Cause of death trends among adults with and without cerebral palsy in the United States, 2013-2017.

BACKGROUND: Adults with cerebral palsy (CP) in the United States die much earlier than those without CP, a health inequality likely shaped by causes of death. Existing research has not considered demographic differences in mortality patterns. OBJECTIVES: To analyze differences in cause of death for adults who did/did not have CP reported on their death certificates and to assess sex and racial-ethnic difference in causes of death among adult decedents with CP. METHODS: Data are from the 2013-2017 US Multiple Cause of Death Mortality files (N = 13,332,871; n = 13,897 with CP). Multiple logistic regression models were used to compare differences in causes of death between adults with and without CP and to determine sex and racial-ethnic differences in causes of death among adults with CP. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated. RESULTS: As compared with decedents without CP, those with CP were more likely to die from pneumonitis (aOR 31.14, 95% CI 29.42-32.96), influenza/pneumonia (8.78, 8.30-9.29), respiratory failure (17.24, 15.19-18.69), and choking (20.66, 18.86-22.62) and less likely to die from heart disease (0.61, 0.58-0.65), cancer (0.12, 0.11-0.13), chronic lower respiratory diseases (0.50, 0.44-0.56), and cerebrovascular diseases (0.66, 0.59-0.75). Among adults with CP, female decedents were more likely than males to die from respiratory failure (1.21, 1.03-1.42), and non-Hispanic Black decedents were more likely than non-Hispanic White decedents to die from heart disease (1.24, 1.07-1.45) and cerebrovascular disease (1.77, 1.29-2.49). CONCLUSIONS: In 2013-2017, heart disease was the leading cause of death for adults with and without CP. However, for people with compared to those without CP, likelihood of death from likely preventable respiratory causes of death was higher. Non-Hispanic Black adults were more likely than non-Hispanic White adults to die from heart and cerebrovascular diseases. Public health, clinical, and rehabilitation efforts must use a multifaceted approach to address respiratory and circulatory health among people with CP. DATABASE: United States National Vital Statistics System of the Centers for Disease Control and Prevention Multiple Cause of Death Mortality files (National Bureau of Economic Research: https://www.nber.org/research/data/vital-statistics-mortality-data-nber).

Ledipasvir-Sofosbuvir for Treating Chronic Hepatitis C: A NICE Single Technology Appraisal-An Evidence Review Group Perspective.

The National Institute for Health and Care Excellence (NICE) invited Gilead, the company manufacturing ledipasvir-sofosbuvir (LDV/SOF), to submit evidence for the clinical effectiveness and cost effectiveness of LDV/SOF for treating chronic hepatitis C. The School of Health and Related Research (ScHARR) Technology Assessment Group was commissioned as the Evidence Review Group (ERG). This paper describes the company's submission (CS), the ERG review and the subsequent decision of the NICE Appraisal Committee (AC). The ERG produced a critical review of the clinical effectiveness and cost-effectiveness evidence of LDV/SOF based upon the CS. The clinical effectiveness data for LDV/SOF were taken from ten trials: three phase III trials and seven phase II trials. Trials compared different durations of LDV/SOF, with and without ribavirin (RBV). There were no head-to-head trials comparing LDV/SOF with any comparator listed in the NICE scope. Data from the trials were mostly from populations with genotype 1 (GT1) disease, although some limited data were available for populations with genotypes 3 and 4. For GT1 treatment-naïve patients, sustained viral response for 12 weeks (SVR12) rates for LDV/SOF ranged from 93.1 to 99.4 % for subgroups of patients with non-cirrhotic disease, whilst SVR rates of 94.1 to 100 % were reported for subgroups of patients with compensated cirrhosis. For GT1 treatment-experienced patients, SVR12 rates ranging from 95.4 to 100 % were reported for subgroups of non-cirrhotic patients, and SVR rates ranging from 81.8 to 100 % were reported within subgroups of patients with compensated cirrhosis. Comparator data were not searched systematically as part of the submission, but were based on the company's previous NICE submission of sofosbuvir, with additional targeted searches. The ERG's critical appraisal of the company's economic evaluation highlighted a number of concerns. The ERG's base case analyses suggested that the incremental cost-effectiveness ratios (ICERs) for LDV/SOF (+RBV) are dependent on (a) treatment durations, (b) whether patients have been previously treated and (c) whether patients have liver cirrhosis or not. The AC concluded that it was appropriate to use the approach taken in the ERG's exploratory analyses, in line with the marketing authorisation, which considered people with and without cirrhosis separately, and estimated the cost effectiveness for each recommended treatment duration of LDV/SOF.

Systematic review, network meta-analysis and exploratory cost-effectiveness model of randomized trials of minimally invasive techniques versus surgery for varicose veins.

BACKGROUND: A Health Technology Assessment was conducted to evaluate the relative clinical effectiveness and cost-effectiveness of minimally invasive techniques (foam sclerotherapy (FS), endovenous laser ablation (EVLA) and radiofrequency ablation (RFA)) for managing varicose veins, in comparison with traditional surgery. METHODS: A systematic review of randomized clinical trials (RCTs) was undertaken to assess the effectiveness of minimally invasive techniques compared with other treatments, principally surgical stripping, in terms of recurrence of varicose veins, Venous Clinical Severity Score (VCSS), pain and quality of life. Network meta-analysis and exploratory cost-effectiveness modelling were performed. RESULTS: The literature search conducted in July 2011 identified 1453 unique citations: 31 RCTs (51 papers) satisfied the criteria for effectiveness review. Differences between treatments were negligible in terms of clinical outcomes, so the treatment with the lowest cost appears to be most cost-effective. Total FS costs were estimated to be lowest, and FS was marginally more effective than surgery. However, relative effectiveness was sensitive to the model time horizon. Threshold analysis indicated that EVLA and RFA might be considered cost-effective if their costs were similar to those for surgery. These findings are subject to various uncertainties, including the risk of bias present in the evidence base and variation in reported costs. CONCLUSION: This assessment of currently available evidence suggests there is little to choose between surgery and the minimally invasive techniques in terms of efficacy or safety, so the relative cost of the treatments becomes one of the deciding factors. High-quality RCT evidence is needed to verify and further inform these findings.

Clinical effectiveness and cost-effectiveness of minimally invasive techniques to manage varicose veins: a systematic review and economic evaluation.

BACKGROUND: Varicose veins are enlarged, visibly lumpy knotted veins, usually in the legs. Uncomplicated varicose veins can cause major discomfort and some complications. They are part of chronic venous disease (CVD), which is reported to have a substantial negative impact on health-related quality of life (HRQoL). Traditional treatments for varicose veins involve surgical stripping and ligation and liquid sclerotherapy (LS), but can be invasive and painful. New minimally invasive treatments offer an alternative. These treatments typically involve use of laser, radiofrequency or foam sclerosant. They are increasingly widely used and offer potential benefits such as reduced complications, faster recovery, fewer physical limitations and improved quality of life. OBJECTIVE: The aim of this report is to evaluate the clinical effectiveness, safety and cost-effectiveness of the minimally invasive techniques of foam sclerotherapy (FS), endovenous laser ablation (EVLA) and radiofrequency ablation (RFA) in comparison with other techniques, including traditional surgical techniques, LS and conservative management, in the management of varicose veins. DATA SOURCES: A systematic search was made of 11 bibliographic databases of published and unpublished literature from their inception to July 2011: MEDLINE; EMBASE; Cumulative Index to Nursing and Allied Health Literature; The Cochrane Library; Biological Abstracts; Science Citation Index (SCI); Social Sciences Citation Index; Conference Proceedings Citation Index-Science; UK Clinical Research Network; Current Controlled Trials; and ClinicalTrials.gov. REVIEW METHODS: A systematic review of randomised controlled trials (RCTs) to assess the clinical effectiveness of minimally invasive techniques compared with other treatments, principally surgical stripping, in terms of recurrence of varicose veins, retreatment and clinical symptoms, as measured by the Venous Clinical Severity Score (VCSS), pain and quality of life. Network meta-analysis and exploratory cost-effectiveness modelling were performed. RESULTS: The literature search identified 1453 unique citations, of which 34 RCTs (54 papers) satisfied the criteria for the clinical effectiveness review. The minimally invasive techniques reported clinical outcomes similar to surgery. Rates of recurrence were slightly lower for EVLA, RFA and FS, especially for longer follow-up periods; VCSS score was lower for EVLA and FS than for stripping, but slightly higher for RFA; short-term pain was less for FS and RFA but higher for EVLA; higher quality-of-life scores were reported for all evaluated interventions than for stripping. Differences between treatments were therefore negligible in terms of clinical outcomes, so the treatment with the lowest cost appears to be most cost-effective. Our central estimate is that total FS costs were lowest and FS is marginally more effective than stripping. However, this result was sensitive to the model time horizon. Threshold analysis indicated that EVLA and RFA might be considered cost-effective if their costs are equivalent to stripping. These findings are subject to uncertainty on account of the risk of bias present in the evidence base and the variation in costs. LIMITATIONS: The relative clinical effectiveness and cost-effectiveness of the techniques are principally based on rates of post-operative technical recurrence rather than symptomatic recurrence, as this was the reported outcome in all trials. The true proportion of treated individuals who are likely to present with symptoms of recurrence requiring retreatment is therefore not certain. A figure reflecting the likely proportion of treated individuals who would experience symptomatic recurrence requiring retreatment (with its associated costs), therefore, had to be calculated by the authors based on a small number of studies. The findings of this report also need to be verified by data from future trials with longer follow-up and using more standardised outcome measures. CONCLUSIONS: This assessment of the currently available evidence suggests there is little to choose between the minimally invasive techniques in terms of efficacy or cost, and each offers a viable, clinically effective alternative to stripping. FS might offer the most cost-effective alternative to stripping, within certain time parameters. High-quality RCT evidence is needed. Future trials should aim to measure and report outcomes in a standardised manner, which would permit more efficient pooling of their results. STUDY REGISTRATION: PROSPERO number CRD42011001355. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Home telemonitoring or structured telephone support programmes after recent discharge in patients with heart failure: systematic review and economic evaluation.

BACKGROUND: Remote monitoring (RM) strategies have the potential to deliver specialised care and management to patients with heart failure (HF). OBJECTIVE: To determine the clinical effectiveness and cost-effectiveness of home telemonitoring (TM) or structured telephone support (STS) strategies compared with usual care for adult patients who have been recently discharged (within 28 days) from acute care after a recent exacerbation of HF. DATA SOURCES: Fourteen electronic databases (including MEDLINE, EMBASE, PsycINFO and The Cochrane Library) and research registers were searched to January 2012, supplemented by hand-searching relevant articles and contact with experts. The review included randomised controlled trials (RCTs) or observational cohort studies with a contemporaneous control group that included the following RM interventions: (1) TM (including cardiovascular implanted monitoring devices) with medical support provided during office hours or 24/7; (2) STS programmes delivered by human-to-human contact (HH) or human-to-machine interface (HM). REVIEW METHODS: A systematic review and network meta-analysis (where appropriate) of the clinical evidence was carried out using standard methods. A Markov model was developed to evaluate the cost-effectiveness of different RM packages compared with usual care for recently discharged HF patients. TM 24/7 or using cardiovascular monitoring devices was not considered in the economic model because of the lack of data and/or unsuitability for the UK setting. Given the heterogeneity in the components of usual care and RM interventions, the cost-effectiveness analysis was performed using a set of costing scenarios designed to reflect the different configurations of usual care and RM in the UK. RESULTS: The literature searches identified 3060 citations. Six RCTs met the inclusion criteria and were added to the 15 trials identified from the previous systematic reviews giving a total of 21 RCTs included in the systematic review. No trials of cardiovascular implanted monitoring devices or observational studies met the inclusion criteria. The methodological quality of the studies varied widely and reporting was generally poor. Compared with usual care, RM was beneficial in reducing all-cause mortality for STS HH [hazard ratio (HR) 0.77, 95% credible interval (CrI) 0.55 to 1.08], TM during office hours (HR 0.76, 95% CrI 0.49 to 1.18) and TM 24/7 (HR 0.49, 95% CrI 0.20 to 1.18); however, these results were statistically inconclusive. The results for TM 24/7 should be treated with caution because of the poor methodological quality of the only included study in this network. No favourable effect on mortality was observed with STS HM. Similar reductions were observed in all-cause hospitalisations for TM interventions, whereas STS interventions had no major effect. A sensitivity analysis, in which a study was excluded because it provided better-than-usual support to the control group, showed larger beneficial effects for most outcomes, particularly for TM during office hours. In the cost-effectiveness analyses, TM during office hours was the most cost-effective strategy with an estimated incremental cost-effectiveness ratio (ICER) of £11,873 per quality-adjusted life-year (QALY) compared with usual care, whereas STS HH had an ICER of £228,035 per QALY compared with TM during office hours. STS HM was dominated by usual care. Similar results were observed in scenario analyses performed using higher costs of usual care, higher costs of STS HH and lower costs of TM during office hours. LIMITATIONS: The RM interventions included in the review were heterogeneous in terms of monitored parameters and HF selection criteria and lacked detail in the components of the RM care packages and usual care (e.g. communication protocols, routine staff visits and resources used). As a result, the economic model developed scenarios for different RM classifications and their costs were estimated using bottom-up costing methods. Although the users can decide which of these scenarios is most representative of their setting, uncertainties still remain about the assumptions made in the estimation of these costs. In addition, the model assumed that the effectiveness of the interventions was constant over time, irrespective of the duration of deployment, and that the intervention was equally effective in different age/severity groups. CONCLUSION: Despite wide variation in usual care and RM strategies, cost-effectiveness analyses suggest that TM during office hours was an optimal strategy (in most costing scenarios). However, clarity was lacking among descriptions of the components of RM packages and usual care and there was a lack of robust estimation of costs. Further research is needed in these areas. STUDY REGISTRATION: PROSPERO registration no. CRD42011001368. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Systematic review, meta-analysis and economic modelling of diagnostic strategies for suspected acute coronary syndrome.

BACKGROUND: Current practice for suspected acute coronary syndrome (ACS) involves troponin testing 10-12 hours after symptom onset to diagnose myocardial infarction (MI). Patients with a negative troponin can be investigated further with computed tomographic coronary angiography (CTCA) or exercise electrocardiography (ECG). OBJECTIVES: We aimed to estimate the diagnostic accuracy of early biomarkers for MI, the prognostic accuracy of biomarkers for major adverse cardiac adverse events (MACEs) in troponin-negative patients, the diagnostic accuracy of CTCA and exercise ECG for coronary artery disease (CAD) and the prognostic accuracy of CTCA and exercise ECG for MACEs in patients with suspected ACS. We then aimed to estimate the cost-effectiveness of using alternative biomarker strategies to diagnose MI, and using biomarkers, CTCA and exercise ECG to risk-stratify troponin-negative patients. DATA SOURCES: We searched MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations; Cumulative Index of Nursing and Allied Health Literature (CINAHL), EMBASE, Web of Science, Cochrane Central Database of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR), NHS Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment database from 1985 (CTCA review) or 1995 (biomarkers review) to November 2010, reviewed citation lists and contacted experts to identify relevant studies. REVIEW METHODS: Diagnostic studies were assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool and prognostic studies using a framework adapted for the project. Meta-analysis was conducted using bayesian Markov chain Monte Carlo simulation. We developed a decision-analysis model to evaluate the cost-effectiveness of alternative biomarker strategies to diagnose MI, and the cost-effectiveness of biomarkers, CTCA or exercise ECG to risk-stratify patients with a negative troponin. Strategies were applied to a theoretical cohort of patients with suspected ACS. Cost-effectiveness was estimated as the incremental cost per quality-adjusted life-year (QALY) of each strategy compared with the next most effective, taking a health-service perspective and a lifetime horizon. RESULTS: Sensitivity and specificity (95% predictive interval) were 77% (29-96%) and 93% (46-100%) for troponin I, 80% (33-97%) and 91% (53-99%) for troponin T (99th percentile threshold), 81% (50-95%) and 80% (26-98%) for quantitative heart-type fatty acid-binding protein (H-FABP), 68% (11-97%) and 92% (20-100%) for qualitative H-FABP, 77% (19-98%) and 39% (2-95%) for ischaemia-modified albumin and 62% (35-83%) and 83% (35-98%) for myoglobin. CTCA had 94% (61-99%) sensitivity and 87% (16-100%) specificity for CAD. Positive CTCA and positive-exercise ECG had relative risks of 5.8 (0.6-24.5) and 8.0 (2.3-22.7) for MACEs. In most scenarios in the economic analysis presentation, high-sensitivity troponin measurement was the most effective strategy with an incremental cost-effectiveness ratio (ICER) of less than the £20,000-30,000/QALY threshold (ICER £7487-17,191/QALY). CTCA appeared to be the most cost-effective strategy for patients with a negative troponin, with an ICER of £11,041/QALY. However, when a lower MACE rate was assumed, CTCA had a high ICER (£262,061/QALY) and the no-testing strategy was optimal. LIMITATIONS: There was substantial variation between the primary studies and heterogeneity in their results. Findings of the economic model were dependent on assumptions regarding the value of detecting and treating positive cases. CONCLUSIONS: Although presentation troponin has suboptimal sensitivity, measurement of a 10-hour troponin level is unlikely to be cost-effective in most scenarios compared with a high-sensitivity presentation troponin. CTCA may be a cost-effective strategy for troponin-negative patients, but further research is required to estimate the effect of CTCA on event rates and health-care costs. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Rituximab for the first-line treatment of stage III-IV follicular lymphoma (review of Technology Appraisal No. 110): a systematic review and economic evaluation.

BACKGROUND: Follicular lymphoma (FL) is a non-Hodgkin's lymphoma which typically presents when the disease is at an advanced stage. The majority of patients receive first-line therapy of rituximab in combination with chemotherapy, with two-thirds receiving cyclophosphamide, vincristine and prednisolone. The clinical and cost-effectiveness of other chemotherapies in combination with rituximab in first-line therapy is not known. OBJECTIVE: To systematically evaluate and appraise the clinical effectiveness and cost-effectiveness of rituximab (MabThera(®), Roche Products) in combination with chemotherapy, compared with chemotherapy alone, for the first-line treatment of symptomatic stage III-IV FL. DATA SOURCES: A systematic review of literature and an economic evaluation were carried out. Key databases [including MEDLINE In-Process & Other Non-Indexed Citations; Cumulative Index to Nursing and Allied Health Literature (CINAHL); EMBASE; The Cochrane Library, including the Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), NHS Economic Evaluation Database (NHS EED) and Health Technology Assessment (HTA) databases; Science Citation Index (SCI); and BIOSIS], plus research registers and conference proceedings, were searched for relevant studies from inception up to October 2010. REVIEW METHODS: One reviewer assessed titles and abstracts of studies identified by the search strategy, obtained the full text of relevant papers and screened them against inclusion criteria. Data from included studies were extracted by one reviewer using a standardised data extraction form and checked by a second reviewer. The quality of included studies was assessed by one reviewer and checked by a second. A patient-level simulation model was developed to estimate the costs and quality-adjusted life-year (QALY) gains from the perspective of the UK NHS and Personal Social Services, with costs and benefits discounted at 3.5% annually. RESULTS: Four randomised controlled trials comparing rituximab plus chemotherapy (R-chemotherapy) with chemotherapy alone in untreated, symptomatic patients with stage III-IV FL were identified. R-chemotherapy compared with chemotherapy alone increased the likelihood of a response to treatment in all four trials, with no additional toxicity of clinical relevance. Overall response rates were significantly improved in all four trials, with a difference between the R-chemotherapy and chemotherapy arms of between 5% and 24%, respectively. Complete response rates were also improved, with a difference between the R-chemotherapy and chemotherapy arms of between 2% and 25%, respectively. Exploratory meta-analyses were conducted; the level of statistical heterogeneity was very high and thus we believe the response rates from the individual trials to be a more robust estimator of the efficacy of the specific R-chemotherapy regimens. Over a follow-up period of 4-5 years, R-chemotherapy significantly increased the overall survival rate compared with chemotherapy alone in three trials, although data for two trials were compromised owing to the use of additional treatments. The incremental cost-effectiveness ratio (ICER) for the addition of rituximab to CVP (cyclophosphamide, vincristine and prednisolone), CHOP (cyclophosphamide, doxorubicin/adriamycin, vincristine and prednisolone) and MCP [mitoxantrone, chlorambucil (Leukeran(®), Aspen) and prednisolone] was £7720, £10,834 and £9316 per QALY gained, respectively, when it was assumed that first-line rituximab maintenance was not used. A scenario analysis is also presented, assuming that responders to R-chemotherapy in first-line induction receive maintenance with rituximab, increasing the ICER to £14,959, £21,687 and £20,493 per QALY gained, respectively. LIMITATIONS: These relate to the sources of data used for the effectiveness in first and second line and the assumed utility values; there is uncertainty about the effect of salvage treatment on patients who had been previously treated with an anthracycline regimen. There is uncertainty whether or not rituximab is as effective in second-line treatment when patients have been previously treated with rituximab. CONCLUSIONS: The results from four randomised trials comparing R-chemotherapy with chemotherapy alone showed an improvement in clinical effectiveness outcomes, with minimal clinically relevant additional adverse events or toxicity. The cost per QALY gained is estimated to be < £25,000 for all three comparisons under our base-case assumption and is considerably lower if first-line rituximab maintenance is not assumed. More data on patients pre-treated with rituximab and on the effect of first-line maintenance with rituximab is required for future work. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Prescribing high-dose lipid-lowering therapy early to avoid subsequent cardiovascular events: is this a cost-effective strategy?

BACKGROUND: While evidence shows high-dose statins reduce cardiovascular events compared with moderate doses in individuals with acute coronary syndrome (ACS), many primary care trusts (PCT) advocate the use of generic simvastatin 40 mg/day for these patients. METHODS AND RESULTS: Data from 28 RCTs were synthesized using a mixed treatment comparison model. A Markov model was used to evaluate the cost-effectiveness of treatments taking into account adherence and the likely reduction in cost for atorvastatin when the patent expires. There is a clear dose-response: rosuvastatin 40 mg/day produces the greatest reduction in low-density lipoprotein cholesterol (56%) followed by atorvastatin 80 mg/day (52%), and simvastatin 40 mg/day (37%). Using a threshold of £20,000 per QALY, if adherence levels in general practice are similar to those observed in RCTs, all three higher dose statins would be considered cost-effective compared to simvastatin 40 mg/day. Using the net benefits of the treatments, rosuvastatin 40 mg/day is estimated to be the most cost-effective alternative. If the cost of atorvastatin reduces in line with that observed for simvastatin, atorvastatin 80 mg/day is estimated to be the most cost-effective alternative. CONCLUSION: Our analyses show that current PCT policies intended to minimize primary care drug acquisition costs result in suboptimal care.

Trabectedin for the treatment of relapsed ovarian cancer.

The paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of trabectedin for the treatment of relapsed platinum-sensitive ovarian cancer, based upon a review of the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The submission addressed only part of the decision problem and did not provide evidence to compare trabectedin (Yondelis®, PharmaMar) and pegylated liposomal doxorubicin hydrochloride (PLDH) (Caelyx®, Schering-Plough) with key comparators. The submission's direct comparison evidence came from one reasonable-quality randomised controlled trial (RCT) of trabectedin and PLDH versus PLDH alone (ET743-OVA-301). The results of the RCT were subdivided into the entire platinum-sensitive population (> 6-month relapse after initial platinum-based chemotherapy) and partially platinum-sensitive (≥ 6- to 12-month relapse) and fully platinum-sensitive (> 12-month relapse) populations. The outcomes included were overall survival, progression-free survival measured by three types of assessor, response rates, adverse effects of treatment, health-related quality of life and cost per quality-adjusted-life-year (QALY) gained. A mixed treatment comparison (MTC) meta-analysis comparing trabectedin and PLDH with single-agent PLDH within the entire platinum-sensitive population, with paclitaxel or with topotecan also formed part of the submission. The RCT data showed that trabectedin plus PLDH compared with PLDH monotherapy had a significant effect on overall survival only within the partially platinum-sensitive subgroup. PFS results reported by the independent radiologists showed significant effects in favour of the trabectedin and PLDH arm for the entire and partially platinum-sensitive populations only. Rates of grade 3 and 4 adverse events were mostly higher in the trabectedin and PLDH arm than in the PLDH alone arm. There were several issues regarding the undertaking of the MTC, and thus the data were not considered robust. Furthermore, the ERG did not believe the MTC to be necessary to answer the decision problem. The manufacturer submitted a de novo cost-effectiveness model. The main analysis compared trabectedin in combination with PLDH versus paclitaxel, topotecan and PLDH (each as monotherapy) in the entire platinum-sensitive population, using results estimated from the MTC. Additional analyses were presented comparing trabectedin in combination with PLDH versus PLDH monotherapy using direct evidence from the OVA-301 trial for the fully, partially and entire platinum-sensitive populations. The cost per QALY gained for trabectedin in combination with PLDH versus PLDH monotherapy was estimated to be £ 70,076 in the main analysis. In the additional analyses, the cost per QALY gained for trabectedin in combination with PLDH versus PLDH monotherapy was £ 94,832, £ 43,996 and £ 31,092 for the entire, partially and fully platinum-sensitive populations, respectively. Additional work was undertaken by the ERG using patient-level data and amending some assumptions to provide a better statistical fit to the Kaplan-Meier data than the exponential distribution assumed by the manufacturer. The ERG base-case estimate of the cost per QALY of trabectedin in combination with PLDH ranged from £46,503 to £54,607 in the partially platinum-sensitive population. At the time of writing, trabectedin in combination with PLDH for the treatment of women with relapsed platinum-sensitive ovarian cancer is not recommended by NICE in the final appraisal determination.

Homebirth, freebirth and doulas: casualty and consequences of a broken maternity system.

In Australia private homebirth remains unfunded and uninsured and publicly funded homebirth models are not widely available. Doulas are increasingly hired by women for support during childbirth and freebirth (birth intentionally unattended by a health professional) appears to be on the rise. The recently released Improving Maternity Services in Australia--The Report of the Maternity Services Review (MSR) exclude homebirth from the funding and insurance reforms proposed. Drawing on recent research we argue that homebirth has become a casualty of a broken maternity system. The recent rise in the numbers of women employing doulas and choosing to birth at home unattended by any health professional, we argue, is in part a consequence of not adequately meeting the needs of women for continuity of midwifery care and non-medicalised birthing options.

A case study of conflict management in bonobos: how does a bonobo (Pan paniscus) mother manage conflicts between her sons and her female coalition partner?

Female coalitions are an important part of the social organization of bonobos. The strength of the mother-son relationship is another essential part of this social structure. A bonobo mother is therefore facing a dilemma when a conflict arises between her sons and her female coalition partners. Will she take her coalition partner's side and favour the social organization of the group or support her son in order to defend her offspring? In order to address this issue, we performed an observational study of the captive group at Planckendael (Belgium) and used social grooming and proximity to assess the relationship between individuals. As a case study, we focused on the relationships between Hortense, one of the group's mothers, her 3 sons Redi, Vifijo and Zamba, and her coalition partner Hermien. Surprisingly, we observed that Hortense preferentially supported her female coalition partner. For Hortense's social status in the group, it may be more important to maintain the strong relationship with her higher-ranking female coalition partner than to support her sons.

Comparative effectiveness regulations and pharmaceutical innovation.

As healthcare reform evolves and takes shape, comparative effectiveness research (CER) appears to be one of the central topics on the national healthcare agenda. Over the past couple of years, comparative effectiveness has been explicitly incorporated in more than ten bills. For example, the passage of the American Recovery and Reinvestment Act of 2009 authorized $US1.1 billion for CER. Comparative effectiveness, when costs are formally considered, offers the hope of efficient resource allocation within US healthcare markets. However, the future operationalization and implementation of comparative effectiveness is uncertain, and there exist potentially negative, and unintended, consequences under certain scenarios. One example, and the focus of this article, is pharmaceutical innovation. Incentives for pharmaceutical R&D could be affected if drug development costs increase as a result of firms having to bear, directly or indirectly, the costs of running larger, randomized, head-to-head comparative effectiveness trials. While this may or may not be the case with current and future comparative effectiveness legislation and its subsequent implementation, the potential consequences for pharmaceutical innovation warrant recognition. This is the purpose of the article. To achieve this goal, we develop several models of clinical trial design, drug development costs and R&D investment. By example, we shed light on the causal links between the models and the ways in which industry R&D investment can be affected.

Early high-dose lipid-lowering therapy to avoid cardiac events: a systematic review and economic evaluation.

OBJECTIVE: To evaluate the cost-effectiveness of high-dose statins (atorvastatin 80 mg/day, rosuvastatin 40 mg/day and simvastatin 80 mg/day) versus simvastatin 40 mg/day in individuals with acute coronary syndrome (ACS). DATA SOURCES: Eleven bibliographic databases, including MEDLINE, CINAHL, EMBASE, Cochrane Database of Systematic Reviews, CENTRAL, DARE and NHS EED, were searched from inception to 2008. REVIEW METHODS: Data relating to study design, baseline patient characteristics, clinical or surrogate outcome, and adverse events were abstracted, and methodological quality was assessed according to standard methods. A synthesis of the available evidence was performed using a Bayesian mixed treatment meta-analysis using both direct and indirect evidence. An existing Markov model was modified to explore the costs and benefits associated with a lifetime of the differing treatment regimens. RESULTS: A total of 3345 titles and abstracts were screened for inclusion in the review of clinical effectiveness and 125 full papers retrieved and assessed in detail. Of these, 30 papers met the inclusion criteria for the review, describing 28 trials. The Bayesian mixed treatment meta-analysis demonstrated a clear dose-response relationship in terms of reductions in low-density lipoprotein cholesterol (LDL-c), with rosuvastatin 40 mg/day achieving the greatest percentage reduction (56%) from baseline, followed by atorvastatin 80 mg/day (52%), simvastatin 80 mg/day (45%) and simvastatin 40 mg/day (37%). Although serious adverse events with statins are rare, their incidence is likely to be greater with higher doses. Several clinical scenarios were used to explore the effect of adherence on the cost-effectiveness of the treatment regimens. Using a threshold of 20,000 pounds per quality-adjusted life-year (QALY) and assuming that the benefits and adherence rates observed in the clinical trials are generalisable to a clinical setting and that individuals who do not tolerate the higher-dose statins are prescribed simvastatin 40 mg/day, then simvastatin 80 mg/day, atorvastatin 80 mg/day and rosuvastatin 40 mg/day would be considered cost-effective compared with simvastatin 40 mg/day in individuals with ACS. Simvastatin 80 mg/day is not well tolerated because of the high incidence rates of less severe adverse events such as myopathy (26-fold higher than rates in those receiving simvastatin 20 mg/day), which are likely to affect adherence levels in clinical practice. The reference case shows that rosuvastatin is the optimal treatment for individuals with a recent history of ACS using a threshold of 20,000 pounds per QALY. However, this is based on the assumption that the additional incremental reductions in LDL-c observed in patients treated with rosuvastatin 40 mg/day compared with atorvastatin will transfer into corresponding changes in relative risks of cardiovascular events. CONCLUSIONS: Simvastatin 80 mg/day cannot be recommended because of the high incidence rates of adverse events. If the cost of atorvastatin decreases in line with that observed for simvastatin when the patent ends in 2011, atorvastatin 80 mg/day will be the most cost-effective treatment for all thresholds; if the cost reduces to 25% of the current value, atorvastatin 80 mg/day will be the most cost-effective treatment for thresholds between 5000 pounds and 30,000 pounds per QALY. Large long-term RCTs reporting effects in terms of clinical events are required to determine the optimum statin use for subgroups.

Impact of overweight and obesity on hospitalization: race and gender differences.

OBJECTIVE: To examine associations between weight status and number of all-cause and cause-specific hospitalizations overall, and by race and gender. DESIGN: Longitudinal cohort study. SUBJECTS: White and black adults (n=15 355) from the Atherosclerosis Risk in Communities Study who were normal weight (body mass index: >or=18.5 to <25.0 kg m(-2); n=4997), overweight (>or=25.0 to <30.0 kg m(-2); n=6100), or obese (>or=30.0 kg m(-2); n=4258) at baseline. MEASUREMENTS: Information on hospitalizations was collected using community and cohort surveillance methods. Negative binomial models adjusted for race, gender, field center, age, physical activity, education level, smoking status, alcoholic beverage consumption and health insurance at baseline. Adjusted numbers of hospitalizations were calculated after setting covariates to the mean value (for continuous variables) or to the average distribution (for categorical variables) observed in the entire cohort and are expressed as the number of hospitalizations per 1000 adults followed over a period of 13 years. RESULTS: The covariate-adjusted average number of all-cause hospitalizations was 1316 per 1000 normal weight, 1543 per 1000 overweight and 2025 per 1000 obese. Normal weight women had significantly fewer hospitalizations than normal weight men (1173 versus 1515 per 1000), but the increase associated with being obese on the number of all-cause hospitalizations was larger in women than men (791 versus 589 per 1000). There was no significant difference detected between the number of hospitalizations in normal weight whites and blacks, and the increase in hospitalizations with overweight or obesity was also not different. Effects of weight status on several primary causes of hospitalization differed by gender and race group. CONCLUSION: Our work suggests that obesity prevention may reduce hospitalizations, a major component of rising healthcare costs. The impact of successful obesity prevention is likely to be larger in women than in men, and similar in blacks and whites.

Assessment: the use of natalizumab (Tysabri) for the treatment of multiple sclerosis (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.

The clinical and radiologic impact of natalizumab (Tysabri) as therapy for multiple sclerosis (MS) is assessed. On the basis of Class I evidence, natalizumab has been demonstrated to reduce measures of disease activity and to improve measures of disease severity in patients with relapsing-remitting (RR) MS (Level A). The relative efficacy of natalizumab compared to current disease-modifying therapies cannot be defined accurately (Level U). Similarly, the value of natalizumab in the treatment of secondary progressive (SP) MS is unknown (Level U). The value of combination therapy using natalizumab and interferon in the treatment of RRMS is also unknown (Level U). There is an increased risk of developing progressive multifocal leukoencephalopathy (PML) in natalizumab-treated patients (Level A for combination therapy, Level C for monotherapy) and possibly an increased risk of other opportunistic infections (Level C). The PML risk in a pooled clinical trial cohort has been estimated to be 1 person for every 1,000 patients treated for an average of 17.9 months, although this figure could change in either direction with more experience with the drug.

Non-invasive assessment of lower extremity muscle composition after incomplete spinal cord injury.

STUDY DESIGN: Cross-sectional study. OBJECTIVE: (1) To quantify intramyocellular lipid (IMCL) content of the soleus muscle. (2) To assess the T(2) relaxation rates in the lower extremity skeletal muscles in persons with incomplete spinal cord injury (SCI). SETTING: Academic Institution, Florida. METHODS: Eight subjects (42+/-10 years old; 70+/-12 kg; 176+/-10 cm) with chronic (17+/-9 months post injury) motor SCI (C4-T12; ASIA C or D) and eight matched healthy controls were tested. Localized unsuppressed proton spectroscopy (H-MRS) was performed to estimate total lipid content and individual lipid components; IMCL and extramyocellular lipid (EMCL) from the soleus muscle. T(2)-weighted imaging of lower extremity muscles yielded muscle T(2) rates. RESULTS: The IMCL content of the soleus muscle was 3.3 times higher in the patient group as compared to controls (P=0.002; 0.0401 (0.0234-0.0849) versus 0.0123 (0.0090-0.0175)). Similarly, EMCL measures were 4.5 times higher as compared to the controls (P=0.002). Significant differences were observed in the T(2) relaxation times of the soleus and gastrocnemius muscles (P<0.05). CONCLUSION: The increased levels of IMCL might interfere with the glucose uptake in skeletal muscle; potentially predisposing persons with incomplete SCI to the development of peripheral insulin resistance. Marked elevations in the T(2) relaxation times of the locomotor muscles are reflective of an altered muscle composition.

Neutralizing antibodies to interferon beta: assessment of their clinical and radiographic impact: an evidence report: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.

The clinical and radiologic impact of developing neutralizing antibodies (NAbs) to interferon beta (IFNbeta) while on this therapy for multiple sclerosis (MS) is assessed. On the basis of Class II and III evidence, it is concluded that treatment of patients with MS with IFNbeta (Avonex, Betaseron, or Rebif) is associated with the production of NAbs (Level A). NAbs in the serum are probably associated with a reduction in the radiographic and clinical effectiveness of IFNbeta treatment (Level B). In addition, the rate of NAb production is probably less with IFNbeta-1a treatment than with IFNbeta-1b treatment, although the magnitude and persistence of this difference is difficult to determine (Level B). Finally, it is probable that there is a difference in seroprevalence due to variability in the dose of IFNbeta injected or in the frequency or route of its administration (Level B). Regardless of the explanation, it seems clear that IFNbeta-1a (as it is currently formulated for IM injection) is less immunogenic than the current IFNbeta preparations (either IFNbeta-1a or IFNbeta-1b) given multiple times per week subcutaneously (Level A). However, because NAbs disappear in some patients even with continued IFNbeta treatment (especially in patients with low titers), the persistence of this difference is difficult to determine (Level B). Although the finding of sustained high-titer NAbs (>100 to 200 NU/mL) is associated with a reduction in the therapeutic effects of IFNbeta on radiographic and clinical measures of MS disease activity, there is insufficient information on the utilization of NAb testing to provide specific recommendations regarding when to test, which test to use, how many tests are necessary, or which cutoff titer to apply (Level U).

The costs of fatal and non-fatal falls among older adults.

OBJECTIVE: To estimate the incidence and direct medical costs for fatal and non-fatal fall injuries among US adults aged >or=65 years in 2000, for three treatment settings stratified by age, sex, body region, and type of injury. METHODS: Incidence data came from the 2000 National Vital Statistics System, 2001 National Electronic Injury Surveillance System-All Injury Program, 2000 Health Care Utilization Program National Inpatient Sample, and 1999 Medical Expenditure Panel Survey. Costs for fatal falls came from Incidence and economic burden of injuries in the United States; costs for non-fatal falls were based on claims from the 1998 and 1999 Medicare fee-for-service 5% Standard Analytical Files. A case crossover approach was used to compare the monthly costs before and after the fall. RESULTS: In 2000, there were almost 10 300 fatal and 2.6 million medically treated non-fatal fall related injuries. Direct medical costs totaled 0.2 billion dollars for fatal and 19 billion dollars for non-fatal injuries. Of the non-fatal injury costs, 63% (12 billion dollars ) were for hospitalizations, 21% (4 billion dollars) were for emergency department visits, and 16% (3 billion dollars) were for treatment in outpatient settings. Medical expenditures for women, who comprised 58% of the older adult population, were 2-3 times higher than for men for all medical treatment settings. Fractures accounted for just 35% of non-fatal injuries but 61% of costs. CONCLUSIONS: Fall related injuries among older adults, especially among older women, are associated with substantial economic costs. Implementing effective intervention strategies could appreciably decrease the incidence and healthcare costs of these injuries.