Methodology for the development of antithrombotic therapy and prevention of thrombosis guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND: To develop the Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: ACCP Evidence-Based Clinical Practice Guidelines (AT9), the American College of Chest Physicians (ACCP) assembled a panel of clinical experts, information scientists, decision scientists, and systematic review and guideline methodologists. METHODS: Clinical areas were designated as articles, and a methodologist without important intellectual or financial conflicts of interest led a panel for each article. Only panel members without significant conflicts of interest participated in making recommendations. Panelists specified the population, intervention and alternative, and outcomes for each clinical question and defined criteria for eligible studies. Panelists and an independent evidence-based practice center executed systematic searches for relevant studies and evaluated the evidence, and where resources and evidence permitted, they created standardized tables that present the quality of the evidence and key results in a transparent fashion. RESULTS: One or more recommendations relate to each specific clinical question, and each recommendation is clearly linked to the underlying body of evidence. Judgments regarding the quality of evidence and strength of recommendations were based on approaches developed by the Grades of Recommendations, Assessment, Development, and Evaluation Working Group. Panel members constructed scenarios describing relevant health states and rated the disutility associated with these states based on an additional systematic review of evidence regarding patient values and preferences for antithrombotic therapy. These ratings guided value and preference decisions underlying the recommendations. Each topic panel identified questions in which resource allocation issues were particularly important and, for these issues, experts in economic analysis provided additional searches and guidance. CONCLUSIONS: AT9 methodology reflects the current science of evidence-based clinical practice guideline development, with reliance on high-quality systematic reviews, a standardized process for quality assessment of individual studies and the body of evidence, an explicit process for translating the evidence into recommendations, disclosure of financial as well as intellectual conflicts of interest followed by management of disclosed conflicts, and extensive peer review.(AU)

A rapid and systematic review of the effectiveness and cost-effectiveness of the taxanes used in the treatment of advanced breast and ovarian cancer.

SECOND-LINE TREATMENT, PACLITAXEL (MEDIAN PROGRESSION-FREE SURVIVAL): The median progression-free survival in the paclitaxel arm was 3.5 months. This was significantly longer than the mitomycin control arm (1.6 months, p = 0.026). BREAST CANCER - SECOND-LINE TREATMENT, PACLITAXEL (MEDIAN OVERALL SURVIVAL): The median length of overall survival in the paclitaxel arm was 12.7 months, compared with 8.4 months in the mitomycin arm. BREAST CANCER - SECOND-LINE TREATMENT, PACLITAXEL (QUALITY OF LIFE): Quality of life was not reported. BREAST CANCER - SECOND-LINE TREATMENT, PACLITAXEL (ECONOMIC EVALUATION): The only economic evaluation that compared paclitaxel with control (mitomycin) was submitted in confidence and has been removed from this report. Six economic evaluations involved comparisons of paclitaxel and docetaxel, which are given below. BREAST CANCER - SECOND-LINE TREATMENT, DOCETAXEL: Four randomised controlled Phase III trials were identified: 303 Study, 304 Study, Scand and Bonneterre. A total of 1092 patients were included. One of these was a preliminary report of a study before completion of accrual (Bonneterre). Patients in the 303 Study had previously received chemotherapy involving alkylating agents; those in the other three had received anthracyclines. There were six economic evaluations on docetaxel. BREAST CANCER - SECOND-LINE TREATMENT, DOCETAXEL (QUALITY OF TRIALS): The 303 and 304 Studies were analysed on an intention to treat basis; the Scand trial excluded a single patient. The length of follow-up ranged from 11 months (Scand) to 23 months (303 Study). At least two-thirds of the participants in these trials had died. The Scand study recommended cross-over to alternate treatment on objective signs of disease progression. Patients crossing over in this way were violating the randomisation; however, no details were given concerning whether or not such patients were censored. In the economic analyses, there were no direct comparisons for the estimation of benefits. BREAST CANCER - SECOND-LINE TREATMENT, DOCETAXEL (MEDIAN PROGRESSION-FREE SURVIVAL): The median progression-free survival in the docetaxel arm ranged from 4.75 months (304 Study) to 7 months (Bonneterre). Patients in the docetaxel arms of the 304 and Scand studies had significantly longer progression-free survivals than controls (4.75 months versus 2.75 months, p = 0.001; 6.3 months versus 3 months, p = 0.001). BREAST CANCER - SECOND-LINE TREATMENT, DOCETAXEL (MEDIAN OVERALL SURVIVAL): The median overall survival in the docetaxel arm ranged from 10.4 months (Scand) to 15 months (303 Study). Patients in the docetaxel arms of the 304 Study survived for significantly longer than the mitomycin plus vinblastine arm (11.4 months versus 8.7 months, p = 0.03). BREAST CANCER - SECOND-LINE TREATMENT, DOCETAXEL (QUALITY OF LIFE): Quality of life was evaluated in two of the trials: the 303 and 304 Studies. There were no significant differences between docetaxel and control in either of these trials in terms of global health status, although differences were apparent on some subscales. These did not appear to follow a consistent pattern across the trials. BREAST CANCER - SECOND-LINE TREATMENT, DOCETAXEL (ECONOMIC EVALUATIONS): All six of these involved comparisons of paclitaxel and docetaxel, where the range of cost-utility ratios for incremental quality-adjusted life-years (QALYs) gained was pound 1990-pound 2431. In addition, three analyses compared docetaxel and vinorelbine. The cost-utility ratio for incremental QALYs gained was pound 14,050 in the only one of these carried out in the UK. OVARIAN CANCER - FIRST-LINE TREATMENT, PACLITAXEL: Four randomised controlled Phase III trials were identified: EORTC, TITGANZ, E1193 and CA139-278. (ABSTRACT TRUNCATED)

Systematic review of water fluoridation.

OBJECTIVE: To review the safety and efficacy of fluoridation of drinking water. DESIGN: Search of 25 electronic databases and world wide web. Relevant journals hand searched; further information requested from authors. Inclusion criteria were a predefined hierarchy of evidence and objectives. Study validity was assessed with checklists. Two reviewers independently screened sources, extracted data, and assessed validity. MAIN OUTCOME MEASURES: Decayed, missing, and filled primary/permanent teeth. Proportion of children without caries. Measure of effect was the difference in change in prevalence of caries from baseline to final examination in fluoridated compared with control areas. For potential adverse effects, all outcomes reported were used. RESULTS: 214 studies were included. The quality of studies was low to moderate. Water fluoridation was associated with an increased proportion of children without caries and a reduction in the number of teeth affected by caries. The range (median) of mean differences in the proportion of children without caries was -5.0% to 64% (14.6%). The range (median) of mean change in decayed, missing, and filled primary/permanent teeth was 0.5 to 4.4 (2.25) teeth. A dose-dependent increase in dental fluorosis was found. At a fluoride level of 1 ppm an estimated 12.5% (95% confidence interval 7.0% to 21.5%) of exposed people would have fluorosis that they would find aesthetically concerning. CONCLUSIONS: The evidence of a beneficial reduction in caries should be considered together with the increased prevalence of dental fluorosis. There was no clear evidence of other potential adverse effects.

Measuring appropriate use of acute beds. A systematic review of methods and results.

A systematic review of the methods used to assess appropriateness of acute bed use and the evidence on the scale of inappropriate use in different patient groups is presented. Issues of generalisability of the findings are also addressed. Criteria based tools are the accepted way of measuring inappropriate days of stay and admissions, although opinion based classification is very common. While a number of tools exist, few have been adequately tested for reliability and validity. The Appropriateness Evaluation Protocol (AEP) is the most commonly used tool, and has been tested more widely. It appears to be both reliable and valid. An estimated 29% of admissions to acute psychiatric may be inappropriate. Regarding days of care after admission, between 24 and 58% of stays were not judged to be appropriate for continued stay on an acute ward. The need for continued acute psychiatric care may become lower as patients experience continued stay in the acute setting. A lack of housing and community support was the most commonly cited reason preventing discharge. Rates of inappropriate use appear to be higher for older patients than for the general population. Wide variation in rates of inappropriate days of stay was found, but it may be safe to assume that inappropriate use is greater than 20% across a wide variety of settings. Reasons for older patients to remain in an acute hospital bed after medically necessary are typically moderate nursing care needs (i.e. long-term care). The estimates of inappropriate use in other groups was found to be highly variable. Before definitive conclusions on the inappropriate use of acute beds can be made, future research needs to take into account the methodological problems discussed here.

Costs and savings of investigational drug services.

The costs and savings resulting from two pharmacy-based investigational drug services (IDSs) for fiscal year 1996-97 were studied. The costs and savings associated with IDSs at two joint institutions were calculated by adding the cost-avoidance figures (money that would most likely have been spent, but was not because of a specific intervention or program) to the money received from services charged to study investigators or patients and subtracting salaries and overhead costs. Only drugs for which the authors could obtain prices were used to calculate cost-avoidance figures. The number of doses of marketed drugs that were provided free or for which the pharmacy was reimbursed by a drug study sponsor between July 1996 and June 1997 was tabulated from pharmacy dispensing records for each study. Investigational drugs that were not marketed or for which no marketed alternative was available were not included in the cost-avoidance calculation but were included in the charges for IDSs. The total cost of IDSs at the two institutions was $249,112. Income (representing cost avoidance and payments received) totaled $2,958,774, giving the IDSs an overall saving of $2,709,662. The two disease categories with the largest cost-avoidance figures were AIDS and oncology. In total, there was a cost avoidance of $2.9 million in drug costs, which is equivalent to 8% of the institutions' annual drug budget for 1996-97. IDSs in two institutions accounted for a combined one-year saving of over $2.7 million, most of which was attributable to cost avoidance from not having to purchase study drugs.