrome-Quality Improvement CathPCI registry 3-year study (ANZACS-QI 37).

BACKGROUND: Coronary heart disease remains one of the leading causes of mortality and morbidity in New Zealand (NZ) and globally. The All New Zealand Acute Coronary Syndrome Quality Improvement (ANZACS-QI) programme includes the CathPCI registry which records all those referred for diagnostic coronary angiography (DCA) and percutaneous coronary intervention (PCI) in NZ. We present the methods and three-years of data from the ANZACS-QI CathPCI registry. METHODS: The data was extracted from the ANZACS QI CathPCI registry from 01/09/2014 to 24/09/2017. The ANZACS-QI data dictionary defines all the clinical, procedural and outcomes variables collected, and standard statistical analyses were applied. RESULTS: 40,870 patients underwent cardiac catheterisation, with a mean age of 65 years, and males making up 67% of the cohort. Indications included acute coronary syndrome 55%, angina with suspected stable coronary disease 28%, valve surgery workup 8%, planned PCI 3%, heart failure/cardiomyopathy 3%, arrhythmia 1% and other 2%. For those undergoing DCA alone, radial access was used in 85% and two-thirds had at least one major artery with >50% stenosis. PCI was performed in 39% of patients. Drug-eluting stents were used in 97%. CONCLUSION: The CathPCI registry records the characteristics and outcomes of all patients undergoing DCA and PCI in NZ hospitals. As part of the ANZACS-QI programme the registry provides an important platform for quality improvement, research and to inform clinical practice.

Tisagenlecleucel for the Treatment of Relapsed or Refractory B-cell Acute Lymphoblastic Leukaemia in People Aged up to 25 Years: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the National Institute for Health and Care Excellence's (NICE's) Single Technology Appraisal (STA) process, Novartis submitted evidence on the clinical effectiveness and cost-effectiveness of tisagenlecleucel for treating paediatric and young adult patients (under the age of 25 years) with relapsed or refractory (r/r) B-cell acute lymphoblastic leukaemia (ALL). This article presents a summary of the Evidence Review Group's (ERG's) independent review of the evidence submission, the committee's deliberations, and the subsequent development of NICE guidance for the use of tisagenlecleucel on the National Health Service (NHS) in England. Tisagenlecleucel is a chimeric antigen receptor-modified T-cell (CAR-T) product, the first of this emerging therapeutic class to be considered by NICE in this indication. The company's evidence submission was based upon three single-arm, phase II studies: ELIANA, ENSIGN, and B2101J. These trials demonstrated a beneficial effect of tisagenlecleucel, with significant extensions in event-free survival (EFS) and overall survival (OS) compared to historical control datasets on blinatumomab and salvage chemotherapy. Adverse events were common; 77% of patients suffered from cytokine release syndrome (CRS), 56% of whom required intensive care unit-level care. The ERG did not consider clofarabine monotherapy an appropriate proxy for salvage chemotherapy. The company presented a hybrid cost-effectiveness model, combining a decision tree and three-state partitioned survival model structure. The majority of quality-adjusted life-years (QALYs) gained were generated through additional life-years in the extrapolated 'long-term survival' phase of the model, where patients were assumed to be 'cured'. The ERG considered the results to be subject to substantial uncertainty, due in part to immature trial data, unresolved long-term treatment effects, and a lack of appropriate comparator data. The ERG implemented a number of changes to the company's model in an alternative base case, producing deterministic incremental cost-effectiveness ratios (ICERs) of £45,397 per QALY gained versus salvage chemotherapy, and £27,732 versus blinatumomab. The probabilistic model produced ICERs of £48,265 per QALY gained versus salvage chemotherapy, and £29,501 versus blinatumomab. The committee considered the ERG's analysis to be most closely aligned with their preferred assumptions, and did not consider tisagenlecleucel to meet both of the end-of-life (EoL) criteria. In recognition of the innovative nature of tisagenlecleucel, and the present immaturity of ongoing clinical trials, the committee considered further data collection would be valuable in resolving uncertainties around OS, the technology's novel mechanism of action, and the management of CRS and B-cell aplasia. The committee therefore recommended tisagenlecleucel for use in the Cancer Drugs Fund (CDF) until the conclusion of the ELIANA study (June 2023). This appraisal highlighted the difficulty of interpreting EoL criteria in the context of curative therapies and the valuation of cure versus extension of life. Further clarification of NICE's position in these situations may be necessary to ensure consistency and equity in their decision-making.

Improving the Prescribing Gap For Guideline Recommended Medications Post Myocardial Infarction.

BACKGROUND: We assessed the effect of a pre-discharge medication checklist on discharge prescription rates of guideline recommended medications following myocardial infarction. In addition, we assessed what proportion of the residual prescribing gap following implementation of the checklist was due to the presence of contraindications. METHODS: We examined baseline prescription rates of guideline recommended medications in 100 patients discharged from our institution following acute myocardial infarction. We then introduced a pre-discharge checklist and reassessed discharge medications and reasons for non-prescription of guideline recommended medications in 447 patients with acute myocardial infarction. RESULTS: We demonstrated a significant gap in the prescription of guideline recommended secondary prevention medications at the time of discharge in our pre-intervention cohort. Introduction of a pre-discharge checklist resulted in a significant improvement in the prescription rates of all guideline recommended secondary prevention medications, with aspirin increasing from 90% to 97% (p=0.004), Adenosine diphosphate (ADP) receptor antagonist from 84% to 96% (p=0.0001), B-blocker from 79% to 87% (p=0.03), statin from 88% to 96% (p=0.002) and angiotensin converting enzyme (ACE) inhibitor from 58% to 70% (p=0.03). The residual gap in prescribing was largely explained by the presence of contraindications or absence of an indication in the case of ACE-inhibitors. Once these were taken into account there was a residual gap of 0-4% which represents genuine non-adherence to the guidelines. CONCLUSIONS: Introduction of a pre-discharge checklist led to significant improvement in prescription rates of all five guideline recommended secondary prevention medications. The residual gap in medication prescription following introduction of the checklist was largely due to the presence of contraindications rather than non-adherence.

Adjunctive colposcopy technologies for assessing suspected cervical abnormalities: systematic reviews and economic evaluation.

BACKGROUND: Dynamic Spectral Imaging System (DySIS)map (DySIS Medical Ltd, Edinburgh, UK) and ZedScan (Zilico Limited, Manchester, UK) can be used adjunctively with conventional colposcopy, which may improve the detection of cervical intraepithelial neoplasia (CIN) and cancer. OBJECTIVES: To systematically review the evidence on the diagnostic accuracy, clinical effectiveness and implementation of DySISmap and ZedScan as adjuncts to standard colposcopy, and to develop a cost-effectiveness model. METHODS: Four parallel systematic reviews were performed on diagnostic accuracy, clinical effectiveness issues, implementation and economic analyses. In January 2017 we searched databases (including MEDLINE and EMBASE) for studies in which DySISmap or ZedScan was used adjunctively with standard colposcopy to detect CIN or cancer in women referred to colposcopy. Risk of bias was assessed with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 tool. Summary estimates of diagnostic accuracy were calculated using bivariate and other regression models when appropriate. Other outcomes were synthesised narratively. A patient-level state-transition model was developed to evaluate the cost-effectiveness of DySISmap and ZedScan under either human papillomavirus (HPV) triage or the HPV primary screening algorithm. The model included two types of clinics ['see and treat' and 'watchful waiting' (i.e. treat later after confirmatory biopsy)], as well as the reason for referral (low-grade or high-grade cytological smear). Sensitivity and scenario analyses were undertaken. RESULTS: Eleven studies were included in the diagnostic review (nine of DySISmap and two of ZedScan), three were included in the clinical effectiveness review (two of DySISmap and one of ZedScan) and five were included in the implementation review (four of DySISmap and one of ZedScan). Adjunctive DySISmap use was found to have a higher sensitivity for detecting CIN grade 2+ (CIN 2+) lesions [81.25%, 95% confidence interval (CI) 72.2% to 87.9%] than standard colposcopy alone (57.91%, 95% CI 47.2% to 67.9%), but with a lower specificity (70.40%, 95% CI 59.4% to 79.5%) than colposcopy (87.41%, 95% CI 81.7% to 91.5%). (Confidential information has been removed.) The base-case cost-effectiveness results showed that adjunctive DySISmap routinely dominated standard colposcopy (it was less costly and more effective). The only exception was for high-grade referrals in a watchful-waiting clinic setting. The incremental cost-effectiveness ratio for ZedScan varied between £272 and £4922 per quality-adjusted life-year. ZedScan also dominated colposcopy alone for high-grade referrals in see-and-treat clinics. These findings appeared to be robust to a wide range of sensitivity and scenario analyses. LIMITATIONS: All but one study was rated as being at a high risk of bias. There was no evidence directly comparing ZedScan with standard colposcopy. No studies directly compared DySIS and ZedScan. CONCLUSIONS: The use of adjunctive DySIS increases the sensitivity for detecting CIN 2+, so it increases the number of high-grade CIN cases that are detected. However, it also reduces specificity, so that more women with no or low-grade CIN will be incorrectly judged as possibly having high-grade CIN. The evidence for ZedScan was limited, but it appears to increase sensitivity and decrease specificity compared with colposcopy alone. The cost-effectiveness of both adjunctive technologies compared with standard colposcopy, under both the HPV triage and primary screening algorithms, appears to be favourable when compared with the conventional thresholds used to determine value in the NHS. FUTURE WORK: More diagnostic accuracy studies of ZedScan are needed, as are studies assessing the diagnostic accuracy for women referred to colposcopy as part of the HPV primary screening programme. STUDY REGISTRATION: This study is registered as PROSPERO CRD42017054515. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Contemporary antiplatelet therapy in acute coronary syndromes: are there differences in outcomes and discontinuation between clopidogrel and ticagrelor?

BACKGROUND/AIM: We studied clinical outcomes and discontinuation rates in a 'real-world' population presenting with myocardial infarction treated with ticagrelor or clopidogrel. METHODS: Between January 2012 and May 2015, 992 patients with acute myocardial infarction undergoing invasive management and adequately pre-treated with dual antiplatelet therapy were prospectively enrolled. Platelet aggregation was measured using the Multiplate analyser. Baseline characteristics, in-hospital outcomes and 1-year outcomes were collected. RESULTS: Patients treated with ticagrelor were younger and less likely to be diabetic, have a previous myocardial infarction or present with a ST-elevation myocardial infarction (all P < 0.05). Those treated with ticagrelor also had lower CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines; 20 ± 9.4 vs 23 ± 10.1, P < 0.0001) and GRACE (119 ± 28 vs 126 ± 32, P = 0.002) scores. High platelet reactivity was greatly reduced with ticagrelor compared to clopidogrel (16.1% vs 37.0%, respectively; P < 0.0001). Non-coronary artery bypass grafting-related thrombolysis in myocardial infarction major and minor bleeding occurred at similar rates in those treated with ticagrelor and clopidogrel. Rates of drug discontinuation in those treated with ticagrelor and clopidogrel were similar in hospital (20.2% vs 16.2%, P = 0.18) and between discharge and 1 year (29.9% vs 27.9%, P = 0.63). However, discontinuation due to dyspnoea, (3.3% vs 0%, P < 0.0001) and discontinuation due to any possible drug-related adverse event (9.3% vs 2.2%, P = 0.0001) was more common in those treated with ticagrelor compared to clopidogrel CONCLUSION: Ticagrelor is paradoxically being used in lower-risk patients rather than those most likely to benefit. Ticagrelor was associated with similar rates of bleeding but higher discontinuation rates due to adverse effects compared to clopidogrel.

The identification and treatment of women with hyperglycaemia in pregnancy: an analysis of individual participant data, systematic reviews, meta-analyses and an economic evaluation.

BACKGROUND: Gestational diabetes mellitus (GDM) is associated with a higher risk of important adverse outcomes. Practice varies and the best strategy for identifying and treating GDM is unclear. AIM: To estimate the clinical effectiveness and cost-effectiveness of strategies for identifying and treating women with GDM. METHODS: We analysed individual participant data (IPD) from birth cohorts and conducted systematic reviews to estimate the association of maternal glucose levels with adverse perinatal outcomes; GDM prevalence; maternal characteristics/risk factors for GDM; and the effectiveness and costs of treatments. The cost-effectiveness of various strategies was estimated using a decision tree model, along with a value of information analysis to assess where future research might be worthwhile. Detailed systematic searches of MEDLINE® and MEDLINE In-Process & Other Non-Indexed Citations®, EMBASE, Cumulative Index to Nursing and Allied Health Literature Plus, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Health Technology Assessment database, NHS Economic Evaluation Database, Maternity and Infant Care database and the Cochrane Methodology Register were undertaken from inception up to October 2014. RESULTS: We identified 58 studies examining maternal glucose levels and outcome associations. Analyses using IPD alone and the systematic review demonstrated continuous linear associations of fasting and post-load glucose levels with adverse perinatal outcomes, with no clear threshold below which there is no increased risk. Using IPD, we estimated glucose thresholds to identify infants at high risk of being born large for gestational age or with high adiposity; for South Asian (SA) women these thresholds were fasting and post-load glucose levels of 5.2 mmol/l and 7.2 mmol/l, respectively and for white British (WB) women they were 5.4 and 7.5 mmol/l, respectively. Prevalence using IPD and published data varied from 1.2% to 24.2% (depending on criteria and population) and was consistently two to three times higher in SA women than in WB women. Lowering thresholds to identify GDM, particularly in women of SA origin, identifies more women at risk, but increases costs. Maternal characteristics did not accurately identify women with GDM; there was limited evidence that in some populations risk factors may be useful for identifying low-risk women. Dietary modification additional to routine care reduced the risk of most adverse perinatal outcomes. Metformin (Glucophage,® Teva UK Ltd, Eastbourne, UK) and insulin were more effective than glibenclamide (Aurobindo Pharma - Milpharm Ltd, South Ruislip, Middlesex, UK). For all strategies to identify and treat GDM, the costs exceeded the health benefits. A policy of no screening/testing or treatment offered the maximum expected net monetary benefit (NMB) of £1184 at a cost-effectiveness threshold of £20,000 per quality-adjusted life-year (QALY). The NMB for the three best-performing strategies in each category (screen only, then treat; screen, test, then treat; and test all, then treat) ranged between -£1197 and -£1210. Further research to reduce uncertainty around potential longer-term benefits for the mothers and offspring, find ways of improving the accuracy of identifying women with GDM, and reduce costs of identification and treatment would be worthwhile. LIMITATIONS: We did not have access to IPD from populations in the UK outside of England. Few observational studies reported longer-term associations, and treatment trials have generally reported only perinatal outcomes. CONCLUSIONS: Using the national standard cost-effectiveness threshold of £20,000 per QALY it is not cost-effective to routinely identify pregnant women for treatment of hyperglycaemia. Further research to provide evidence on longer-term outcomes, and more cost-effective ways to detect and treat GDM, would be valuable. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013004608. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Systematic review and meta-analysis of the risk of severe and life-threatening thromboembolism in cancer patients receiving anti-EGFR monoclonal antibodies (cetuximab or panitumumab).

Cancer-associated thromboembolism is a substantial problem in clinical practice. An increase in the level of fibrinopeptide A (a substance associated with hypercoagulable states) has been observed in humans exposed to fluorouracil. Anti-EGFR monoclonal antibodies cetuximab and panitumumab, which are now widely used in patients with metastatic colorectal cancer, could prolong the uncovering of endothelial structures resulting from flouorouracil or other co-administered agents, thus favouring several factors leading to thromboembolism. We performed a systematic review and meta-analysis of randomised, controlled trials assessing whether cancer patients receiving anti-EGFR monoclonal antibodies cetuximab and panitumumab are at increased risk of thromboembolic events. We searched electronic databases (Medline, Embase, Web of Science, Central) and reference lists. Phase II/III randomised, controlled trials comparing standard anti-cancer regimens with or without anti-EGFR monoclonal antibodies and reporting serious venous thromboembolic events were included in the analysis. Seventeen studies (12,870 patients) were considered for quantitative analysis. The relative risk (RR) for venous thromboembolism (18 comparisons) was 1.46 (95% CI 1.26 to 1.69); the RR of pulmonary embolism, on the basis of eight studies providing nine comparisons, was 1.55 (1.20 to 2.00). Cancer patients receiving anti-EGFR monoclonal antibodies-containing regimens are approximately 1.5 times more likely to experience venous or pulmonary embolism, compared to those treated with the same regimens without anti-EGFR monoclonal antibodies. Clinicians should consider patient's baseline thromboembolic risk when selecting regimens that include cetuximab or panitumumab. Potential non-reporting of these important adverse events remains a concern. PROSPERO registration number is CRD42014009165.

The use of measures of obesity in childhood for predicting obesity and the development of obesity-related diseases in adulthood: a systematic review and meta-analysis.

BACKGROUND: It is uncertain which simple measures of childhood obesity are best for predicting future obesity-related health problems and the persistence of obesity into adolescence and adulthood. OBJECTIVES: To investigate the ability of simple measures, such as body mass index (BMI), to predict the persistence of obesity from childhood into adulthood and to predict obesity-related adult morbidities. To investigate how accurately simple measures diagnose obesity in children, and how acceptable these measures are to children, carers and health professionals. DATA SOURCES: Multiple sources including MEDLINE, EMBASE and The Cochrane Library were searched from 2008 to 2013. METHODS: Systematic reviews and a meta-analysis were carried out of large cohort studies on the association between childhood obesity and adult obesity; the association between childhood obesity and obesity-related morbidities in adulthood; and the diagnostic accuracy of simple childhood obesity measures. Study quality was assessed using Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) and a modified version of the Quality in Prognosis Studies (QUIPS) tool. A systematic review and an elicitation exercise were conducted on the acceptability of the simple measures. RESULTS: Thirty-seven studies (22 cohorts) were included in the review of prediction of adult morbidities. Twenty-three studies (16 cohorts) were included in the tracking review. All studies included BMI. There were very few studies of other measures. There was a strong positive association between high childhood BMI and adult obesity [odds ratio 5.21, 95% confidence interval (CI) 4.50 to 6.02]. A positive association was found between high childhood BMI and adult coronary heart disease, diabetes and a range of cancers, but not stroke or breast cancer. The predictive accuracy of childhood BMI to predict any adult morbidity was very low, with most morbidities occurring in adults who were of healthy weight in childhood. Predictive accuracy of childhood obesity was moderate for predicting adult obesity, with a sensitivity of 30% and a specificity of 98%. Persistence of obesity from adolescence to adulthood was high. Thirty-four studies were included in the diagnostic accuracy review. Most of the studies used the least reliable reference standard (dual-energy X-ray absorptiometry); only 24% of studies were of high quality. The sensitivity of BMI for diagnosing obesity and overweight varied considerably; specificity was less variable. Pooled sensitivity of BMI was 74% (95% CI 64.2% to 81.8%) and pooled specificity was 95% (95% CI 92.2% to 96.4%). The acceptability to children and their carers of BMI or other common simple measures was generally good. LIMITATIONS: Little evidence was available regarding childhood measures other than BMI. No individual-level analysis could be performed. CONCLUSIONS: Childhood BMI is not a good predictor of adult obesity or adult disease; the majority of obese adults were not obese as children and most obesity-related adult morbidity occurs in adults who had a healthy childhood weight. However, obesity (as measured using BMI) was found to persist from childhood to adulthood, with most obese adolescents also being obese in adulthood. BMI was found to be reasonably good for diagnosing obesity during childhood. There is no convincing evidence suggesting that any simple measure is better than BMI for diagnosing obesity in childhood or predicting adult obesity and morbidity. Further research on obesity measures other than BMI is needed to determine which is the best tool for diagnosing childhood obesity, and new cohort studies are needed to investigate the impact of contemporary childhood obesity on adult obesity and obesity-related morbidities. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013005711. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The Clinical and Cost Effectiveness of Aflibercept in Combination with Irinotecan and Fluorouracil-Based Therapy (FOLFIRI) for the Treatment of Metastatic Colorectal Cancer Which has Progressed Following Prior Oxaliplatin-Based Chemotherapy: a Critique of the Evidence.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer of aflibercept (Sanofi) to submit clinical and cost-effectiveness evidence for aflibercept in combination with irinotecan and fluorouracil-based therapy [irinotecan/5-fluorouracil/folinic acid (FOLFIRI)] for the treatment of metastatic colorectal cancer which has progressed following prior oxaliplatin-based chemotherapy, as part of the Institute's Single Technology Appraisal process. The Centre for Reviews and Dissemination and Centre for Health Economics at the University of York were commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and the resulting NICE guidance TA307 issued in March 2014. The ERG critically reviewed the evidence presented in the manufacturer's submission and identified areas requiring clarification, for which the manufacturer provided additional evidence. The clinical effectiveness data were derived from one good-quality double-blind randomised controlled trial (RCT), the VELOUR trial, which compared aflibercept plus FOLFIRI with placebo plus FOLFIRI. This RCT found a small but statistically significant increase in overall survival (OS); the difference in median OS was 1.44 months (13.5 months in the aflibercept group and 12.06 months in the placebo group). There was also a statistically significant increase in progression-free survival (PFS) with aflibercept; the difference in median PFS was 2.23 months (6.9 months in the aflibercept group and 4.67 months in the placebo group). However, grade 3-4 adverse events were more frequent in the aflibercept group than the placebo group: 83.5% compared with 62.5%. Treatment-emergent adverse events led to permanent discontinuation of treatment in 26.8% of patients in the aflibercept group and 12.1% of patients in the placebo group. The manufacturer's submission included an estimation of mean OS benefit based on extrapolation of the data, which was considerably longer than the median OS benefit reported (4.7 vs. 1.44 months). The ERG considered this to be an over estimate. The base-case incremental cost-effectiveness ratio (ICER) for the overall population was reported by the manufacturer to be £36,294 per quality-adjusted life-year (QALY). After correcting the model programming and updating the model to include the ERG's preferred parameter estimates, the ICER from the ERG's alternative base case was £54,368 per QALY. The extrapolation of the OS curves was the key cost-effectiveness driver and a major source of uncertainty in the model. Additional scenarios related to the extrapolation of OS undertaken by the ERG resulted in ICERs between £62,894 and £92,089 per QALY. After consideration of the manufacturer's submission and the ERG's critique, and submissions from other stakeholders, the NICE Appraisal Committee concluded that aflibercept in combination with irinotecan and fluorouracil-based therapy could not be considered a cost effective use of National Health Service resources for treating metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen. Aflibercept in combination with irinotecan and fluorouracil-based therapy is not recommended for the treatment of metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen in NICE guidance TA307.

Resistance to UV-induced apoptosis by ß-HPV5 E6 involves targeting of activated BAK for proteolysis by recruitment of the HERC1 ubiquitin ligase.

UV exposure is the main etiological agent in the development of non-melanoma skin cancer (NMSC), but mounting evidence suggests a co-factorial role for ß-genus HPV types early in tumor initiation or progression. UV damage initiates an apoptotic response, driven at the mitochondrial level by BCL-2 family proteins, that eliminates damaged cells that may accumulate deleterious mutations and acquire tumorigenic properties. BAK is a pro-apoptotic BCL-2 protein that functions ultimately to form pores that permeabilize the mitochondrial outer membrane, thereby committing a cell to death, a process involving changes in BAK phosphorylation and conformation. The E6 protein of ß-type HPV5 signals BAK for proteasomal degradation, a function that confers protection from UV-induced apoptosis. We find that HPV5 E6 does not constitutively target BAK for proteolysis, but targets the latter stages of BAK activation, following changes in phosphorylation and conformation. A mutational analysis identified the lysine residue on BAK required for proteolysis, and a functional siRNA screen identified the HECT domain E3 ubiquitin ligase HERC1 as being required for E6-mediated BAK degradation. We show that HERC1 interacts with BAK in E6-expressing cells that have been damaged by UV, and provide evidence that the interaction of HERC1 with BAK requires access to a hydrophobic surface on BAK that binds BH3 domains of BCL-2 proteins. We also show that HERC1 contains a putative BH3 domain that can bind to BAK. These findings reveal a specific and unique mechanism used by the HPV5 E6 protein to target BAK.

Safety and effectiveness of recombinant human bone morphogenetic protein-2 for spinal fusion: a meta-analysis of individual-participant data.

BACKGROUND: Recombinant human bone morphogenetic protein-2 (rhBMP-2) is widely used to promote fusion in spinal surgery, but its safety has been questioned. PURPOSE: To evaluate the effectiveness and safety of rhBMP-2. DATA SOURCES: Individual-participant data obtained from the sponsor or investigators and data extracted from study publications identified by systematic bibliographic searches through June 2012. STUDY SELECTION: Randomized, controlled trials of rhBMP-2 versus iliac crest bone graft (ICBG) in spinal fusion surgery for degenerative disc disease and related conditions and observational studies in similar populations for investigation of adverse events. DATA EXTRACTION: Individual-participant data from 11 eligible of 17 provided trials sponsored by Medtronic (Minneapolis, Minnesota) (n = 1302) and 1 of 2 other eligible trials (n = 106) were included. Additional aggregate adverse event data were extracted from 35 published observational studies. DATA SYNTHESIS: Primary outcomes were pain (assessed with the Oswestry Disability Index [ODI] or Short Form-36), fusion, and adverse events. At 24 months, ODI scores were 3.5% lower (better) with rhBMP-2 than with ICBG (95% CI, 0.5% to 6.5%) and radiographic fusion was 12% higher (CI, 2% to 23%). At or shortly after surgery, pain was more common with rhBMP-2 (odds ratio, 1.78 [CI, 1.06 to 2.95]). Cancer was more common after rhBMP-2 (relative risk, 1.98 [CI, 0.86 to 4.54]), but the small number of events precluded definite conclusions. LIMITATION: The observational studies were diverse and at risk of bias. CONCLUSION: At 24 months, rhBMP-2 increases fusion rates, reduces pain by a clinically insignificant amount, and increases early postsurgical pain compared with ICBG. Evidence of increased cancer incidence is inconclusive. PRIMARY FUNDING SOURCE: Yale University Open Data Access Project.

Risk estimation versus screening performance: a comparison of six risk algorithms for cardiovascular disease.

BACKGROUND: Risk of future cardiovascular disease (CVD) events is typically estimated from risk factors such as age, sex, blood pressure and cholesterol. Many 'risk algorithms' exist to estimate CVD risk. All should have similar screening performances because of the dominant effect of age in predicting who will and will not have a CVD event, regardless of the accuracy of CVD risk estimation. Six CVD risk algorithms were compared (Framingham 1991, Framingham 2008, Reynolds risk, ASSIGN, SCORE and QRISK2), each differing in the risk factors used and in CVD outcomes. METHODS: The six algorithms were applied to a simulated sample of 500,000 people aged 40-74, based on the population of England. CVD risk was calculated for each individual using all risk algorithms, and who did and did not have a CVD event in 10 years was simulated according to those estimated risks. Screening performance was assessed by estimating the detection rate (sensitivity) and false-positive rate (1 - specificity) at a range of cut-off values of CVD risk for each algorithm. The accuracy (calibration) of risk estimation was compared across the six algorithms. RESULTS: At a 20% false-positive rate the detection rates of the six algorithms ranged from 72% to 79%. The estimated risk cut-offs to achieve the same false-positive rate varied five-fold, from 4% to 21% because of the different risk factors and outcomes considered. CONCLUSIONS: All six risk algorithms had similar screening performances. The accuracy (calibration) of CVD risk estimation does not materially affect screening performance. In distinguishing who will and will not develop CVD it is screening performance that matters rather than the accuracy of the risk estimation.

Individual patient data meta-analysis of time-to-event outcomes: one-stage versus two-stage approaches for estimating the hazard ratio under a random effects model.

Meta-analyses of individual patient data (IPD) provide a strong and authoritative basis for evidence synthesis. IPD are particularly useful when the outcome of interest is the time to an event. Methodological developments now enable the meta-analysis of time-to-event IPD using a single model, allowing treatment effect and across-trial heterogeneity parameters to be estimated simultaneously. This differs from the standard approaches used with aggregate data, and also predominantly with IPD. Facilitated by a simulation study, we investigate what these new 'one-stage' random-effects models offer over standard 'two-stage' approaches. We find that two-stage approaches represent a robust, reliable and easily implementable way to estimate treatment effects and account for heterogeneity. Nevertheless, one-stage models can be used to provide a deeper insight into the data. Software for fitting one-stage Cox models with random effects using Restricted Maximum Likelihood methodology is made available, and its use demonstrated on an IPD meta-analysis assessing post-operative radio therapy for patients with non-small cell lung cancer. Copyright © 2011 John Wiley & Sons, Ltd.

Same-day discharge is feasible and safe in the majority of elderly patients undergoing elective percutaneous coronary intervention.

BACKGROUND: Same-day discharge after elective percutaneous coronary intervention (PCI) is safe in the majority of patients. However, the elderly have more comorbidities and less favorable coronary and peripheral arterial anatomy, which may preclude safe same-day discharge after PCI. We assessed the feasibility and safety of same-day discharge in an elderly cohort of patients. METHODS: A total of 1,580 consecutive patients undergoing elective PCI in a single center between January 2001 and January 2009 were included in the study. We compared the outcomes of elderly patients aged 75 or older to control patients under the age of 75 years. Patients were examined 6 hours post procedure and discharged if there were no complications. RESULTS: Of the 1,580 study patients 212 (13.4%) were elderly and 1,365 (86.6%) were younger controls. The elderly were more likely to be female, hypertensive and to have had previous coronary artery bypass graft (CABG) surgery and less likely to be smokers or to have hyperlipidemia (all p < 0.05). The number of lesions treated and their complexity were similar in both groups. Procedural success, in-hospital major adverse cardiac events (MACE) and the rates of same-day discharge were also similar in both groups. Same-day discharge was achieved in the majority (84%) of the elderly. There were no deaths within 24 hours of discharge. Readmission within 24 hours of discharge was rare (< 0.7%) in both groups. The 30-day MACE rate was low in both the elderly (3.3%) and control groups (3.6%; p = 1.0). CONCLUSIONS: Same-day discharge is safe and feasible in the majority of elderly patients following elective PCI.