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In the EVIDENCE trial discount viagra soft 100mg without prescription, which compared interferon high-dose discount viagra soft 50mg without prescription, high-frequency interferon beta-1a ® ® (Rebif ) 44 mcg to low-dose interferon beta-1a IM (Avonex ) 30 mcg over 2 years buy viagra soft 50mg visa, neutralizing ® antibodies were detected at least once in 26% of patients receiving high-dose Rebif and in 3% ® of those receiving low dose Avonex (P<0 buy viagra soft 50 mg amex. Neutralizing antibodies developed earlier with high-dose treatment (58% by week 24, compared with 14% in the low-dose group). Relapse rates 45 were similar in antibody-positive and antibody-negative patients. The proportion of patients developing neutralizing antibodies was reported in the ® REGARD study of interferon beta-1a (Rebif ). The rate was 60/138 (16%) at 24 weeks, 93/355 Disease-modifying drugs for multiple sclerosis Page 49 of 120 Final Report Update 1 Drug Effectiveness Review Project (26%) at 48 weeks, 91/319 (29%) at 72 weeks, and 102/374 (27%) at 96 weeks or last observation carried forward. Neutralizing antibodies had no effect on clinical efficacy: there was no difference in time to first relapse for those positive at any time and those negative (hazard ratio, 1. Although there was an association between neutralizing antibody status and clinical outcome shown in several studies, none found the detrimental effect of positive antibody status to be greater with one of the beta interferons than another. The conclusions that could be drawn from these studies were limited for several reasons: most were not of sufficient duration to show an effect of neutralizing antibodies on clinical status, the numbers of patients taking each drug may not have been sufficient to show a difference between treatments, and lack of control for confounding factors limited the validity of their results. Evidence correlating comparative clinical outcomes to the antibody status of the individual beta interferons was incomplete and inadequate to make conclusions. Longer-term trials will be needed to clarify the role of this difference in antigenicity and its correlation of clinical outcomes over longer periods of time. Development of antibodies to natalizumab An analysis of the AFFIRM and SENTINEL trials reported the incidence and clinical effects of 117 antibodies to natalizumab that developed over 2 years of therapy. In AFFIRM, 57 of 625 patients (9%) tested positive for antibodies at any time during the study; 3% were transiently positive and 6% were persistently positive throughout the study. Most (88%) patients developed antibodies by week 12 of treatment. Results were similar in SENTINEL, in which natalizumab was added to interferon beta-1a therapy, with 12% of patients testing positive for antibodies to natalizumab during the 2-year study, 5% transiently positive, and 96% showing antibodies by week 12 of treatment. In AFFIRM, 34% of patients who were persistently antibody-positive had sustained disability progression, compared with 17% of patients who were antibody-negative. The proportion of patients with sustained disability progression who were transiently antibody- positive was identical to that of patients who were antibody-negative. In contrast, in the SENTINEL study, patients who were persistently antibody-positive did not show a reduced effect of natalizumab on disability progression compared with those who were antibody-negative (P=0. The cumulative proportion of patients with sustained disability progression over 2 years was 24% in antibody-negative patients, 19% in transiently-positive patients, and 20% in persistently positive patients. What is the effectiveness of disease-modifying treatments for patients with a clinically isolated syndrome? Summary of the Evidence • Evidence suggested that all 3 interferon beta-1 products and glatiramer acetate reduced the probability of converting from clinically isolated syndrome to clinically definite multiple sclerosis over 2 to 5 year periods. Disease-modifying drugs for multiple sclerosis Page 50 of 120 Final Report Update 1 Drug Effectiveness Review Project ® • At 3 years, interferon beta-1a IM (Avonex ) was superior to placebo (relative risk, 0. Detailed Assessment Previous systematic review A Cochrane systematic review evaluated the efficacy and safety of treatment with beta interferons on the proportion of patients delayed to convert from clinically isolated syndrome to 118 119 clinically definite multiple sclerosis. Three trials were included in the review: CHAMPS, 120 121 ETOMS, and BENEFIT. This review did not include a comparison of interferon beta-1a to interferon beta-1b; it combined the interferons and considered them as a group for analysis. Overall, meta-analysis showed that fewer patients converted to CDMS with beta interferon treatment compared with placebo after 1 year (pooled odds ratio, 0. Direct evidence No head-to-head trials have been conducted. Indirect evidence Five placebo-controlled trials (in 12 publications) assessed disease-modifying drugs in patients 119-130 121 with a clinically isolated syndrome (Tables 21 and 22). One trial was rated good quality and the rest were fair. All 5 trials showed a statistically significant reduction in the proportion of patients and the time to converting to clinically definite multiple sclerosis compared with placebo with relative risks or hazard ratios in the 0. Because there were apparent clinical differences in the populations enrolled, an indirect meta-analysis of these data was not undertaken. The 3 trials of interferon beta-1a products were low dose with weekly injections, while ® the study of interferon beta-1b (Betaseron ), the BENEFIT study, used every other day dosing. The dose of glatiramer acetate in the PreCIS study was 20 mg daily, the standard dose for treatment of multiple sclerosis. The patient populations enrolled in the studies were somewhat different, with ® 120 the study of interferon beta-1a SC (Rebif ) enrolling patients with multifocal presentation, a higher percentage with gadolinium enhancing brain lesions, and lesions with larger median 121, 126 volume compared with the other studies (see Table 21). All patients enrolled in CHAMPS Disease-modifying drugs for multiple sclerosis Page 51 of 120 Final Report Update 1 Drug Effectiveness Review Project received standardized corticosteroid treatment for the initial episode and were enrolled within 2 weeks of initial symptom presentation, while patients in the other studies were enrolled within 2 or 3 months of initial presentation and treatment of the episode was not standardized. Only 127 patients with monofocal lesions were enrolled in the trial of glatiramer acetate. In contrast, the ® BENEFIT study of interferon beta-1b (Betaseron ) and 1 of the studies of interferon beta-1a ® 130 (Avonex ) enrolled patients with at least 2 silent magnetic resonance imaging lesions, and 131 may represent patients at higher risk for progressing to multiple sclerosis. While the primary endpoint of conversion to clinically definite multiple sclerosis was defined slightly differently in the studies, they were based primarily on a relapse of the initial or new symptoms. The BENEFIT trial also used the McDonald criteria, which incorporate magnetic resonance imaging findings. All of the studies reported a 3-year follow-up, with the exception of ETOMS, which 120 followed patients for 2 years. The CHAMPS trial was stopped early after a planned interim 126 analysis indicated a significant difference in benefit between the groups. Patients enrolled in the CHAMPS who had not converted to multiple sclerosis at the end of the 3-year trial were offered enrollment in CHAMPIONS, a 5-year open-label, investigator-initiated extension 123 study. Fifty-three percent (203 of 383) of patients who had participated in CHAMPS enrolled in CHAMPIONS. Patients who had been assigned to interferon beta-1a during the trial were considered the immediate treatment group and those assigned to placebo and given interferon beta-1a during the extension study were considered the delayed treatment group. The analysis compared the conversion rate between these 2 groups and found that the 5-year cumulative incidence rate in the immediate treatment group was 36% compared with 49% in the delayed treatment group (adjusted hazard ratio 0. Multivariate analysis indicated that the factors associated with conversion to multiple sclerosis were randomization to the delayed treatment group and younger age at enrollment in the CHAMPS. The BENEFIT trial included a 5-year follow-up phase. Patients were eligible to enter the follow-up phase after 2 years in the placebo-controlled phase, and were offered treatment with ® 129 interferon beta-1b (Betaseron ) 250 mcg SC every other day for up to 5 years. Patients ® initially randomized to interferon beta-1b (Betaseron ) were considered the early treatment group and those initially randomized to placebo were considered the delayed treatment group. Eighty-nine percent (418 of 468) of patients who participated in the placebo-controlled phase entered the follow-up phase. After 5 years, the risk for clinically definite multiple sclerosis was lower in the early treatment group (46%) than the delayed treatment group (57%) (hazard ratio, 0. Disease-modifying drugs for multiple sclerosis Page 52 of 120 Final Report Update 1 Drug Effectiveness Review Project Table 21. Efficacy of drugs for multiple sclerosis in patients with a clinically isolated syndrome Baseline Study Drug dose/schedule presentation Conversion to multiple Quality Duration N Mean age sclerosis Interferon beta-1a % treated with CHAMPS steroids: 100% Cumulative probability Jacobs 2000 % with gadolinium Interferon β-1a 35% ® enhancing lesions 28% Placebo 50% (Avonex ) 30 mcg IM weekly 383 Fair 3 years Median volume of Relative risk 0. Disease-modifying drugs for multiple sclerosis Page 53 of 120 Final Report Update 1 Drug Effectiveness Review Project In a post hoc analysis of the CHAMPS data, only patients considered at high risk of conversion to multiple sclerosis (≥9 T2-weighted hyperintense lesions and ≥1 gadolinium enhanced lesion) were included. This was a small group of patients (N=91; 24% of the total enrolled). The relative risk of conversion to multiple sclerosis was found to be 0. In the BENEFIT study of interferon beta-1b (Betaseron ), multiple subgroup analyses were undertaken, examining the effects in monofocal compared with multifocal presentation, and patients with or without gadolinium enhanced lesions or ≥ 9 T2- weighted hyperintense lesions. The results indicated a significant benefit in all groups, with hazard ratios for conversion to multiple sclerosis ranging from 0. In the trial of glatiramer acetate, post hoc subgroup analyses showed a better response in women (hazard ratio, 0. In patients with 9 or more T2 lesions at baseline, the hazard ratio was 0. Because these were subgroup analyses, with relatively small numbers of patients in each group, these results should be interpreted with caution. Adverse events Rates of discontinuation of assigned treatment for reasons other than conversion to multiple sclerosis are shown in Table 22. All comparisons are to placebo; there is no direct evidence. In ® the BENEFIT trial of interferon beta-1b (Betaseron ) more patients either discontinued interferon early or were lost to follow-up compared with placebo (21% compared with 16%). Withdrawals due to adverse events were significantly higher with interferon beta-1b ® (Betaseron ) than placebo, and higher with glatiramer acetate compared with placebo, but ® 119 significantly lower with interferon beta-1a IM (Avonex ) compared with placebo. The trial of ® interferon beta-1a SC 22 mcg (Rebif ) reported only 3 withdrawals due to adverse events, but did not specify to which group(s) the patients had been assigned. The studies did not describe methods of ascertaining adverse events and the reporting of adverse events was sparse. The incidence of adverse events was significantly higher in the beta interferon and glatiramer acetate groups compared with the placebo groups for most commonly occurring adverse events such as influenza-like syndrome and injection-site reactions. Rates of serious adverse events were not different from placebo in any trial, and rates of depression were not significantly higher than placebo in the 2 trials reporting this outcome (interferon beta-1b ® ® (Betaseron ) and interferon beta-1a (Avonex ). Disease-modifying drugs for multiple sclerosis Page 54 of 120 Final Report Update 1 Drug Effectiveness Review Project Table 22. Adverse events of beta interferons in patients with a clinically isolated syndrome Interferon Adverse event rates Study Dose/schedule Withdrawal due to adverse events Treatment vs. In a 5-year, open-label extension arm of the CHAMPS study, only serious adverse events (N=13 in 6% of patients overall) were reported and none were considered related to interferon 123 beta-1a. Other typical and concerning adverse events associated with interferon beta-1a were not discussed or reported. In the 5-year follow-up phase of the BENEFIT trial, the incidence and nature of adverse events was similar to that reported at the end of the 2-year placebo-controlled Disease-modifying drugs for multiple sclerosis Page 55 of 120 Final Report Update 1 Drug Effectiveness Review Project period. More patients in the delayed treatment group discontinued due to adverse events (12% 129 compared with 2%). Do disease-modifying treatments for multiple sclerosis differ in harms? Summary of the Evidence Adverse events and long-term safety Beta interferons • Comparative adverse event reporting was limited with multiple studies using different ® doses of the same product, most frequently with interferon beta-1a SC (Rebif ). We have ® used data pertaining to interferon beta-1a SC (Rebif ) 44µg SC 3 times weekly dosing when pooling all trial data. Comparative tolerability of beta interferon Adverse event Relative frequencies based on pooled trial rates ® ® Interferon β-1a SC (Rebif ) 60. Disease-modifying drugs for multiple sclerosis Page 56 of 120 Final Report Update 1 Drug Effectiveness Review Project • Elevated liver enzymes were also very common among beta interferon-treated patients, particularly during the first year of treatment.

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Abuse discount 50mg viagra soft overnight delivery, dependence order viagra soft 50 mg fast delivery, and epileptic seizures after zolpidem withdrawal: Review and case report viagra soft 100 mg line. Misuse of zopiclone and convulsions during withdrawal best viagra soft 50 mg. Zolpidem dependence in a patient with former polysubstance abuse. Zolpidem dependence case series: Possible neurobiological mechanisms and clinical management. Three cases of zolpidem dependence treated with fluoxetine: the serotonin hypothesis. Zolpidem tolerance and dependence - Two case reports. Sakkas P, Psarros C, Masdrakis V, Liappas J, Christodoulou GN. Vartzopoulos D, Bozikas V, Phocas C, Karavatos A, Kaprinis G. Insomnia Page 55 of 86 Final Report Update 2 Drug Effectiveness Review Project 160. Haasen C, Mueller-Thomsen T, Fink T, Bussopulos A, Reimer J. Zopiclone dependence after insomnia related to torticollis. A case of parenteral zolpidem dependence with opioid-like withdrawal symptoms. International Journal of Psychiatry in Clinical Practice. Quaglio G, Lugoboni F, Fornasiero A, Lechi A, Gerra G, Mezzelani P. Dependence on zolpidem: Two case reports of detoxification with flumazenil infusion. Physical dependence following zopiclone usage: A case report. Hajak G, Muller WE, Wittchen HU, Pittrow D, Kirch W. Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: A review of case reports and epidemiological data. New-onset transient hallucinations possibly due to eszopiclone: a case study. Primary Care Companion to the Journal of Clinical Psychiatry. Zaleplon overdose associated with sleepwalking and complex behavior. Journal of the American Academy of Child & Adolescent Psychiatry. Incidence of cancer in individuals receiving chronic zopiclone or eszopiclone requires prospective study. Fatal overdose of zopiclone in an elderly woman with bronchogenic carcinoma. Zopiclone withdrawal: an unusual cause of delirium in the elderly. Zolpidem, vascular headache, and hallucinations in an adolescent. Insomnia Page 56 of 86 Final Report Update 2 Drug Effectiveness Review Project 180. Amnesia possibly associated with zolpidem administration. Worsening hepatic encephalopathy secondary to zolpidem. Zolpidem-associated hallucinations and serotonin reuptake inhibition: a possible interaction. Zolpidem-related delirium: A case report Journal of Clinical Psychiatry. Zolpidem-induced delirium with mania in an elderly woman. Journal of the American Academy of Child & Adolescent Psychiatry. Zolpidem and hallucinations Annals of Emergency Medicine. Amnestic sleep-related eating disorder associated with zolpidem. Zolpidem after long-acting benzodiazepines: Possible interaction. Zolpidem-induced psychosis in an older woman Journal of the American Geriatrics Society. Somnambulism due to probable interaction of valproic acid and zolpidem. Insomnia Page 57 of 86 Final Report Update 2 Drug Effectiveness Review Project 201. Toner LC, Tsambiras BM, Catalano G, Catalano MC, Cooper DS. Central nervous system side effects associated with zolpidem treatment. Tripodianakis J, Potagas C, Papageorgiou P, Lazaridou M, Matikas N. A Novel Clinical Pattern of Visual Hallucination after Zolpidem Use. Visual hallucinations and amnesia associated with the use of zolpidem International Journal of Clinical Pharmacology and Therapeutics. One rare side effect of zolpidem--sleepwalking: a case report. Zolpidem addiction in a pregnant woman with a history of second-trimester bleeding. Progress in Neuro-Psychopharmacology & Biological Psychiatry. Pseudohallucinations after zolpidem intake: a case report. Visual hallucinations and amnesia associated with zolpidem triggered by fluvoxamine: a possible interaction. Letsas KP, Filippatos GS, Kounas SP, Efremidis M, Sideris A, Kardaras F. QT interval prolongation and Torsades de Pointes in a patient receiving zolpidem and amiodarone. Zolpidem and amnestic sleep related eating disorder. Sharan P, Bharadwaj R, Grover S, Padhy SK, Kumar V, Singh J. Dependence syndrome and intoxication delirium associated with zolpidem. Compulsive activity and anterograde amnesia after zolpidem use. Clinical Toxicology: The Official Journal of the American Academy of Clinical Toxicology & European Association of Poisons Centres & Clinical Toxicologists. Eszopiclone coadministered with escitalopram in patients with insomnia and comorbid generalized anxiety disorder. The effects of ramelteon on respiration during sleep in subjects with moderate to severe chronic obstructive pulmonary disease. Insomnia Page 58 of 86 Final Report Update 2 Drug Effectiveness Review Project Appendix A. Literature search strategies Newer Drugs for Insomnia included interventions: 1. Quality assessment methods for drug class reviews for the Drug Effectiveness Review Project The purpose of this document is to outline the methods used by the Oregon Evidence-based Practice Center, based at Oregon Health & Science University, and subcontracting Evidence- based Practice Centers to produce drug class reviews for the Drug Effectiveness Review Project. The methods outlined in this document ensure that the products created in this process are methodologically sound, scientifically defensible, reproducible, and well documented. This document were adapted from the Procedure Manual developed by the Methods Work Group of the United States Preventive Services Task Force (version 1. It also incorporates material from the NHS Centre for Reviews and Dissemination’s Undertaking Systematic Reviews of Research on Effectiveness: CRD’s Guidance for Carrying Out or nd Commissioning Reviews (2 edition, 2001) and “The Database of Abstracts of Reviews of Effects (DARE)” in Effectiveness Matters, vol. All included studies and systematic reviews are assessed for quality and assigned a rating of “good,” “fair,” or “poor”. Studies that have a fatal flaw in one or more criteria are rated poor quality. Studies that meet all criteria are rated good quality. The “fair quality” category is broad, and studies with this rating vary in their strengths and weaknesses: The results of some fair-quality studies are likely to be valid, while others only might be valid. A poor-quality trial is not valid—the results are at least as likely to reflect flaws in the study design as a true difference between the compared drugs. For Controlled Trials Assessment of Internal Validity 1. Was assignment to the treatment groups really random? Adequate approaches to sequence generation: Computer-generated random numbers Random numbers tables Inferior approaches to sequence generation: Use of alternation, case record numbers, date of birth, or day of week Not reported 2. Adequate approaches to concealment of randomization: Centralized or pharmacy-controlled randomization Serially numbered, identical containers On-site computer based system with a randomization sequence that is not readable until allocation Other approaches sequence to clinicians and patients Inferior approaches to concealment of randomization: Use of alternation, case record number, date of birth, or day of week Open random numbers lists Insomnia Page 60 of 86 Final Report Update 2 Drug Effectiveness Review Project Serially numbered envelopes (Even sealed opaque envelopes can be subject to manipulation. Were the groups similar at baseline in terms of prognostic factors? Were outcome assessors blinded to the treatment allocation? Was the patient kept unaware of the treatment received? Did the article include an intention-to-treat analysis or provide the data needed for one (that is, number of subjects assigned to each group, number of subjects who finished in each group, and the results for all subjects who finished)? Did the article report attrition, crossovers, adherence, and contamination?

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Elevations in ALT (>3 times the upper limit of normal) were rare in efficacy trials of pioglitazone and rosiglitazone generic 50mg viagra soft with mastercard, with either no cases or reported incidences of less than 1% order viagra soft 50 mg line. Risk of fracture Based on data from ADOPT purchase 100mg viagra soft overnight delivery, in February 2007 GlaxoSmithKline issued a safety warning regarding increased risk of fractures associated with use of rosiglitazone cheap viagra soft 50mg free shipping. An analysis of these 240 data found significantly more female patients who received rosiglitazone experienced fractures than did female patients who received either metformin or glyburide (9. The majority of these fractures were in the upper arm (humerus), hand, or foot. The observed incidence of fractures for male patients in ADOPT was similar among the 3 treatment groups. At GlaxoSmithKline’s request, an independent safety committee reviewed an interim analysis of fractures in another large ongoing, long-term, controlled rosiglitazone clinical trial, which compared rosiglitazone in combination with either metformin or sulfonylurea to combination therapy with metformin and sulfonylurea. The results of the preliminary analysis were reported to GSK as being consistent with the observations from ADOPT. Heart failure and other cardiac adverse events The product label states that rosiglitazone is not indicated in combination with insulin based on an increased incidence of cardiac failure and other cardiovascular adverse events observed in 241 patients on insulin plus rosiglitazone compared with patients using insulin plus placebo. Patients who experienced heart failure were on average older, had a longer duration of diabetes, and were for the most part taking rosiglitazone 8 mg daily. Two placebo-controlled trials of pioglitazone added to insulin reported incidences of 218 238 congestive heart failure of 12. Over the course of the study, overnight hospitalization for congestive heart failure was reported in 9. This adverse event associated with pioglitazone was more marked in patients using insulin at baseline and in patients over 64 years of age. No difference in cardiovascular mortality between the treatment groups was observed. Observational studies of adverse events Direct evidence comparing pioglitazone with rosiglitazone: Harms Overview 18 The previous Drug Effectiveness Review Project TZDs report included 12 observational studies that compared adverse events in patients taking pioglitazone with those in patients taking rosiglitazone. Five of these were designed to assess specific adverse events; in the others, adverse events were reported but were not the primary outcome. In this update, we did not include additional observational studies aiming to assess the risk of cardiovascular adverse events or fractures for people taking TZDs because it was felt that sufficient, and stronger, evidence from systematic reviews was already available. We did include 2 additional 243, 244 observational studies in this section of the report for the current update. The main results of these studies related to this key question are summarized in Table 65 and Evidence Table 21. Lower extremity and pulmonary edema The prevalence of edema was the primary outcome in a retrospective chart review of 99 patients 245 receiving thiazolidinediones in combination with insulin. Among patients taking pioglitazone, there was an increase in edema with increasing dose (1. There was 1 case of pulmonary edema in a patient taking rosiglitazone. Four of these had existing congestive heart 247 failure treated with diuretics. Another study reported edema in patients with documented heart failure. Fluid retention was seen with the use of both pioglitazone (15. Two patients (11%) had physical signs of pulmonary edema, but the study does not report which drug the patients were taking. Macular edema The manufacturer of rosiglitazone issued a warning letter in December 2005 regarding post- marketing reports of new onset and worsening diabetic macular edema for patients receiving 248 rosiglitazone. The incidence is not reported, but the warning letter states that reports were very rare. In the majority of these cases, the patients also reported concurrent peripheral edema. We identified no reports of macular edema in placebo-controlled trials or observational studies. Heart failure A retrospective cohort study used claims data to assess the risk of developing heart failure in 249 patients taking pioglitazone (N=1347) or rosiglitazone (1882) for up to 40 months. Compared with a control group of patients who did not take thiazolidinediones, the hazard ratio for pioglitazone was 1. There was no significant difference in the risk of developing heart failure between these 2 drugs (P=0. A retrospective database study designed to assess the prevalence of edema found no documentation of new-onset heart failure or exacerbations of existing heart failure in patients 245 initiating thiazolidinediones therapy plus insulin. The study authors caution, however, that documentation of heart failure was poor and that the data may be unreliable. Weight gain Seven comparative observational studies reported weight gain in follow-up periods ranging from 244, 246, 250-255 8 weeks to 1 year (Table 64). There was no difference in the amount of weight gain in patients taking pioglitazone compared with rosiglitazone in any study. Range of weight gain reported in comparative observational studies Weight gain with Weight gain with a Study Duration pioglitazone (kg) rosiglitazone (kg) 255 King 2000 16 weeks 0. Evidence comparing pioglitazone or rosiglitazone to active controls: Harms Ten observational studies reported adverse events associated with thiazolidinediones compared 243, 256-264 with other active drugs (Table 65, Evidence Table 21). The adverse events they examined included mortality, coronary heart disease events, heart failure, cancer or adenoma incidence, edema, weight gain and progression to insulin use. Because these studies did not report results separately for pioglitazone and rosiglitazone or they included only 1 of the thiazolidinediones, they do not provide information about the comparative safety of the thiazolidinediones. They do provide information about thiazolidinediones as a class compared with other antidiabetic agents. In 2 studies, thiazolidinediones were not associated with increased mortality compared 258, 261 with other oral hypoglycemic agents. In 1 study, pioglitazone was associated with reduced 243 all-cause mortality compared with other oral antidiabetic medications. In older patients with heart failure thiazolidinediones, either alone or combined with metformin, were associated with a lower risk of death over a 15-month period compared with patients not treated with an insulin 261 sensitizer. Two studies reported the incidence of coronary heart disease events (myocardial infarction or revascularization) with thiazolidinediones compared with metformin or sulfonylureas. A good-quality study using United States health insurance data found no increased risk of coronary heart disease events in patients initiating thiazolidinedione monotherapy 257 compared with those initiating metformin plus sulfonylurea combination therapy. The other found similar risks with rosiglitazone compared with sulfonylureas, metformin, or insulin, either 262 alone or in combination. Both studies also found no increased risk in the individual components of the composite outcome with thiazolidinedione use. Observational studies comparing adverse events associated with thiazolidinediones to adverse events associated with active controls Author, Year Data source, Sample Size Population (Quality) Comparison description Main outcomes Main results Adjusted odds ratio (95% CI) TZD vs. HR with propensity 243 2009 Rosiglitazone integrated All-cause adjustment, each compared to 19,717 vs. Lewis Nested case- Adjusted OR (95% CI) of any 263 2008 control; Kaiser adenoma on first colonoscopy, TZD vs. Hospital admission for congestive heart failure was the main outcome in a fair-quality 259 cohort study that used data from a Kaiser Permanente diabetes registry. Relative to patients initiating therapy with sulfonylureas, patients initiating therapy with thiazolidinediones were no more likely to experience a hospitalization for heart failure after an average of 10. A case-control study based on Oregon Medicaid claims data, in contrast, found a trend suggesting increased risk of hospitalization for heart failure associated with exposure to 265 thiazolidinediones within the previous 60 days. Increased risk was also found with exposure to insulin and to the combination of insulin plus thiazolidinediones, but not for other oral antidiabetic agents. A series of nested case-control studies found no difference in the incidence of breast, colon, or prostate cancer associated with exposure to thiazolidinediones compared with other 260 oral diabetic medications or insulin. A case-control study found a slightly higher odds of having an adenoma on first colonoscopy for subjects with type 2 diabetes exposed to TZDs 263 compared with those not exposed to TZDs. A study conducted in 500 primary care patients in Germany found fewer patients 256 progressed to insulin therapy when taking pioglitazone than when taking a sulfonylurea. However, because this study did not control for confounders and did not clearly report its recruitment strategy and other methods, these results may have a high risk of bias. The previous Drug Effectiveness Review Project TZDs report identified 43 additional 266-303 uncontrolled studies of adverse events associated with individual thiazolidinediones. The results of these studies were consistent with evidence from randomized controlled trials and comparative observational studies. Conclusions that can be drawn from this body of evidence are limited because the studies do not provide information about comparative harms. Fixed-dose Combination Products (FDCPs) or Dual Therapy Summary of findings for Fixed Dose Combination Products or Dual Therapy: Harms Harms in children • We did not find any evidence meeting inclusion/exclusion criteria for children. Harms in adults • We found no head-to-head trials that compared harms between any 2 FDCPs (insufficient strength of evidence). Rates of gastrointestinal adverse effects with Avandamet or dual therapy were high (28 to 47%), but were the same or slightly lower than those with metformin monotherapy (moderate strength of evidence). The 2 included trials were a 28 week trial (N=874) comparing 2 dosages of Avandaryl with glimepiride monotherapy and rosiglitazone monotherapy, and a 20 week trial (N=40) comparing concurrent use of rosiglitazone and glimepiride with rosiglitazone monotherapy. Evidence was limited to 1 trial (N=1,091, with outcomes reported at 24 and 54 weeks) including dual 31, 32 therapy with sitagliptin and metformin. Rates were slightly higher for sitagliptin 100 plus metformin 1000 compared with sitagliptin 100 monotherapy or with metformin 1000 monotherapy at 24 weeks (17. Detailed assessment for FDCPs and Dual Therapy: Harms We identified studies that have been conducted specifically using fixed-dose combination tablets 183, 185 comprised of rosiglitazone/metformin (Avandamet ), , rosiglitazone/glimepiride 186 139 (Avandaryl ), and pioglitazone/metformin (Actoplus Met ). Two of these were new since 139, 183 the 2007 Drug Effectiveness Review Project report on FDCPs. No studies were identified that used the fixed-dose combination tablets comprised of 189 190 pioglitazone/glimepiride (Duetact ) or sitagliptin/metformin (Janumet ). The safety of Duetact and Janumet have been established based on trials using the co-administration of their separate components. More detailed descriptions and summary tables for the studies in this section are provided in the corresponding section of Key Question 1 (Detailed assessment for FDCPs and Dual Therapy) related to efficacy. Details of included studies are found in Tables 37, 39, 41, and 43 and in Evidence Tables 5, 11. Throughout this section, meta-analyses were not performed due to an insufficient number of studies or heterogeneity of study populations, interventions, outcomes, and designs. No comparative cohort studies, case-control studies or systematic reviews were identified reporting harms. Table 66 summarizes adverse events of Avandamet (metformin + rosiglitazone) and rosiglitazone/metformin dual therapy in adults with type 2 diabetes. Head-to-head trials We found no head-to-head trials of Avandamet or dual therapy with metformin and rosiglitazone comparing them with other FDCPs that met inclusion criteria. Two trials compared Avandamet with metformin monotherapy; 1 of them also compared Avandamet with rosiglitazone monotherapy. The dual therapy trial compared concurrent use of metformin and rosiglitazone with metformin monotherapy. Mortality and withdrawals One death occurred in the dual therapy arm of 1 trial; no other deaths during or shortly after treatment were reported.

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H. Kliff. Case Western Reserve University.