Michaela Blundell

Erlotinib monotherapy for the maintenance treatment of non-small cell lung cancer after previous platinum-containing chemotherapy: a NICE single technology appraisal.

The UK National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of erlotinib (Roche) to submit evidence for the clinical and cost effectiveness of erlotinib as monotherapy for the maintenance treatment of patients with non-small cell lung cancer (NSCLC) and stable disease following previous treatment with four cycles of platinumcontaining therapy. The Liverpool Reviews and Implementation Group(LRiG) at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG) for this appraisal.The ERG reviewed the clinical- and cost-effectiveness evidence in two stages and in accordance with the decision problem defined by NICE. The analysis of the submitted models assessed the appropriateness of the approach taken by the manufacturer in modelling the decision problem. Analysis also included reliability of model implementation and the extent of conformity to published standards and prevailing norms of practice within the health economics modelling community. Particular attention was paid to issues likely to have substantial impact on the base-case cost-effectiveness results.Clinical evidence was derived from a multi-centre, double-blind, randomized, phase III study designed to address the overall population of NSCLC patients. Outcomes included progression-free survival (PFS) and overall survival (OS). The recruited population was mainly from outside of Western Europe and no patients in the pivotal trial had received pemetrexed as a firstline therapy, which is now accepted clinical practice in the UK. The evidence considered in this article includes only the population for whom marketing authorizations has been received–that is, patients with stable disease following first-line therapy.The trial reported a small but statistically significant increase in both PFS and OS in patients with stable disease receiving erlotinib compared with placebo. However, no significant difference was identified in OS when patients with non-squamous disease and stable disease were considered as a subgroup.The economic evidence was focussed on the ERG’s assessment of three economic models that related to patients with stable disease and compared erlotinib with placebo in the squamous and non-squamous populations and erlotinib with pemetrexed in the non-squamous population. The incremental cost-effectiveness ratios (ICERs) reported by the manufacturer were £39 936 per QALY gained (stable disease, all); £35 491 per QALY gained (stable disease, squamous); and £40 020 per QALY gained (stable disease, nonsquamous). In comparison with pemetrexed, in the cases where erlotinib was considered to be superior or equivalent, erlotinib dominated. In the cases where erlotinib was considered to be slightly inferior, then the ICERs ranged between £91 789 and £511 351 per QALY gained; these ICERs appear in the south-west corner of a cost-effectiveness plane, i.e. erlotinib is cheaper but less effective than pemetrexed.The ERG recalculated the base-case cost-effectiveness results in the manufacturer’s submission, considering nine key areas where corrections and/or adjustments were required, related to time horizon, discounting logic, costs of erlotinib and pemetrexed, cost of second-line chemotherapy, unit costs, utility values, PFS and OS. This resulted in ERG-revised ICERs for the stable disease squamous population of £44 812 per QALY gained, in the stable disease non-squamous population of £68 120 per QALY gained, and, when erlotinib was compared with pemetrexed, the result was £84 029 per QALY gained. All values were above NICE’s perceived willingness-to-pay threshold. After the second Appraisal Committee meeting, the Committee did not recommend the use of erlotinib in this patient population.

Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events (review of Technology Appraisal No. 90): a systematic review and economic analysis.

BACKGROUND Occlusive vascular events such as myocardial infarction (MI), ischaemic stroke and transient ischaemic attack (TIA) are the result of a reduction in blood flow associated with an artery becoming narrow or blocked through atherosclerosis and atherothrombosis. Peripheral arterial disease is the result of narrowing of the arteries that supply blood to the muscles and other tissues, usually in the lower extremities. The primary objective in the treatment of all patients with a history of occlusive vascular events and peripheral arterial disease is to prevent the occurrence of new occlusive vascular events. OBJECTIVES To assess the clinical effectiveness and cost-effectiveness of clopidogrel and modified-release dipyridamole (MRD) alone or with aspirin (ASA) compared with ASA (and each other where appropriate) in the prevention of occlusive vascular events in patients with a history of MI, ischaemic stroke/TIA or established peripheral arterial disease. To consider the clinical effectiveness and cost-effectiveness of clopidogrel in patients with multivascular disease. This review is an update of the evidence base for the National Institute for Health and Clinical Excellence (NICE) guidance Technology Appraisal No. 90 (TA90) entitled Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events (2005). DATA SOURCES Four electronic databases (EMBASE, MEDLINE, Web of Science and The Cochrane Library) were searched for randomised controlled trials (RCTs) and economic evaluations. Submissions to NICE by the manufacturers of the interventions were also considered. REVIEW METHODS A systematic review of clinical effectiveness and cost-effectiveness was conducted. To manage heterogeneity between trials, indirect analysis (using a mixed-treatment methodology) was performed on selected clinical outcomes. A new economic model was developed to assess incremental costs per life-year gained [quality-adjusted life-years (QALYs)]. RESULTS For evidence of clinical effectiveness, four RCTs were identified: CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events), ESPRIT (European/Australasian Stroke Prevention in Reversible Ischaemia Trial), PRoFESS (Prevention Regimen For Effectively avoiding Second Strokes) and ESPS-2 (Second European Stroke Prevention Study). In CAPRIE (patients with MI, ischaemic stroke or peripheral arterial disease), statistically significant outcomes in favour of clopidogrel were noted for the primary outcome (first occurrence of ischaemic stroke, MI or vascular death) compared with ASA [relative risk reduction 8.7%; 95% confidence interval (CI) 0.3% to 16.5%; p = 0.043]. In ESPRIT (patients with ischaemic stroke/TIA) for the primary outcome (first occurrence of death from all vascular causes, non-fatal stroke, non-fatal MI or major bleeding complication), the risk of event occurrence was statistically significantly lower in the MRD + ASA arm than in the ASA arm [hazard ratio (HR) 0.80; 95% CI 0.66 to 0.98], with no statistically significant difference in bleeding events between the two arms. In PRoFESS (patients with ischaemic stroke) the rate of recurrent stroke of any type (primary outcome) was similar in the MRD + ASA and clopidogrel groups, and the null hypothesis (that MRD + ASA was inferior to clopidogrel) could not be rejected. In ESPS-2 (patients with ischaemic stroke/TIA), on the primary outcome of stroke, statistically significant differences in favour of MRD + ASA were observed compared with ASA and MRD alone (relative risk 0.76; 95% CI 0.63 to 0.93). The outcomes addressed in the mixed-treatment comparisons (limited by the available data) for the ischaemic stroke/TIA population confirmed the results of the direct comparisons. The 11 economic evaluations included in the review of cost-effectiveness indicated that for patients with previous peripheral arterial disease, ischaemic stroke or MI, clopidogrel is cost-effective compared with ASA, and for patients with previous ischaemic stroke/TIA, treatment with MRD + ASA is cost-effective compared with any other treatment in patients in the secondary prevention of occlusive vascular events. The relevance of the review was limited as the economic evaluations were not based on the most current clinical data. Cost-effectiveness results generated from the Assessment Groups de novo economic model suggested that the most cost-effective approach for patients with ischaemic stroke/TIA is clopidogrel followed by MRD + ASA then ASA. For patients with MI, the most cost-effective approach is ASA followed by clopidogrel. For patients with established peripheral arterial disease, the most cost-effective approach is clopidogrel followed by ASA. For patients with multivascular disease, clopidogrel followed by ASA is the most cost-effective approach. Incremental cost-effectiveness ratios (ICERs) were also calculated for patients who are intolerant to ASA. Assuming that the branded price for clopidogrel is used and TA90 guidance is not applied, all of the ICERs range between £2189 and £13,558 per QALY gained. Probabilistic sensitivity analyses were fully consistent with these findings. CONCLUSIONS The evidence suggests that the most cost-effective treatment for patients with ischaemic stroke/TIA is clopidogrel followed by MRD + ASA followed by ASA; for patients with MI, ASA followed by clopidogrel; and for patients with established peripheral arterial disease or multivascular disease, clopidogrel followed by ASA. FUNDING The National Institute for Health Research Health Technology Assessment programme.

The British antibiotic and silver-impregnated catheters for ventriculoperitoneal shunts multi-centre randomised controlled trial (the BASICS trial): study protocol

BackgroundInsertion of a ventriculoperitoneal shunt (VPS) for the treatment of hydrocephalus is one of the most common neurosurgical procedures in the UK, but failures caused by infection occur in approximately 8% of primary cases. VPS infection is associated with considerable morbidity and mortality and its management results in substantial cost to the health service. Antibiotic-impregnated (rifampicin and clindamycin) and silver-impregnated VPS have been developed to reduce infection rates. Whilst there is some evidence showing that such devices may lead to a reduction in VPS infection, there are no randomised controlled trials (RCTs) to support their routine use.Methods/designOverall, 1,200 patients will be recruited from 17 regional neurosurgical units in the UK and Ireland. Patients of any age undergoing insertion of their first VPS are eligible. Patients with previous indwelling VPS, active and on-going cerebrospinal fluid (CSF) or peritoneal infection, multiloculated hydrocephalus requiring multiple VPS or neuroendoscopy, and ventriculoatrial or ventriculopleural shunt planned will be excluded. Patients will be randomised 1:1:1 to either standard silicone (comparator), antibiotic-impregnated, or silver-impregnated VPS. The primary outcome measure is time to VPS infection. Secondary outcome measures include time to VPS failure of any cause, reason for VPS failure (infection, mechanical failure, or patient failure), types of bacterial VPS infection (organism type and antibiotic resistance), and incremental cost per VPS failure averted.DiscussionThe British antibiotic and silver-impregnated catheters for ventriculoperitoneal shunts multi-centre randomised controlled trial (the BASICS trial) is the first multi-centre RCT designed to determine whether antibiotic or silver-impregnated VPS reduce early shunt infection compared to standard silicone VPS. The results of this study will be used to inform current neurosurgical practice and may potentially benefit patients undergoing shunt surgery in the future.Trial registrationInternational Standard Randomised Controlled Trial Number:ISRCTN49474281.

Antibiotic-impregnated catheters for prevention of bloodstream infection – Authors’ reply

www.thelancet.com Vol 388 November 5, 2016 2235 authors clearly point out, several other factors might have determined these important outcomes, such as mortality rather than bloodstream infection. This also means that a decrease in the incidence of bloodstream infections alone, which can otherwise be effectively treated, does not justify widespread preventive use of antibiotic catheters. Finally, a KaplanMeier curve for the primary outcome suggests that the benefi ts of antibiotic catheters are likely to be seen only if the catheters are used for longer durations (>7 days). If this observation holds true in a possible subgroup analysis, the information obtained might be helpful to selectively recommend antibiotic catheter use in patients anticipated to have longer catheter duration.