Evidence For Clinical Effectiveness Research Articles

Dabigatran etexilato per la prevenzione del tromboembolismo venoso in pazienti sottoposti a sostituzione elettiva di anca o ginocchio

The National Institute for Health and Clinical Excellence (NICE) invited Boehringer Ingelheim GmbH, the manufacturer of dabigatran etexilate (DBG), to submit evidence on the clinical and cost effectiveness of this drug for the primary prevention of venous thromboembolism (VTE) in adult patients who have undergone total hip replacement (THR) or total knee replacement (TKR) surgery, as part of NICE’s single technology appraisal process. The comparators were enoxaparin and fondaparinux, as identified in the scope issued by NICE. The School of Health and Related Research at the University of Sheffield was commissioned to act as the Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and NICE’s subsequent decisions. Clinical-effectiveness evidence for DBG versus enoxaparin was derived from two randomized, double-blind, noninferiority trials, one for THR and the other for TKR. Clinical-effectiveness evidence for DBG versus fondaparinux was taken from a mixed treatment comparison (MTC) and from one study. The results presented show that DBG at the licensed dose of 220 mg and 150 mg once daily was noninferior to enoxaparin (40 mg once daily) in terms of the primary efficacy outcome of total VTE and all-cause mortality. In the MTC, fondaparinux was found to be more effective than DBG; the level of statistical significance was not reported. The manufacturer’s cost-effectiveness model estimated that at a dose of 220 mg once a day, DBG dominated enoxaparin in both THR and TKR. At a dose of 150 mg daily, DBG dominated enoxaparin in THR, while enoxaparin dominated DBG in TKR. At a dose of 220 mg daily, DBG was less cost effective than fondaparinux in THR. The cost per QALY gained for fondaparinux versus DBG was £11 111 (year 2008 values). At a dose of 150 mg daily, DBG was less cost effective than fondaparinux in THR. The cost per QALY gained for fondaparinux versus DBG was £6857 (year 2008 values). In TKR, both DBG doses were dominated by fondaparinux. There was some evidence that DBG was more cost effective than enoxaparin; however, these results were based on only one trial each in THR and TKR. Fondaparinux appeared to be more cost effective than DBG; however, this was based on indirect comparisons. NICE concluded that although there was uncertainty in the evidence base, DBG was very likely to be of equivalent clinical and cost effectiveness to enoxaparin or fondaparinux in the prevention of VTE. The NICE Appraisal Committee (AC) acknowledged that oral administration of DBG, without the need for monitoring, would reduce administration costs and that it may support adherence to treatment. Therefore, the AC concluded that DBG should be recommended as an option in the circumstances in which enoxaparin (or fondaparinux as an alternative) may be offered.

Clinical effectiveness and cost-effectiveness of first-line chemotherapy for adult patients with locally advanced or metastatic non-small cell lung cancer: a systematic review and economic evaluation

The National Institute for Health and Care Excellence (NICE) has issued multiple guidance for the first-line management of patients with lung cancer and recommends different combinations of chemotherapy treatments. This review provides a synthesis of clinical effectiveness and cost-effectiveness evidence supporting current guidance. To evaluate the clinical effectiveness and cost-effectiveness of first-line chemotherapy currently licensed in Europe and recommended by NICE, for adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). Three electronic databases (MEDLINE, EMBASE and The Cochrane Library) were searched from 2001 to August 2010. Trials that compared first-line chemotherapy currently licensed in Europe and recommended by NICE in chemotherapy-naive adult patients with locally advanced or metastatic NSCLC were included. Data on key outcomes including, but not limited to, overall survival (OS), progression-free survival (PFS) and adverse events (AEs) were extracted. For the assessment of cost-effectiveness, outcomes included incremental cost per quality-adjusted life-year (QALY) gained. Analyses were performed for three NSCLC subpopulations: patients with predominantly squamous disease, patients with predominantly non-squamous disease and patients with epidermal growth factor receptor (EGFR) mutation-positive (M+) status. Meta-analysis and mixed-treatment comparison methodology were conducted where appropriate. Twenty-three trials involving > 11,000 patients in total met the inclusion criteria. The quality of the trials was poor. In the case of patients with squamous disease, there were no statistically significant differences in OS between treatment regimes. The mixed-treatment comparison demonstrated that, in patients with non-squamous disease, pemetrexed (Alimta®, Eli Lilly and Company; PEM) + platinum (PLAT) increases OS statistically significantly compared with gemcitabine (Gemzar®, Eli Lilly and Company; GEM) + PLAT [hazard ratio (HR) = 0.85; 95% confidence interval (CI) 0.74 to 0.98] and that paclitaxel (Abraxane®, Celgene Corporation; PAX) + PLAT increases OS statistically significantly compared with docetaxel (Taxotere®, Sanofi-aventis; DOC) + PLAT (HR = 0.79, 95% CI 0.66 to 0.93). None of the comparisons found any statistically significant differences in OS among patients with EGFR M+ status. Direct meta-analysis showed a statistically significant improvement in PFS with gefitinib (Iressa®, AstraZeneca; GEF) compared with DOC + PLAT and PAX + PLAT (HR = 0.49; 95% CI 0.33 to 0.73; and HR = 0.38; 95% CI 0.24 to 0.60, respectively). No papers related to UK decision-making were identified. A de novo economic model was developed. Using list prices (British National Formulary), cisplatin (CIS) doublets are preferable to carboplatin doublets, but this is reversed if electronic market information tool prices are used, in which case drug administration costs then become more important than drug acquisition costs. For patients with both squamous and non-squamous disease, moving from low to moderate willingness-to-pay thresholds, the preferred drugs are PAX → GEM → DOC. However, in patients with non-squamous disease, PEM + CIS resulted in increased OS and would be considered cost-effective up to £35,000 per QALY gained. For patients with EGFR M+, use of GEF compared with PAX or DOC yields very high incremental cost-effectiveness ratios. Vinorelbine (Navelbine®, Pierre Fabre Pharmaceutical Inc.) was not shown to be cost-effective in any comparison. Poor trial quality and a lack of evidence for all drug comparisons complicated and limited the data analysis. Outcomes and adverse effects are not consistently combined across the trials. Few trials reported quality-of-life data despite their relevance to patients and clinicians. The results of this comprehensive review are unique to NSCLC and will assist clinicians to make decisions regarding the treatment of patients with advanced NSCLC. The design of future lung cancer trials needs to reflect the influence of factors such as histology, genetics and the new prognostic biomarkers that are currently being identified. In addition, trials will need to be adequately powered so as to be able to test for statistically significant clinical effectiveness differences within patient populations. New initiatives are in place to record detailed information on the precise chemotherapy (and targeted chemotherapy) regimens being used, together with data on age, cell type, stage of disease and performance status, allowing for very detailed observational audits of management and outcomes at a population level. It would be useful if these initiatives could be expanded to include the collection of health economics data. The National Institute for Health Research Health Technology Assessment.

Reviewing the Evidence to Inform the Population of Cost-Effectiveness Models within Health Technology Assessments

Health technology assessments (HTAs) typically require the development of a cost-effectiveness model, which necessitates the identification, selection, and use of other types of information beyond clinical effectiveness evidence to populate the model parameters. The reviewing activity associated with model development should be transparent and reproducible but can result in a tension between being both timely and systematic. Little procedural guidance exists in this area. The purpose of this article was to provide guidance, informed by focus groups, on what might constitute a systematic and transparent approach to reviewing information to populate model parameters. A focus group series was held with HTA experts in the United Kingdom including systematic reviewers, information specialists, and health economic modelers to explore these issues. Framework analysis was used to analyze the qualitative data elicited during focus groups. Suggestions included the use of rapid reviewing methods and the need to consider the trade-off between relevance and quality. The need for transparency in the reporting of review methods was emphasized. It was suggested that additional attention should be given to the reporting of parameters deemed to be more important to the model or where the preferred decision regarding the choice of evidence is equivocal. These recommendations form part of a Technical Support Document produced for the National Institute for Health and Clinical Excellence Decision Support Unit in the United Kingdom. It is intended that these recommendations will help to ensure a more systematic, transparent, and reproducible process for the review of model parameters within HTA.

Oncolytic virotherapy: the questions and the promise.

Oncolytic virotherapy is a new strategy to reduce tumor burden through selective virus replication in rapidly proliferating cells. Oncolytic viruses are members of at least ten virus families, each with its advantages and disadvantages. Here, I briefly review the recent advances and key challenges, as exemplified by the best-studied platforms. Recent advances include preclinical proof of feasibility, clinical evidence of tolerability and effectiveness, and the development of new strategies to improve efficacy. These include engineered tumor selectivity and expression of antitumorigenic genes that could function independently of virus replication, identification of combinatorial therapies that accelerate intratumoral virus propagation, and modification of immune responses and vascular delivery for treatment of metastatic disease. Key challenges are to select "winners" from the distinct oncolytic platforms that can stimulate anti-cancer immunity without affecting virus replication and can lyse cancer stem cells, which are most likely responsible for tumor maintenance, aggressiveness, and recurrence. Preventing the emergence of resistant tumor cells during virotherapy through the activation of multiple death pathways, the development of a better understanding of the mechanisms of cancer stem-cell lysis, and the development of more meaningful preclinical animal models are additional challenges for the next-generation of engineered viruses.

The Promise and Peril of Mobile Health Applications for Diabetes and Endocrinology

We are in the midst of what some have called a "mobile health revolution". Medical applications ("apps") for mobile phones are proliferating in the marketplace and clinicians are likely encountering patients with questions about the medical value of these apps. We conducted a review of medical apps focused on endocrine disease. We found a higher percentage of relevant apps in our searches of the iPhone app store compared with the Android marketplace. For our diabetes search in the iPhone store, the majority of apps (33%) focused on health tracking (blood sugars, insulin doses, carbohydrates), requiring manual entry of health data. Only two apps directly inputted blood sugars from glucometers attached to the mobile phone. The remainder of diabetes apps were teaching/training apps (22%), food reference databases (8%), social blogs/forums (5%), and physician directed apps (8%). We found a number of insulin dose calculator apps which technically meet criteria for being a medically regulated mobile application, but did not find evidence for FDA-approval despite their availability to consumers. Far fewer apps were focused on other endocrine disease and included medical reference for the field of endocrinology, access to endocrine journals, height predictors, medication trackers, and fertility apps. Although mobile health apps have great potential for improving chronic disease care, they face a number of challenges including lack of evidence of clinical effectiveness, lack of integration with the health care delivery system, the need for formal evaluation and review and organized searching for health apps, and potential threats to safety and privacy.

Abstract P368: Risk Factor Interventions are Effective for Preventing Cardiovascular Events in HIV-Infected Patients on Antiretroviral Therapy: A Systematic Review and Meta-analysis

Introduction: The declining rate of HIV-related deaths has become rather slow in recent times, largely because of the rising incidence of cardiovascular events associated with the disease and its long-term treatment with anti-retroviral drugs. While conclusive evidences support the effectiveness of cardiovascular risk factor interventions in the general population, there is a dearth of such evidence of clinical effectiveness in certain high-risk subgroups, particularly HIV-infected patients on antiretroviral treatment. Objective: To evaluate the clinical effectiveness of risk factor interventions in preventing cardiovascular disease in HIV-positive patients on antiretroviral treatment (ART) and summarize the effect size. Design and methods: Systematic review of randomized controlled trials investigating the effects of interventions in modifying ART-associated risk factors for cardiovascular disease. Trials were eligible for inclusion if they were published in the last 12 years [2000 to June 2012] and participants were HIV-positive, on ART and having more than one ART-associated cardiovascular risk factor. Results: In total, 2,071 HIV-positive participants from 10 randomized trials were included in the review. The interventions evaluated comprised lifestyle modification, lipid-lowering treatment and smoking cessation. Overall, the main results showed significant improvements in total cholesterol [P<0.0001], LDL cholesterol [P<0.0001], HDL cholesterol [P<0.002], triglycerides [P<0.001], apolipoprotein B levels [P=0.036], adiposity [<0.001], anthropometry [P<0.001], insulin sensitivity [P<0.05], HbA1c levels [P<0.001], FBG levels [P=0.017], adiponectin levels [P<0.05], dietary intake [P<0.001], smoking abstinence [P<0.0001] and Framingham score [P=0.03]. The results also showed improvements in systolic [from 145.6±14.5 mmHg to 122.8±5.2 mmHg] and diastolic blood pressure [from 84.7±1.7 mmHg to 80.1±3.8 mmHg]; however, there was no improvement in carotid intima-media thickness [P=0.61] or inflammatory biomarkers [P=0.973 to 0.110]. Conclusion: In conclusion, this review presents evidence suggesting that cardiovascular risk factor interventions are effective in HIV-infected persons on ART. However, cardiovascular screening programs targeting people living with HIV and primary studies assessing the effectiveness (clinical and cost) of multiple risk factor interventions in this sub-group are needed.

Foot Care

Foot Care

POTENTIAL OF THE MODERN ACE INHIBITOR ZOFENOPRIL IN CLINICAL PRACTICE: CARDIOPROTECTIVE, ANTI-ISCHEMIC, AND ANTIATHEROGENIC EFFECTS

The review discusses various aspects of angiotensin-converting enzyme (ACE) inhibitor therapy in patients with cardiovascular disease (CVD), including acute myocardial infarction (AMI). The focus is on the modern ACE inhibitor zofenopril, its specific pharmacological characteristics, and additional cardioprotective, anti-ischemic, and antiatherogenic effects. The existing evidence of clinical effectiveness of zofenopril and its potential for a wider use in clinical practice are also addressed.

Cost-Effectiveness of Cetuximab, Cetuximab Plus Irinotecan, and Panitumumab for Third and Further Lines of Treatment for KRAS Wild-Type Patients with Metastatic Colorectal Cancer

ObjectivesTo estimate the cost-effectiveness of cetuximab monotherapy, cetuximab plus irinotecan, and panitumumab monotherapy compared with best supportive care (BSC) for the third and subsequent lines of treatment of patients with Kirsten rat sarcoma wild-type metastatic colorectal cancer from the perspective of the UK National Health Service. MethodsAn “an area under the curve” cost-effectiveness model was developed. The clinical effectiveness evidence for both cetuximab and panitumumab was taken from a single randomized controlled trial (RCT) in each case and for cetuximab plus irinotecan from several sources. ResultsPatients are predicted to survive for approximately 6 months on BSC, 8.5 months on panitumumab, 10 months on cetuximab, and 16.5 months on cetuximab plus irinotecan.Panitumumab is dominated, and cetuximab is extended dominated. An incremental cost-effectiveness ratio (ICER) of £95,000 per quality-adjusted life-year (QALY) was estimated for cetuximab versus BSC and is likely to be relatively accurate, because the relevant clinical evidence is taken from a high-quality RCT. The estimated ICER for panitumumab versus BSC, at £187,000 per QALY, is less certain due to assumptions in the adjustment for the substantial crossing-over of patients in the RCT. The ICER for cetuximab plus irinotecan versus BSC, at £88,000 per QALY, is least certain due to substantial uncertainty about progression-free survival, treatment duration, and overall survival. Nonetheless, when key parameters are varied within plausible ranges, all three treatments always remain poor value for money. ConclusionsAll three treatments are highly unlikely to be considered cost-effective in this patient population in the United Kingdom. We explain how the reader can adapt the model for other countries.

Interrelationships among enrichment with diagnostics, probability of success and demonstration of effectiveness in clinical trials

Background: Prevalence of disease phenotype in clinical practice is often not given adequate importance during formulation, validation, and implementation of diagnostic tests in clinical research and development. After promising biomarkers have been identified as potential screening diagnostics, an important strategic question for optimal decision-making in clinical development of a therapeutic is when to choose an enrichment study design over the traditional all-comer randomized control trial design. Methods: A hypothetical example of a cholesterol lowering treatment is used to illustrate influences of key statistical criteria and clinical considerations for choosing study designs. Computer simulations demonstrate how results of such analyses can aid in deciding whether or not to choose enrichment study designs. Results: This study shows how understanding of disease prevalence in practice, predictive values of diagnostic test, and prespecified establishment of a clinically meaningful minimum effectiveness all need to be integrated to insure clinical trial success and appropriate benefit to targeted patient subgroups. The most important statistical and clinical considerations were the anticipated effect size, phenotype prevalence, predictive values of diagnostics test, study power, and desired clinically meaningful difference. Conclusions: This study illustrates how successful clinical studies can be designed with careful planning and utilization of computer simulations to increase not only the probability of trial success but also to demonstrate to payers convincing evidence of clinical effectiveness. A six-step checklist is recommended as an evidence-based guideline to assist in decision-making on whether or not to adopt a diagnostics enriched clinical study design.

Evaluation of the clinical effectiveness of tests

Increasingly, diagnostic tests are required to demonstrate evidence of clinical effectiveness before being recommended for clinical use and funding. However, the methods for evaluating diagnostic tests are not straightforward. The impact of diagnostic tests on health outcomes is less direct than that of pharmaceutical agents and is dependent on the sequence of actions taken as a consequence of the test results. The different purposes of diagnostic tests and the less direct effect on health outcomes require different study designs to those used for the evaluation of pharmaceutical products and a more careful interpretation of results. Greater collaboration between researchers designing laboratory-based qualifi-cation studies and researchers designing clinical validation studies could achieve a process of evaluation for biomarkers that is both more reliable and efficient. This session will discuss some of the factors necessary for the evaluation of diagnostic tests, using the example of B-type natriuretic peptide for the diagnosis of heart failure.

A Global View of Direct Access and Patient Self-Referral to Physical Therapy: Implications for the Profession

International policy advocates for direct access, but the extent to which it exists worldwide was unknown. The purpose of this study was to map the presence of direct access to physical therapy services in the member organizations of the World Confederation for Physical Therapy (WCPT) in the context of physical therapist practice and health systems. A 2-stage, mixed-method, descriptive study was conducted. A purposive sample of member organizations of WCPT in Europe was used to refine the survey instrument, followed by an online survey sent to all WCPT member organizations. Data were analyzed using descriptive statistics, and content analysis was used to analyze open-ended responses to identify themes. A response rate of 68% (72/106) was achieved. Direct access to physical therapy was reported by 58% of the respondents, with greater prevalence in private settings. Organizations reported that professional (entry-level) education equipped physical therapists for direct access in 69% of the countries. National physical therapy associations (89%) and the public (84%) were thought to be in support of direct access, with less support perceived from policy makers (35%) and physicians (16%). Physical therapists' ability to assess, diagnose, and refer patients on to specialists was more prevalent in the presence of direct access. The findings may not be representative of the Asia Western Pacific (AWP) region, where there was a lower response rate. Professional legislation, the medical profession, politicians, and policy makers are perceived to act as both barriers to and facilitators of direct access. Evidence for clinical effectiveness and cost-effectiveness and examples of good practice are seen as vital resources that could be shared internationally, and professional leadership has an important role to play in facilitating change and advocacy.

Diagnosis and treatment of failed back surgery syndrome in the UK: mapping of practice using a cross-sectional survey.

Chronic back pain is a serious public health issue, associated with poor quality of life and disability. There is a specific group of chronic back pain sufferers whose pain persists despite their having undergone anatomically successful lumbosacral spine surgery. These patients are known as having failed back surgery syndrome (FBSS) and are frequently seen in pain clinics. It is currently unclear what constitutes routine practice in terms of diagnosis and treatment of FBSS in the UK. To map the diagnosis of and provision of care for patients with FBSS. A cross-sectional survey of specialist pain clinics in the UK. This first attempt to survey 241 pain clinics in the UK achieved a response rate of 52%. The results of this survey suggest that patients at UK pain clinics were often diagnosed with FBSS between 6 and 12 months after surgery. Treatment is often initiated when patients report a level of pain between 3 and 5 cm (on a 10-cm visual analogue scale) and a range of therapeutic options are pursued in the hope of addressing the range of presenting symptoms. It is evident from the findings of this survey that, though there is some variation, pain specialists in the UK identify and handle patients with FBSS as a separate clinical entity. Direct, randomised comparisons of interventions should be the focus of research into appropriate treatment regimens going forward. Also, evidence of clinical effectiveness will need to incorporate elements of patient acceptance of interventions.

Quality assessment of systematic reviews or meta-analyses of nursing interventions conducted by Korean reviewers

BackgroundA systematic review is used to investigate the best available evidence of clinical safety and effectiveness of healthcare intervention. This requires methodological rigor in order to minimize bias and random error. The purpose of this study is to assess the quality of systematic reviews or meta-analyses for nursing interventions conducted by Korean researchers.MethodsWe searched electronic databases from 1950 to July 2010, including ovidMEDLINE, ovidEMBASE, and Korean databases, including KoreaMed, Korean Medical Database, and Korean studies Information Service System etc. Two reviewers independently screened and selected all references, and assessed the quality of systematic reviews or meta-analyses using the “Assessment of Multiple Systematic Reviews" (AMSTAR) tool.ResultsTwenty two systematic reviews or meta-analyses were included in this study. The median overall score (out of 11) for included reviews was 5 (range 2–11) and the mean overall score for AMSTAR was 4.7 (95% confidence interval 3.8-5.7). Nine out of 22 reviews were rated as low quality (AMSTAR score 0–4), 11 were rated as moderate quality (AMSTAR score 5–8), and two reviews were categorized as high quality (AMSTAR score 9–11).ConclusionsThe methodological quality of published reviews on nursing interventions conducted by Korean reviewers was assessed as low to moderate. In order to use the best available evidence in clinical decision making, reviewers should conduct systematic reviews or meta- analyses using rigorous research methods.

The NICE Medical Technologies Evaluation Programme (MTEP): manufacturer submission challenges

The purpose of this report was to explore and describe the challenges that healthcare sector manufacturers face when producing a submission to the NICE Evaluation Pathway (EP) Programme for medical technologies. The EP Programme was developed to evaluate new and innovative medical technologies to inform adoption of efficient and cost effective devices and diagnostics in the NHS. The premise was to produce recommendations based on a similar process currently used for pharmaceutical products. A submission requires manufacturers to complete a data capture template collating high quality clinical and cost effectiveness evidence for their device. This includes indicating how the device integrates into current NHS clinical pathways and how it performs in relation to current best practice. The time scale for completion of a submission is an approximated 6 weeks. Particular consideration was given to small and medium enterprises (SMEs), and availability and access to resources and skills. A consultation process was undertaken to ascertain the opinion of small, medium and large manufacturers in the healthcare sector who could potentially submit an application to the EP programme. The results of this process would highlight any real or perceived barriers identified by manufacturers that could prevent them from submitting to the new EP programme. The EP programme was renamed after preparation of this report to the Medical Technologies Evaluation Programme (MTEP), and details are available here: http://www.nice.org.uk/mt.

The effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer’s disease (review of Technology Appraisal No. 111): a systematic review and economic model.

Alzheimer’s disease (AD) is the most commonly occurring form of dementia. It is predominantly a disease of later life, affecting 5% of those over 65 in the UK.Review and update guidance to the NHS in England and Wales on the clinical effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine [acetylcholinesterase inhibitors (AChEIs)] and memantine within their licensed indications for the treatment of AD, which was issued in November 2006 (amended September 2007 and August 2009).Electronic databases were searched for systematic reviews and/or metaanalyses, randomised controlled trials (RCTs) and ongoing research in November 2009 and updated in March 2010; this updated search revealed no new includable studies. The databases searched included The Cochrane Library (2009 Issue 4, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials), MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, PsycINFO, EconLit, ISI Web of Science Databases--Science Citation Index, Conference Proceedings Citation Index, and BIOSIS; the Centre for Reviews and Dissemination (CRD) databases--NHS Economic Evaluation Database, Health Technology Assessment, and Database of Abstracts of Reviews of Effects.The clinical effectiveness systematic review was undertaken following the principles published by the NHS CRD. We included RCTs whose population was people with AD. The intervention and comparators depended on disease severity, measured by the Mini Mental State Examination (MMSE).mild AD (MMSE 21-26)--donepezil, galantamine and rivastigmine; moderate AD (MMSE 10-20)--donepezil, galantamine, rivastigmine and memantine; severe AD (MMSE < 10)--memantine. Comparators: mild AD (MMSE 21-26)--placebo or best supportive care (BSC); moderate AD (MMSE 10-20)--donepezil, galantamine, rivastigmine, memantine, placebo or BSC; severe AD (MMSE < 10)--placebo or BSC. The outcomes were clinical, global, functional, behavioural, quality of life, adverse events, costs and cost-effectiveness. Where appropriate, data were pooled using pair-wise meta-analysis, multiple outcome measures, metaregression and mixedtreatment comparisons. The decision model was based broadly on the structure of the three-state Markov model described in the previous technology assessment report, based upon time to institutionalisation, parameterised with updated estimates of effectiveness, costs and utilities.Notwithstanding the uncertainty of our results, we found in the base case that the AChEIs are probably cost saving at a willingness-to-pay (WTP) of £’30,000 per qualityadjusted life-year (QALY) for people with mild-to-moderate AD. For this class of drugs, there is a > 99% probability that the AChEIs are more cost-effective than BSC. These analyses assume that the AChEIs have no effect on survival. For the AChEIs, in people with mild to moderate AD, the probabilistic sensitivity analyses suggested that donepezil is the most cost-effective, with a 28% probability of being the most cost-effective option at a WTP of £’30,000 per QALY (27% at a WTP of £’20,000 per QALY). In the deterministic results, donepezil dominates the other drugs and BSC, which, along with rivastigmine patches, are associated with greater costs and fewer QALYs. Thus, although galantamine has a slightly cheaper total cost than donepezil (£’69,592 vs £’69,624), the slightly greater QALY gains from donepezil (1.616 vs 1.617) are enough for donepezil to dominate galantamine.The probability that memantine is cost-effective in a moderate to severe cohort compared with BSC at a WTP of £’30,000 per QALY is 38% (and 28% at a WTP of £’20,000 per QALY). The deterministic ICER for memantine is £’32,100 per/QALY and the probabilistic ICER is £’36,700 per/QALY.Trials were of 6 months maximum follow-up, lacked reporting of key outcomes, provided no subgroup analyses and used insensitive measures. Searches were limited to English language, The model does not include behavioural symptoms and there is uncertainty about the model structure and parameters.The additional clinical effectiveness evidence identified continues to suggest clinical benefit from the AChEIs in alleviating AD symptoms, although there is debate about the magnitude of the effect. Although there is also new evidence on the effectiveness of memantine, it remains less supportive of this drug’s use than the evidence for AChEIs. The conclusions concerning cost-effectiveness are quite different from the previous assessment. This is because both the changes in effectiveness and costs between drug use and non-drug use underlying the ICERs are very small. This leads to highly uncertain results, which are very sensitive to change. RESEARCH PRIORITIES: RCTs to include mortality, time to institutionalisation and quality of life, powered for subgroup analysis.The National Institute for Health Research Health Technology Assessment programme.

Herbal medicines used in the treatment of diabetes mellitus in Arunachal Himalaya, northeast, India

Ethnopharmacological relevanceMedicinal plants have played an important role in treating and preventing a variety of diseases throughout the world. Khampti tribal people living in the far-flung Lohit district of the Eastern Arunachal Himalaya, India still depend on medicinal plants and most of them have a general knowledge of medicinal plants which are used for treating a variety of ailments. This survey was undertaken in Lohit district in order to inventory the medicinal plants used in folk medicine to treat diabetes mellitus. Materials and methodsField investigations were conducted in seventeen remote villages of Lohit district starting from April 2002 to May 2004 through interviews among 251 key informants who were selected randomly during our household survey. To elucidate community domains and determine differences in indigenous traditional knowledge of medicinal plants with anti-diabetic efficacy, we repeated our field survey starting from April 2008 to May 2010 with one hundred traditional healers locally called as “Chau ya” in Khampti of Lohit district. “Chau ya” traditional healers who know and use medicinal plants for treating diabetes mellitus were interviewed using a semi-structured questionnaire. ResultsThis study reports an ethnobotanical survey of medicinal plants in Lohit district of Arunachal Pradesh reputed for the treatment of diabetes mellitus. Forty-six plant species were identified in the study area to treat diabetes mellitus by the Khamptis “Chau ya” traditional healers. Comparative published literature survey analysis of this study with other ethnobotanical surveys of plants used traditionally in treating diabetes mellitus suggests that eleven plant species make claims of new reports on antidiabetic efficacy. These plant species are Begonia roxburghii, Calamus tenuis, Callicarpa arborea, Cuscuta reflexa, Dillenia indica, Diplazium esculentum, Lectuca gracilis, Millingtonia hortensis, Oxalis griffithii, Saccharum spontaneum, and Solanum viarum. Some of the plants reported in this study have an antidiabetic effect on rodent models but none have sufficient clinical evidence of effectiveness. ConclusionsThe wide variety of medicinal plants that are used to treat diabetes mellitus in this area supports the importance of plants in the primary healthcare system of the rural people of Lohit district of Arunachal Pradesh. The finding of new plant uses in the current study reveals the importance of the documentation of such ethnobotanical knowledge.

A systematic review of the clinical effectiveness and cost-effectiveness of Pharmalgen® for the treatment of bee and wasp venom allergy.

A systematic review of the clinical effectiveness and cost-effectiveness of Pharmalgen® for the treatment of bee and wasp venom allergy.

Dabigatran Etexilate for the Prevention of Venous Thromboembolism in Patients Undergoing Elective Hip or Knee Surgery

The National Institute for Health and Clinical Excellence (NICE) invited Boehringer Ingelheim GmbH, the manufacturer of dabigatran etexilate (DBG), to submit evidence on the clinical and cost effectiveness of this drug for the primary prevention of venous thromboembolism (VTE) in adult patients who have undergone total hip replacement (THR) or total knee replacement (TKR) surgery, as part of NICE's single technology appraisal process. The comparators were enoxaparin and fondaparinux, as identified in the scope issued by NICE. The School of Health and Related Research at the University of Sheffield was commissioned to act as the Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and NICE's subsequent decisions. Clinical-effectiveness evidence for DBG versus enoxaparin was derived from two randomized, double-blind, noninferiority trials, one for THR and the other for TKR. Clinical-effectiveness evidence for DBG versus fondaparinux was taken from a mixed treatment comparison (MTC) and from one study. The results presented show that DBG at the licensed dose of 220 mg and 150 mg once daily was noninferior to enoxaparin (40 mg once daily) in terms of the primary efficacy outcome of total VTE and all-cause mortality. In the MTC, fondaparinux was found to be more effective than DBG; the level of statistical significance was not reported. The manufacturer's cost-effectiveness model estimated that at a dose of 220 mg once a day, DBG dominated enoxaparin in both THR and TKR. At a dose of 150 mg daily, DBG dominated enoxaparin in THR, while enoxaparin dominated DBG in TKR. At a dose of 220 mg daily, DBG was less cost effective than fondaparinux in THR. The cost per QALY gained for fondaparinux versus DBG was £11,111 (year 2008 values). At a dose of 150 mg daily, DBG was less cost effective than fondaparinux in THR. The cost per QALY gained for fondaparinux versus DBG was £6857 (year 2008 values). In TKR, both DBG doses were dominated by fondaparinux. There was some evidence that DBG was more cost effective than enoxaparin; however, these results were based on only one trial each in THR and TKR. Fondaparinux appeared to be more cost effective than DBG; however, this was based on indirect comparisons. NICE concluded that although there was uncertainty in the evidence base, DBG was very likely to be of equivalent clinical and cost effectiveness to enoxaparin or fondaparinux in the prevention of VTE. The NICE Appraisal Committee (AC) acknowledged that oral administration of DBG, without the need for monitoring, would reduce administration costs and that it may support adherence to treatment. Therefore, the AC concluded that DBG should be recommended as an option in the circumstances in which enoxaparin (or fondaparinux as an alternative) may be offered.

Dronedarone for the Treatment of Atrial Fibrillation

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of dronedarone (Multaq®, Sanofi-Aventis Limited, UK) to submit evidence on the clinical and cost effectiveness of the anti-arrhythmic drug (AAD) for the treatment of atrial fibrillation (AF) and atrial flutter, as part of the Institute's single technology appraisal (STA) process. The Centre for Reviews and Dissemination and the Centre for Health Economics, both 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 NICE's subsequent decisions regarding the use of dronedarone within the UK NHS. The ERG review comprised a critique of the submitted evidence on the clinical effectiveness and cost effectiveness of dronedarone. The ERG examined the search strategy used to obtain relevant evidence, the selection of studies included in the assessment, outcome measures chosen and statistical methods employed. The ERG also validated the manufacturer's decision analytic model and used it to explore the robustness of the cost-effectiveness results to key assumptions. The main clinical effectiveness evidence supporting the use of dronedarone as a treatment for AF came from four randomized controlled trials. These trials were compared with a broader set of trials examining the effectiveness of other AADs for AF: amiodarone, sotalol and class 1c agents (flecainide and propafenone). The evidence suggested that all AADs decreased the recurrence of AF but dronedarone had the smallest effect. A mixed treatment comparison analysis of the trials showed that dronedarone was associated with a lower risk of all-cause mortality than other AADs, but this was highly uncertain. There was limited evidence to assess the effect of dronedarone on stroke, and no statistically significant differences between dronedarone and other AADs were found for treatment discontinuation. From the evidence presented by the manufacturer, dronedarone appeared highly cost effective in each of the population groups examined compared with using standard baseline therapy alone as first-line treatment, or compared with sotalol or amiodarone as first-line AAD, with incremental cost-effectiveness ratios (ICERs) well below £20,000 per QALY gained. The ICER for dronedarone relative to class 1c agents was around £19,000 per QALY. Although the evidence presented by the manufacturer indicated that dronedarone was cost effective, the estimates of treatment effect relative to other AADs and safety in the longer term were highly uncertain. The NICE Appraisal Committee in its preliminary guidance did not recommend the use of dronedarone for AF. However, following the response from a large number of consultees and commentators, NICE revised its preliminary guidance to allow the use of the drug in a specific subgroup of AF patients with additional cardiovascular risk factors.