Literature Search ® To identify relevant citations buy 250 mg sumycin with visa, we searched Ovid MEDLINE (1966 - December 2009) cheap sumycin 250mg overnight delivery, the ® th Cochrane Database of Systematic Reviews (4 quarter 2009) purchase sumycin 250 mg with amex, the Cochrane Central Register of ® th th Controlled Trials (4 quarter, 2009), and the Database of Abstracts of Reviews of Effects (4 Quarter 2009) using terms for included drugs, indications, and study designs (see Appendix C for complete search strategies). We attempted to identify additional studies through hand searches of reference lists of included studies and reviews. In addition, we searched the US Food and Drug Administration Center for Drug Evaluation and Research, the Canadian Agency for Drugs and Technology in Health, and the National Institute for Health and Clinical Excellence web sites for medical and statistical reviews and technology assessments. Finally, we requested dossiers of published and unpublished information from the relevant pharmaceutical companies for this review. All received dossiers were screened for studies or data not found through other searches. Study Selection Selection of included studies was based on the inclusion criteria created by the Drug Effectiveness Review Project participants, as described above. Two reviewers independently assessed titles and/or abstracts of citations identified from literature searches for inclusion, using the criteria described below. Full-text articles of potentially relevant abstracts were retrieved and a second review for inclusion was conducted by reapplying the inclusion criteria. Results published only in abstract form were not included because inadequate details were available for quality assessment, however if we were provided with enough information to conduct quality assessment we did include the study. Disease-modifying drugs for multiple sclerosis Page 18 of 120 Final Report Update 1 Drug Effectiveness Review Project Data Abstraction The following data were abstracted from included trials: study design, setting, population characteristics (including sex, age, ethnicity, diagnosis), eligibility and exclusion criteria, interventions (dose and duration), comparisons, numbers screened, eligible, enrolled, and lost to follow-up, method of outcome ascertainment, and results for each outcome. Data were abstracted by one reviewer and checked by a second. We recorded intention-to-treat results when reported. If true intention-to-treat results were not reported, but loss to follow-up was very small, we considered these results to be intention-to-treat results. In cases where only per-protocol results were reported, we calculated intention-to-treat results if the data for these calculations were available. Validity Assessment We assessed the internal validity (quality) of trials based on the predefined criteria (see www. These criteria are based on the US Preventive Services Task Force and the National Health Service Centre for Reviews and Dissemination (United Kingdom) 18, 19 criteria. We rated the internal validity of each trial based on the methods used for randomization, allocation concealment, and blinding; the similarity of compared groups at baseline; maintenance of comparable groups; adequate reporting of dropouts, attrition, crossover, adherence, and contamination; loss to follow-up; and the use of intention-to-treat analysis. Trials that had fatal flaws were rated “poor-quality”; trials that met all criteria were rated “good- quality”; the remainder were rated “fair-quality. A poor-quality trial is not valid in that the results are at least as likely to reflect flaws in the study design as the true difference between the compared drugs. A fatal flaw is reflected by failing to meet combinations of items of the quality assessment checklist. A particular randomized trial might receive 2 different ratings: 1 for effectiveness and another for adverse events. The overall strength of evidence for a particular key question reflects the quality, consistency, and power of the set of studies relevant to the question. The criteria for observational studies of adverse events reflect aspects of the study design that are particularly important for assessing adverse event rates. We rated observational studies as good quality for adverse event assessment if they adequately met 6 or more of the 7 predefined criteria, fair quality if they met 3 to 5 criteria, and poor quality if they met 2 or fewer criteria. Included systematic reviews were also rated for quality (see appendix C) based on pre- defined criteria, based on a clear statement of the questions(s), inclusion criteria, adequacy of search strategy, validity assessment and adequacy of detail provided for included studies, and appropriateness of the methods of synthesis. Grading the Strength of Evidence We graded strength of evidence based on the guidance established for the Evidence-based 20 Practice Center Program of the Agency for Healthcare Research and Quality. Developed to grade the overall strength of a body of evidence, this approach incorporates 4 key domains: risk Disease-modifying drugs for multiple sclerosis Page 19 of 120 Final Report Update 1 Drug Effectiveness Review Project of bias (includes study design and aggregate quality), consistency, directness, and precision of the evidence. It also considers other optional domains that may be relevant for some scenarios, such as a dose-response association, plausible confounding that would decrease the observed effect, strength of association (magnitude of effect), and publication bias. Table 2 describes the grades of evidence that can be assigned. Grades reflect the strength of the body of evidence to answer key questions on the comparative effectiveness, efficacy and harms of disease-modifying drugs for multiple sclerosis. Grades do not refer to the general efficacy or effectiveness of pharmaceuticals. Two reviewers independently assessed each domain for each outcome and differences were resolved by consensus. We chose outcomes related to relapse and disease progression. Magnetic resonance imaging findings were considered intermediate outcomes and were not assessed. Definitions of the grades of overall strength of evidence Grade Definition High confidence that the evidence reflects the true effect. Further research is very unlikely to High change our confidence in the estimate of effect. Moderate confidence that the evidence reflects the true effect. Further research may change our Moderate confidence in the estimate of the effect and may change the estimate. Low confidence that the evidence reflects the true effect. Further research is likely to change our Low confidence in the estimate of the effect and is likely to change the estimate. Insufficient Evidence either is unavailable or does not permit estimation of an effect. Data Synthesis We constructed evidence tables showing the study characteristics, quality ratings, and results for all included studies. We reviewed studies using a hierarchy of evidence approach, where the best evidence is the focus of our synthesis for each question, population, intervention, and outcome addressed. Studies that evaluated 1 disease-modifying drug for multiple sclerosis against another provided direct evidence of comparative effectiveness and adverse event rates. Direct comparisons were preferred over indirect comparisons; similarly, effectiveness and long-term safety outcomes were preferred to efficacy and short-term tolerability outcomes. In theory, trials that compare a disease-modifying drug for multiple sclerosis to placebo 22, 23 can also provide evidence about effectiveness. This is known as an indirect comparison and can be difficult to interpret for a number of reasons, primarily issues of heterogeneity between trial populations, interventions, and assessment of outcomes. Data from indirect comparisons are used to support direct comparisons, where they exist, and are also used as the primary comparison where no direct comparisons exist. Such indirect comparisons should be interpreted with caution. Meta-analyses were conducted to summarize data and obtain more precise estimates on outcomes for which studies were homogeneous enough to provide a meaningful combined estimate. In order to determine whether meta-analysis could be meaningfully performed, we considered the quality of the studies and heterogeneity across studies in study design, patient Disease-modifying drugs for multiple sclerosis Page 20 of 120 Final Report Update 1 Drug Effectiveness Review Project population, interventions, and outcomes. When meta-analysis could not be performed, the data were summarized qualitatively. The Q statistic and the I statistic (the proportion of variation in study estimates due to heterogeneity) were calculated to 25, 26 assess heterogeneity in effects between studies. Meta-analysis was performed using Stats 27 Direct (Cam code, United Kingdom) and the meta package in R. If necessary, indirect meta-analyses were done to compare interventions for which there were no head-to-head comparisons and where there was a common comparator intervention 23 across studies. We used the method described by Bucher et al, to perform indirect analyses. Indirect comparisons usually agree with direct comparisons, though large discrepancies have 28, 29 been reported in some cases. In addition, indirect comparisons also result in less precise estimates of treatment effects compared with the same number of similarly sized head-to-head trials because methods for indirect analyses incorporate additional uncertainty from combining 22, 23 different sets of trials.
A diabetes outcome progression trial (ADOPT): an international multicenter study of the comparative efficacy of rosiglitazone buy sumycin 250mg fast delivery, glyburide order 250 mg sumycin fast delivery, and metformin in recently diagnosed type 2 diabetes order 250 mg sumycin with visa. A Diabetes Outcome Progression Trial (ADOPT): baseline characteristics of Type 2 diabetic patients in North America and Europe. Diabetic medicine : a journal of the British Diabetic Association. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Rosiglitazone evaluated for cardiovascular outcomes--an interim analysis. Adding liraglutide to oral antidiabetic drug monotherapy: efficacy and weight benefits. Ragaglitazar improves glycemic control and lipid profile in type 2 diabetic subjects: a 12-week, double-blind, placebo-controlled dose-ranging study with an open pioglitazone arm. Long-term efficacy and tolerability of add-on pioglitazone therapy to failing monotherapy compared with addition of gliclazide or metformin in patients with type 2 diabetes. Gastaldelli A, Ferrannini E, Miyazaki Y, Matsuda M, Mari A, DeFronzo RA. Thiazolidinediones improve beta-cell function in type 2 diabetic patients. A randomized, double-blind, placebo-controlled, clinical trial of the effects of pioglitazone on glycemic control and dyslipidemia in oral antihyperglycemic medication-naive patients with type 2 diabetes mellitus. Kipnes MS, Krosnick A, Rendell MS, Egan JW, Mathisen AL, Schneider RL. Pioglitazone hydrochloride in combination with sulfonylurea therapy improves glycemic control in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study. Metabolic effects of pioglitazone in combination with insulin in patients with type 2 diabetes mellitus whose disease is not adequately controlled with insulin therapy: Results of a six-month, randomized, double-blind, prospective, multicenter, parallel-group study. Honisett SY, Stojanovska L, Sudhir K, Kingwell BA, Dawood T, Komesaroff PA. Rosiglitazone lowers blood pressure and increases arterial compliance in postmenopausal women with type 2 diabetes. Raskin P, Rappaport EB, Cole ST, Yan Y, Patwardhan R, Freed MI. Rosiglitazone short- term monotherapy lowers fasting and post-prandial glucose in patients with type II diabetes. Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone reduces clinical inflammatory responses in type 2 diabetes with coronary artery disease after coronary angioplasty. Rosiglitazone taken once daily provides effective glycaemic control in patients with Type 2 diabetes mellitus. Glycemic control with glyburide/metformin tablets in combination with rosiglitazone in patients with type 2 diabetes: a randomized, double-blind trial. A randomized, placebo-controlled trial assessing the effects of rosiglitazone on echocardiographic function and cardiac status in type 2 diabetic patients with New York Heart Association Functional Class I or II Heart Failure. Rosiglitazone improves myocardial glucose uptake in patients with type 2 diabetes and coronary artery disease: a 16-week randomized, double-blind, placebo-controlled study. Negro R, Mangieri T, Dazzi D, Pezzarossa A, Hassan H. Rosiglitazone effects on blood pressure and metabolic parameters in nondipper diabetic patients. Effect of rosiglitazone on restenosis after coronary stenting in patients with type 2 diabetes. Pioneer study: PPARgamma activation results in overall improvement of clinical and metabolic markers associated with insulin resistance independent of long-term glucose control. Effect of early addition of rosiglitazone to sulphonylurea therapy in older type 2 diabetes patients (>60 years): the Rosiglitazone Early vs. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Preventative effects of rosiglitazone on restenosis after coronary stent implantation in patients with type 2 diabetes. Davidson JA, Perez A, Zhang J, The Pioglitazone 343 Study G. Addition of pioglitazone to stable insulin therapy in patients with poorly controlled type 2 diabetes: results of a double- blind, multicentre, randomized study. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. A randomized comparison of pioglitazone to inhibit restenosis after coronary stenting in patients with type 2 diabetes. Pioglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with type 2 diabetes mellitus: an intravascular ultrasound scanning study. Effect of metformin plus roziglitazone compared with metformin alone on glycaemic control in well-controlled Type 2 diabetes. Effects of rosiglitazone added to submaximal doses of metformin compared with dose escalation of metformin in type 2 diabetes: the EMPIRE Study. Rosenstock J, Rood JA, Cobitz AR, Biswas N, Chou H, Garber A. Initial treatment with rosiglitazone/metformin fixed-dose combination therapy compared with monotherapy with either rosiglitazone or metformin in patients with uncontrolled type 2 diabetes. Initial treatment with fixed-dose combination rosiglitazone/glimepiride in patients with previously untreated type 2 diabetes. McCluskey D, Touger MS, Melis R, Schleusener DS, McCluskey D. Results of a randomized, double-blind, placebo-controlled study administering glimepiride to patients with type 2 diabetes mellitus inadequately controlled with rosiglitazone monotherapy. DuetactÒ Product Information and Data Dossier: Submitted to the Drug Effectiveness Review Project; 2007. JanumetÒ Product Information and Data Dossier: Submitted to the Drug Effectiveness Review Project; 2007. Melikian C, White TJ, Vanderplas A, Dezii CM, Chang E. Adherence to oral antidiabetic therapy in a managed care organization: a comparison of monotherapy, combination therapy, and fixed-dose combination therapy. Greater reductions in A1C in type 2 diabetic patients new to therapy with glyburide/metformin tablets as compared to glyburide co- administered with metformin. Vanderpoel DR, Hussein MA, Watson-Heidari T, Perry A. Adherence to a fixed-dose combination of rosiglitazone maleate/metformin hydrochloride in subjects with type 2 diabetes mellitus: a retrospective database analysis. Goldstein BJ, Weissman PN, Wooddell MJ, Waterhouse BR, Cobitz AR. Reductions in biomarkers of cardiovascular risk in type 2 diabetes with rosiglitazone added to metformin compared with dose escalation of metformin: an EMPIRE trial sub-study. Progressive reduction in body weight after treatment with the amylin analog pramlintide in obese subjects: a phase 2, randomized, placebo- controlled, dose-escalation study. Pramlintide as an adjunct to insulin in patients with type 2 diabetes in a clinical practice setting reduced A1C, postprandial glucose excursions, and weight. Exenatide elicits sustained glycaemic control and progressive reduction of body weight in patients with type 2 diabetes inadequately controlled by sulphonylureas with or without metformin. Nelson P, Poon T, Guan X, Schnabel C, Wintle M, Fineman M. The incretin mimetic exenatide as a monotherapy in patients with type 2 diabetes. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Fabunmi R, Nielsen LL, Quimbo R, Misurski D, Wade R, al. Patient characteristics, drug adherence patterns, and hypoglycemia costs for patients with type 2 diabetes mellitus newly initiated on exenatide or insulin glargine. FDA News Release: FDA significantly restricts access to the diabetes drug Avandia 09/23/1010 2010.
Placebo controlled trials of beta blockers for migraine Author Number Year withdrawn/ Method of Country lost to fu/ adverse effects Study Design analyzed Outcomes assessment? Placebo controlled trials of beta blockers for migraine Author Withdrawals due Year to adverse events Country (% purchase 250mg sumycin, adverse Study Design Adverse effects reported n/enrolled n) Comments Pindolol Ekbom NR Withdrawals: pin=4; 1971 pla=0 Sweden Withdrawals due to: Fair quality Orthostatic RCT hypotension=2 Increased headache=1 Dizziness/cystopyel itis=1 Sjaastad Untoward effects noted: pin=3/28(10 500 mg sumycin overnight delivery. Placebo controlled trials of beta blockers for migraine Author Year Allowed other Country Interventions (drug purchase sumycin 250 mg, medications/ Study Design Eligibility criteria Exclusion criteria regimen, duration) interventions Propranolol Borgesen Diagnosis of migraine (Ad Hoc Committee Cardiac disease; asthma or diabetes Propranolol (pro) 120 mg Symptomatic treatments 1974 on Classification of Headache, 1962); mellitus; physical or neurological daily allowed (e. Placebo controlled trials of beta blockers for migraine Author Year Age Other population Number screened/ Country Method of outcome assessment Gender characteristics eligible/ Study Design and timing of assessment Ethnicity (diagnosis, etc) enrolled Propranolol Borgesen Patient forms: 1) severity on 3-point Mean Classical migraine (# pts/%): NR/NR/45 entered 1974 scale (severe=forcing patient to stay age=37. Placebo controlled trials of beta blockers for migraine Author Number Year withdrawn/ Method of Country lost to fu/ adverse effects Study Design analyzed Outcomes assessment? Placebo controlled trials of beta blockers for migraine Author Withdrawals due Year to adverse events Country (%, adverse Study Design Adverse effects reported n/enrolled n) Comments Propranolol Borgesen Data NR; pro=pla for pro=0 1974 #/severity of complaints of pla=2 Denmark fatigue drowsiness and diarrhea Fair quality RCT Crossover Dahlof NR NR Looked at 1987 longlasting Sweden prophylactic effect following Fair quality discontinuance RCT Crossover Beta blockers Page 368 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 16. Placebo controlled trials of beta blockers for migraine Author Number Year withdrawn/ Method of Country lost to fu/ adverse effects Study Design analyzed Outcomes assessment? Placebo controlled trials of beta blockers for migraine Author Withdrawals due Year to adverse events Country (%, adverse Study Design Adverse effects reported n/enrolled n) Comments Diamond Frequency of most Phases I & II 1982 common adverse events(# combined: United States patients/%) pla=3/245(1. Placebo controlled trials of beta blockers for migraine Author Year Age Other population Number screened/ Country Method of outcome assessment Gender characteristics eligible/ Study Design and timing of assessment Ethnicity (diagnosis, etc) enrolled Diener Headache diary Mean age: pro n=78; pla n=55 235/214/214 1996 pro=40; Mean migraine history(years): Germany pla=39 pro=21; pla=19 % female: Migraine with aura(#/% Fair quality pro=76. Placebo controlled trials of beta blockers for migraine Author Number Year withdrawn/ Method of Country lost to fu/ adverse effects Study Design analyzed Outcomes assessment? Diener 40 withdrawn/0 lost to fu/214 pro n=78; pla n=55 NR 1996 analyzed per ITT; 174 Migraine frequency(#/% patients with >/= 50% reduction of attacks): Germany analyzed per protocol pro=33/42. Placebo controlled trials of beta blockers for migraine Author Withdrawals due Year to adverse events Country (%, adverse Study Design Adverse effects reported n/enrolled n) Comments Diener Overall adverse Overall withdrawals 1996 effects(#/% patients): due to adverse Germany pro=19/24. Placebo controlled trials of beta blockers for migraine Author Year Allowed other Country Interventions (drug, medications/ Study Design Eligibility criteria Exclusion criteria regimen, duration) interventions Forssman Diagnosis of migraine; age between 16 and Pregnancy or suspicion of pregnancy; Propranolol (pro) 240 mg Previously prescribed 1976 55 years; at least three attacks per month indication of renal or heart disease, daily acute medication allowed Sweden hypertension, diabetes or asthma; Placebo (pla) x 12 weeks, (not specified); oral history of earlier treatment of migraine then crossover contraceptives Fair quality with propranolol RCT Crossover Kuritzky Patients aged 17-53, suffering from NR Long acting propranolol (LA Analgesics 1987 classical or common migraine for at least 2 pro) 160 mg daily Israel years with at least 3 attacks per month Placebo (pla) Fair quality RCT Crossover Beta blockers Page 377 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 16. Placebo controlled trials of beta blockers for migraine Author Year Age Other population Number screened/ Country Method of outcome assessment Gender characteristics eligible/ Study Design and timing of assessment Ethnicity (diagnosis, etc) enrolled Forssman Printed record card: 1) begin/end Mean Classic migraine=5/32(15. Placebo controlled trials of beta blockers for migraine Author Number Year withdrawn/ Method of Country lost to fu/ adverse effects Study Design analyzed Outcomes assessment? Forssman 8(20%) withdrawn/0 lost to Attack frequency of propranolol relative to placebo (# patients/%): Good NR 1976 fu/32 analyzed effect(>/= 50% improvement)=11/34. Placebo controlled trials of beta blockers for migraine Author Withdrawals due Year to adverse events Country (%, adverse Study Design Adverse effects reported n/enrolled n) Comments Forssman Most common side effects pro=2 1976 reported(# pts/%) pla=2 Sweden Increase in weight > 2 kg: pro=5(13. Placebo controlled trials of beta blockers for migraine Author Year Allowed other Country Interventions (drug, medications/ Study Design Eligibility criteria Exclusion criteria regimen, duration) interventions Malvea Age range of 25-57 with common migraine Pregnancy, bronchial asthma, Propranolol (pro)
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