Omalizumab for the treatment of severe persistent allergic asthma: a systematic review and economic evaluation.

BACKGROUND: Allergic asthma is a long-term disorder of the airways resulting from overexpression of immunoglobulin E (IgE) in response to environmental allergens. Patients with poorly controlled asthma are at high risk of exacerbations requiring additional treatment, including hospitalisations. Severe exacerbations are potentially life threatening. Guidelines identify five treatment steps for both adults and children. Omalizumab (Xolair(®)) is a recombinant DNA-derived humanised monoclonal antibody indicated as an add-on therapy in patients aged ≥ 6 years with severe persistent allergic asthma uncontrolled at treatment step 4 or 5. OBJECTIVE: To determine the clinical effectiveness, safety and cost-effectiveness of omalizumab, as an add-on therapy to standard care, within its licensed indication, compared with standard therapy alone for the treatment of severe persistent allergic asthma in adults and adolescents aged ≥ 12 years and children aged 6-11 years. DATA SOURCES: Eleven electronic databases (including MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials) and additional sources including regulatory agency reports were searched from inception to October 2011. Additional data sources include: the manufacturer's submission (MS); two previous National Institute for Health and Care Excellence (NICE) single technology appraisal (STA) submissions; and existing reviews on the safety of omalizumab and oral corticosteroids (OCSs). REVIEW METHODS: Systematic reviews of the clinical effectiveness and cost-effectiveness evidence for omalizumab were performed. The primary outcome was number of clinically significant (CS) exacerbations. Other outcomes included asthma symptoms, unscheduled health-care use, asthma-related mortality, OCS use and health-related quality of life (HRQoL). Because of methodological and clinical heterogeneity between trials, a narrative synthesis was applied. Pragmatic reviews with best evidence syntheses were used to assess adverse events of omalizumab and OCSs. The cost-effectiveness of omalizumab was assessed from the perspective of the UK NHS in the two separate populations: adults and adolescents, and children, using a cohort Markov model. Costs and outcomes were discounted at 3.5% per annum. Results are presented for additional subgroup populations: (1) hospitalised for asthma in the previous year, (2) adults and adolescents on maintenance OCSs and (3) three or more exacerbations in the previous year. RESULTS: Eleven randomised controlled trials (RCTs) and 13 observational studies were identified, including four RCTs/subgroups in the adult licensed population and one subgroup in children. A minority of patients were on maintenance OCSs. No evidence comparing omalizumab with OCSs was identified. Omalizumab significantly reduced the incidence of CS exacerbations in both adults and children [adults: INvestigatioN of Omalizumab in seVere Asthma Trial (INNOVATE): rate ratio 0.74; 95% CI 0.55 to 1.00; children IA-05 EUP (the a priori subgroup of patients who met the European Medicines Agency license criteria) 0.66; 95% CI 0.44 to 1.00]. Significant benefits were observed for a range of other outcomes in adults. Subgroup evidence showed benefits in adults on maintenance OCSs. Evidence for an OCS-sparing effect of omalizumab was limited but consistent. Omalizumab is available as 75 mg and 150 mg prefilled syringes at prices of £128.07 and £256.15 respectively. The incremental cost-effectiveness ratio (ICER) for adults and adolescents is £83,822 per quality-adjusted life-year (QALY) gained, whereas the ICER for children is £78,009 per QALY gained. The results are similar for the subgroup population of ≥ 3 exacerbations in the previous year, whereas the ICER for the other subgroup populations are lower; £46,431 for the hospitalisation subgroup in adults and adolescents, £44,142 for the hospitalisation subgroup in children and £50,181 for the maintenance OCS subgroup. CONCLUSION: Omalizumab reduces the incidence of CS exacerbations in adults and children, with benefits on other outcomes in adults. Limited, underpowered subgroup evidence exists that omalizumab reduces exacerbations and OCS requirements in adults on OCSs. Evidence in children is weaker and more uncertain. The ICERs are above conventional NHS thresholds of cost-effectiveness. The key drivers of cost-effectiveness are asthma-related mortality risk and, to a lesser extent, HRQoL improvement and OCS-related adverse effects. An adequately powered double-blind RCT in both adults and children on maintenance OCSs and an individual patient data meta-analysis of existing trials should be considered. A registry of all patients on omalizumab should be established. STUDY REGISTRATION: The study was registered as PROSPERO CRD42011001625. FUNDING: This report was commissioned by the National Institute for Health Research Health Technology Assessment programme on behalf of NICE as project number HTA 10/128/01.

Resultados en pacientes con rotura del tendón de Aquiles tratados quirúrgicamente con técnica convencional frente a pacientes tratados con técnica mínimamente invasiva. Evolución a dos años / Outcomes in patients with Achilles tendon rupture surgically managed with conventional technique vs patients treated with minimally invasive technique. Two-year outcome

Objetivo: Comparar dos técnicas quirúrgicas para la resolución de la rotura del tendón de Aquiles en pacientes jóvenes deportistas ocasionales. Pacientes y métodos: Estudio de 25 pacientes intervenidos quirúrgicamente: 18 con técnica convencional, con un punto de Kessler central, y siete casos tratados con técnica mini-open, con doble punto de Kessler lateral y medial al tendón. Resultados: Entre los 18 pacientes operados con técnica convencional, uno presentó dehiscencia de la herida y otro infección de la herida. Entre los siete pacientes operados con técnica mínimamente invasiva no se observaron complicaciones. Con esta técnica se redujo el tiempo quirúrgico, y la reincorporación laboral y a las actividades cotidianas fue significativamente más rápida. El porcentaje de adherencias y dehiscencias de la herida también se redujo por la menor superficie expuesta. Conclusiones: La cirugía mínimamente invasiva en la rotura del tendón de Aquiles ofrece una recuperación más rápida e inserción laboral y deportiva en menor tiempo; también reduce los tiempos quirúrgicos (AU)

Objective: To compare two surgical techniques for solving Achilles tendon rupture in young recreational athletes. Patients and methods: Study performed in 25 patients undergoing surgery: 18 with conventional technique, with a central Kessler stitch, and seven cases treated with mini-open technique, with double Kessler stitch lateral and medial to the tendon. Results: Of the 18 patients operated with conventional technique, one had wound dehiscence and another wound infection. No complications were seen in the seven patients operated with a minimally invasive technique. This technique reduced surgical time and return to work and activities of daily living was significantly faster. The percentage of wound adhesions and dehiscences also decreased owing to the smaller surface exposed. Conclusions: Minimally invasive surgery in Achilles tendon rupture provides a faster recovery and return to work and sports in a shorter time; it also reduces surgical times (AU)

Sugammadex for reversal of neuromuscular block after rapid sequence intubation: a systematic review and economic assessment.

Sugammadex 16 mg kg⁻¹ can be used for the immediate reversal of neuromuscular block 3 min after administration of rocuronium and could be used in place of succinylcholine for emergency intubation. We have systematically reviewed the efficacy and cost-effectiveness and made an economic assessment of sugammadex for immediate reversal. The economic assessment investigated whether sugammadex appears cost-effective under various assumptions about the value of any reduction in recovery time with sugammadex, the likelihood of a 'can't intubate, can't ventilate' (CICV) event, the age of the patient, and the length of the procedure. Three trials were included in the efficacy review. Sugammadex administered 3 or 5 min after rocuronium produced markedly faster recovery than placebo or spontaneous recovery from succinylcholine-induced block. No published economic evaluations were found. Our economic analyses showed that sugammadex appears more cost-effective, where the value of any reduction in recovery time is greater, where the reduction in mortality compared with succinylcholine is greater, and where the patient is younger, for lower probabilities of a CICV event and for long procedures which do not require profound block throughout. Because of the lack of evidence, the value of some parameters remains unknown, which makes it difficult to provide a definitive assessment of the cost-effectiveness of sugammadex in practice. The use of sugammadex in combination with high-dose rocuronium is efficacious. Further research is needed to clarify key parameters in the analysis and to allow a fuller economic assessment.

Sugammadex compared with neostigmine/glycopyrrolate for routine reversal of neuromuscular block: a systematic review and economic evaluation.

The cost-effectiveness of sugammadex for the routine reversal of muscle relaxation produced by rocuronium or vecuronium in UK practice is uncertain. We performed a systematic review of randomized controlled trials of sugammadex compared with neostigmine/glycopyrrolate and an economic assessment of sugammadex for the reversal of moderate or profound neuromuscular block (NMB) produced by rocuronium or vecuronium. The economic assessment aimed to establish the reduction in recovery time and the 'value of time saved' which would be necessary for sugammadex to be potentially cost-effective compared with existing practice. Three trials indicated that sugammadex 2 mg kg⁻¹ (4 mg kg⁻¹) produces more rapid recovery from moderate (profound) NMB than neostigmine/glycopyrrolate. The economic assessment indicated that if the reductions in recovery time associated with sugammadex in the trials are replicated in routine practice, sugammadex would be cost-effective if those reductions are achieved in the operating theatre (assumed value of staff time, £4.44 per minute), but not if they are achieved in the recovery room (assumed value of staff time, £0.33 per minute). However, there is considerable uncertainty in these results. Sugammadex has the potential to be cost-effective compared with neostigmine/glycopyrrolate for the reversal of rocuronium-induced moderate or profound NMB, provided that the time savings observed in trials can be achieved and put to productive use in clinical practice. Further research is required to evaluate the effects of sugammadex on patient safety, predictability of recovery from NMB, patient outcomes, and efficient use of resources.

Sugammadex for the reversal of muscle relaxation in general anaesthesia: a systematic review and economic assessment.

BACKGROUND: Sugammadex (Bridion) is a newly developed agent for the reversal of neuromuscular blockade (NMB) induced by rocuronium or vecuronium. Sugammadex can reverse profound blockade and can be given for immediate reversal and its use would avoid the potentially serious adverse effects of the currently used agent, succinylcholine. Also, sugammadex can reverse NMB more quickly and predictably than existing agents. OBJECTIVES: To determine the clinical effectiveness and cost-effectiveness of sugammadex for the reversal of muscle relaxation after general anaesthesia in UK practice following routine or rapid induction of NMB. DATA SOURCES: Medical databases [including MEDLINE, EMBASE, CINAHL, Science Citation Index, BIOSIS and Cochrane Central Register of Controlled Trials (CENTRAL), conference proceedings, internet sites and clinical trials registers] were searched to identify published and unpublished studies. The main searches were carried out in May 2008 and supplemented by current awareness updates up until November 2008. REVIEW METHODS: For the clinical effectiveness review, randomised controlled trials of sugammadex against placebo or an active comparator (neostigmine + glycopyrrolate) for the reversal of moderate or profound NMB and for immediate reversal (spontaneous recovery from succinylcholine-induced blockade) were included. The primary effectiveness outcome was speed of recovery from NMB, as measured by objective monitoring of neuromuscular function. For the cost-effectiveness review, a de novo economic assessment considered the routine induction of NMB and the rapid induction and/or reversal of NMB, and threshold analyses were carried out on a series of pairwise comparisons to establish how effective sugammadex needs to be to justify its cost. RESULTS: The review of clinical effectiveness included four randomised active-control trials of sugammadex, nine randomised placebo-controlled trials and five studies in special populations. A total of 2132 titles and abstracts and 265 full-text publications were screened. The included trials indicated that sugammadex produces more rapid recovery from moderate or profound NMB than placebo or neostigmine. Median time to recovery from moderate blockade was 1.3-1.7 minutes for rocuronium + sugammadex, 21-86 minutes for rocuronium + placebo and 17.6 minutes for rocuronium + neostigmine. In profound blockade, median time to recovery was 2.7 minutes for rocuronium + sugammadex, 30 to > 90 minutes for rocuronium + placebo, and 49 minutes for rocuronium + neostigmine. Results for vecuronium were similar. In addition, recovery from NMB was faster with rocuronium reversed by sugammadex 16 mg/kg after 3 minutes (immediate reversal) than with succinylcholine followed by spontaneous recovery (median time to primary outcome 4.2 versus 7.1 minutes). The evidence base for modelling cost-effectiveness is very limited. However, assuming that the reductions in recovery times seen in the trials can be achieved in routine practice and can be used productively, sugammadex [2 mg/kg (4 mg/kg)] is potentially cost-effective at its current list price for the routine reversal of rocuronium-induced moderate (profound) blockade, if each minute of recovery time saved can be valued at approximately 2.40 pounds (1.75 pounds) or more. This is more likely to be achieved if any reductions in recovery time are in the operating room (estimated value of 4.44 pounds per minute saved) rather than the recovery room (estimated value of 0.33 pounds per minute saved). The results were broadly similar for rocuronium- and vecuronium-induced blockade. For rapid reversal of NMB it appeared that any reduction in morbidity from adopting sugammadex is unlikely to result in significant cost savings. LIMITATIONS: The evidence base was not large and many of the published trials were dose-finding and safety studies with very small sample sizes. Also, some relevant outcomes, in particular patient experience/quality of life and resources/costs used, were either not investigated or not reported. In addition, it is likely that the patients included in the efficacy trials were relatively young and in good general health compared with the overall surgical population. Regarding the economic evaluation, there appears to be no evidence linking measures of clinical efficacy to patients' health-related quality of life and mortality risks. CONCLUSIONS: Sugammadex may be a cost-effective option compared with neostigmine + glycopyrrolate for reversal of moderate NMB and also provides the facility to recover patients from profound blockade. Rocuronium + sugammadex could be considered as a replacement for succinylcholine for rapid induction (and reversal) of NMB, although this may not be a cost-effective option in some types of patient at current list prices for sugammadex. Considerable uncertainties remain about whether the full benefits of sugammadex can be realised in clinical practice.

Topotecan for the treatment of recurrent and stage IVB carcinoma of the cervix.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of topotecan in combination with cisplatin for the treatment of recurrent and stage IVB carcinoma of the cervix, in accordance with the licensed indication, based upon the evidence submission from the manufacturer to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The outcomes measured were overall survival, progression-free survival, response rates, adverse effects of treatment, health-related quality of life (HRQoL) and quality-adjusted life-years (QALYs) gained. The manufacturer stated that topotecan plus cisplatin is the only combination regimen to date to have demonstrated a statistically significant survival advantage compared to cisplatin monotherapy in the licensed population. The clinical evidence came from three clinical trials comparing topotecan plus cisplatin with cisplatin monotherapy (GOG-0179), topotecan plus cisplatin with paclitaxel plus cisplatin (GOG-0169), and four cisplatin-based combination therapies: topotecan plus cisplatin, paclitaxel plus cisplatin, gemcitabine plus cisplatin, and vinorelbine plus cisplatin (GOG-0204). Results from GOG-0179 showed greater median overall survival with topotecan plus cisplatin than with cisplatin monotherapy: 9.4 months versus 6.5 months. Similar results were also reported for median progression-free survival. Response rates also showed an advantage with topotecan plus cisplatin compared with cisplatin monotherapy. The response rates in patients receiving cisplatin monotherapy were very low, but the potential reasons for this were not discussed in the manufacturer's submission. Patients receiving topotecan plus cisplatin experienced a greater number of adverse events and the ERG was concerned with some of the assumptions related to HRQoL. In the base-case direct comparison, the incremental cost-effectiveness ratio (ICER) of topotecan plus cisplatin versus cisplatin monotherapy was 17,974 pounds per QALY in the main licensed population, 10,928 pounds per QALY in the cisplatin-naive population (including stage IVB patients) and 32,463 pounds per QALY in sustained cisplatin-free interval patients. In response to the point for clarification raised by the ERG, the manufacturer submitted a revised indirect comparison incorporating HRQoL and a longer time horizon. Where the hazard ratio derived from GOG-0169 was employed, paclitaxel plus cisplatin was dominated by topotecan plus cisplatin, but, where the hazard ratio from GOG-0204 was adopted, paclitaxel plus cisplatin was found to have an ICER of 13,260 pounds per QALY versus topotecan plus cisplatin. At present there is a paucity of evidence available on the clinical effects of topotecan plus cisplatin and the effects of palliative treatment in general for women with advanced and recurrent carcinoma of the cervix. Further trials, or the implementation of registries, are required to establish the efficacy and safety of topotecan plus cisplatin. The guidance issued by NICE on 28 October 2009 as a result of the STA states that topotecan in combination with cisplatin is recommended as a treatment option for women with recurrent or stage IVB cervical cancer, only if they have not previously received cisplatin. Women who have previously received cisplatin and are currently being treated with topotecan in combination with cisplatin for the treatment of cervical cancer should have the option to continue therapy until they and their clinicians consider it appropriate to stop.

Use of non-randomised evidence alongside randomised trials in a systematic review of endovascular aneurysm repair: strengths and limitations.

OBJECTIVE: To assess whether limitations of randomised controlled trials (RCTs) of endovascular aneurysm repair (EVAR) can be addressed by evidence from non-randomised studies. DESIGN: Analysis of data from a systematic review. METHODS: We conducted a review of EVAR versus open repair or non-surgical management of abdominal aortic aneurysms. In addition to RCTs, we included pre-specified registries of EVAR and open repair. RESULTS: The six included RCTs randomised patients in 2003 and earlier. Of the three registries included, one contributed data on a large (>8000) sample of patients treated with newer generation EVAR devices and followed up for up to 8 years. However, treatment dates of these patients overlapped with those of the RCTs. The other registries were of limited usefulness. A large (>45,000) controlled observational study published while the review was in progress broadly supported the findings of RCTs comparing EVAR with open surgery. A comparison of outcomes across all studies did not support the hypothesis that the findings of the RCTs are no longer representative of clinical practice. CONCLUSIONS: Both randomised and non-randomised sources of evidence have strengths and weaknesses for assessing the effectiveness of EVAR. Further research should explore the optimum use of registry data, including patient-level analyses.

Endovascular stents for abdominal aortic aneurysms: a systematic review and economic model.

OBJECTIVE: To determine the clinical effectiveness and cost-effectiveness of endovascular aneurysm repair (EVAR) of infrarenal abdominal aortic aneurysms (AAAs) in patients at varying levels of risk. DATA SOURCES: The following bibliographic databases were searched (2005-February 2007): BIOSIS Previews, CINAHL, Cochrane Central Register of Controlled Trials, EMBASE, ISI Proceedings, MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, Science Citation Index and Zetoc Conferences. REVIEW METHODS: A systematic review of the clinical effectiveness of EVAR was performed using standard methods. Meta-analysis was employed to estimate a summary measure of treatment effect on relevant outcomes based on intention to treat analyses. A second systematic review was undertaken to identify existing cost-effectiveness analyses of EVAR compared with open surgery and non-surgical interventions. Two new decision models were developed to inform the review. RESULTS: Six RCTs were included in the clinical effectiveness review. Thirty-four studies evaluated the role of patients' baseline characteristics in predicting risks of particular outcomes after EVAR. The majority were based on data relating to devices in current use from the EUROSTAR registry. Compared with open repair EVAR reduces operative mortality (odds ratio 0.35, 95% CI 0.19 to 0.63) and medium-term aneurysm-related mortality (hazard ratio 0.49, 95% CI 0.29 to 0.83) but offers no significant difference in all-cause mortality. EVAR is associated with increased rates of complications and reinterventions, which are not offset by any increase in health-related quality of life. EVAR trial 2 comparing EVAR with non-surgical management in patients unfit for open repair found no differences in mortality between groups; however, substantial numbers of patients randomised to non-surgical management crossed over to receive surgical repair of their aneurysm. The cost-effectiveness systematic review identified six published decision models. Both models considered relevant for the decision in the UK concluded that EVAR was not cost-effective on average compared with open repair at a threshold of 20,000 pounds per quality-adjusted life-year (QALY). Another model concluded that EVAR would be on average more cost-effective than no surgical intervention in unfit patients at this threshold. The Medtronic model concluded that EVAR was more cost-effective than open repair for fit patients at this threshold. The York economic evaluations found that EVAR is not cost-effective compared with open repair on average at a threshold of 30,000 pounds per QALY, with the results very sensitive to model assumptions and the baseline risk of operative mortality. Exploratory analysis to evaluate management options in patients unsuitable for open surgery suggested that the cost-effectiveness of EVAR may be sensitive to aneurysm size and patient's age at operation. Indicative modelling suggests that EVAR may be cost-effective for small aneurysms in some patient groups. Ongoing RCTs will provide further evidence relating to these patients. CONCLUSION: Open repair is more likely to be cost-effective than EVAR on average in patients considered fit for open surgery. EVAR is likely to be more cost-effective than open repair for a subgroup of patients at higher risk of operative mortality. These results are based on extrapolation of mid-term results of clinical trials. Evidence does not currently support EVAR for the treatment of ruptured aneurysms. Further follow-up of the existing UK trials should be undertaken and the relative costs of procedures and devices should be investigated further.

Cyclic voltammetry determination of epinephrine with a carbon fiber ultramicroelectrode.

A carbon fiber ultramicroelectrode was used for the electroanalytical determination of epinephrine in biological fluids (urine) by cyclic voltammetry. The ultramicroelectrode was subjected to an electrochemical pretreatment in order to improve the epinephrine adsorption on the electrode surface. With this preconcetration step, detection limits of 7.8 ng ml(-1) and determination limits of 27.6 ng ml(-1) can be reached. The method was contrasted with native fluorescence determination-similar results were obtained.

Predictive assessment of vocal efficiency (PAVE). A method for voice therapy outcome measurement.

A prospective study was carried out to examine the degree to which a standard voice assessment could discriminate between the potential benefits of two different voice therapy programmes for individual patients. The study encompassed 200 dysphonia subjects who were referred for voice therapy and had completed treatment within a prescribed two-year period. A standard assessment procedure was carried out on first attendance for each patient and guidelines were used to assign patients to different treatment programmes on the basis of the assessment results. The assessment discriminated well between patients requiring voice therapy to change physiological parameters of voice usage and patients able to self adjust voice usage, and provided an objective means of measuring outcomes.

Determination of abscisic acid by cathodic stripping square wave voltammetry.

In this paper a study is accomplished on behavior in a mercury electrode, of the phytohormone abscisic acid and of the conditions of accumulation in a HMDE. A mechanism is proposed of reduction based on its electrochemical behavior and proving the product of the reduction through mass spectrometry of bulks. A method is proposed for the determination of Abscisic acid (ABA) with a quantification limit of 58 ng ml(-1). The procedure is applied wing determination of ABA in pears through the combination of high performance liquid chromatography (HPLC) with electrochemical quantification.