By G. Sebastian. North Dakota State University--Fargo.
C om parative clinicaltrials A uth or generic plaquenil 200mg overnight delivery, Y ear O utcom es Transderm alvs cheap plaquenil 200mg on-line. O xybutyninIR D avila O x yTD vsO x yIR 2001 R eductioninm eanincontinenceepisodesat6wks: 4 effective 200 mg plaquenil. R CT = R andom ControlledTrial,U TI = U rinaryTractInfection,N S = N ostatisticaldifference Overactive bladder 96 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. C om parative clinicaltrials A uth or, A dverse effects assessed? O xybutyninIR D avila Invalidatedquestionnairetoevaluatetitrationforpresenceandseverityof 10sym ptom sassessedat2,4 2001 and6wks. R CT = R andom ControlledTrial,U TI = U rinaryTractInfection,N S = N ostatisticaldifference Overactive bladder 97 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. C om parative clinicaltrials A uth or, Y ear W ith drawals due to adverse events C om m ents Transderm alvs. O xybutyninIR D avila O x yIR :1(drym outh) 2001 O x yTD :1contactderm atitisduetopatch *Padtest= patientfillsbladderto300m l,thenperform saseriesof m aneuvers,i. R CT = R andom ControlledTrial,U TI = U rinaryTractInfection,N S = N ostatisticaldifference Overactive bladder 98 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. C om parative clinicaltrials A uth or, Study Design Y ear Setting Eligibility criteria Exclusioncriteria Transderm alvs. Tolterodine SR D m ochowski R CT M enandwom en,aged>18,taking current Historyof urinarytractsurgeryinprevious6m onths,diagnosisof interstitial 2003 M ulticenter pharm acologic treatm entforoveractivebladder cystitis,urethralsyndrom e,painfulbladdersyndrom e,oroverflow urinary U SA with beneficialresponse(bypatientresponse). Post-washout:>/= 4urgeurinaryincontinent episodes,with eitherpureurgeorpredom inant urge,24orm orevoids,andanaverageurinary voidvolum eof 350m lorlessover3days. R CT Patients≥18with O ABsym ptom s(including Patientswith clinicallysignificantBO O ,apostvoidresidualvolum eof 2004 M ulticenter urgency,urgeincontinence,orfrequency)for≥3 >200m l,stressincontinence,presenceof aneurologicalcausefordetrusor International m onths;post-run-ineligibilityincludedan m uscleoveractivity,evidenceof U TI orof bladderstones,previouspelvic averagefrequencyof ≥8voids/24h and3 irradiation,previousorcurrentm alignantdiseaseof thepelvic organs,any episodesof urgencyand/or3episodesof m edicalconditioncontraindicating theuseof antim uscaric m edication incontinenceduring 3-dayvoiding period. R CT = R andom ControlledTrial,U TI = U rinaryTractInfection,N S = N ostatisticaldifference Overactive bladder 99 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. C om parative clinicaltrials A uth or, Interventions (drug,regim en, O th erinterventions/ M eth od ofO utcom e A ssessm entand Tim ing of Y ear duration) m edications A ssessm ent Transderm alvs. Tolterodine SR D m ochowski O x ybutynintransderm al(O x yTD )3. Q O L instrum entandVAS Tolterodinesustainedrelease(TolSR )4 incontinencem anagem ent "periodically. PlaceboBID ; Patient-reportedvoiding diary(episodesof urgencyand 2004 Tolterodine2m g BID (Tol); incontinence,tim esof voiding,volum evoided/void,pad Solifenacin5m g Q D (Sol5); use,andepisodesof sleep disturbance)atwks0,4,8,& Solifenacin10m g Q D (Sol10) 12 *Padtest= patientfillsbladderto300m l,thenperform saseriesof m aneuvers,i. R CT = R andom ControlledTrial,U TI = U rinaryTractInfection,N S = N ostatisticaldifference Overactive bladder 100 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. C om parative clinicaltrials N um berscreened/ A ge O th erpopulation A uth or, eligible/ G ender ch aracteristics N um berwith drawn/ Y ear enrolled Eth nicity (diagnosis,etc) lostto fu/analyz ed Transderm alvs. R CT = R andom ControlledTrial,U TI = U rinaryTractInfection,N S = N ostatisticaldifference Overactive bladder 101 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. C om parative clinicaltrials A uth or, Y ear O utcom es Transderm alvs. Tolterodine SR D m ochowski M eanchangeinincontinenceepisodesperdayat12wks: 2003 O x y-2. Changeinm eannum berof urgencyepisodes/24h: 2004 Tolterodine:-38%,p= 0. R CT = R andom ControlledTrial,U TI = U rinaryTractInfection,N S = N ostatisticaldifference Overactive bladder 102 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. C om parative clinicaltrials A uth or, A dverse effects assessed? Tolterodine SR D m ochowski M ethodof assessm entnotreported 2003 Applicationsitereactions: O x y32/121(25. R CT = R andom ControlledTrial,U TI = U rinaryTractInfection,N S = N ostatisticaldifference Overactive bladder 103 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. C om parative clinicaltrials A uth or, Y ear W ith drawals due to adverse events C om m ents Transderm alvs. R CT = R andom ControlledTrial,U TI = U rinaryTractInfection,N S = N ostatisticaldifference Overactive bladder 104 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. C om parative clinicaltrials A uth or, Study Design Y ear Setting Eligibility criteria Exclusioncriteria Chapple,etal. R CT, M enandwom enaged≥18y,O ABSym ptom sfor StressIncontinence(SI)orM ix edIncontinencewhereSI waspredom inant 2005 E urope ≥ 3m ,outpatient,dem onstratedU I (≥1 andneurogenic D O STAR episode/24h)andurinaryfrequency(≥8 (datafrom m icturitions/d)and ≥1U rgencyepisodes/24h uncorrectedproof) during 3-dayvoiding diaryperiod Chappleetal R CT M enandwom enaged≥18y,O ABSym ptom sfor StressIncontinence(SI)orM ix edIncontinencewhereSI waspredom inant 2007 E urope ≥ 3m ,outpatient,dem onstratedU I (≥1 andneurogenic D O STAR post-hoc episode/24h)andurinaryfrequency(≥8 m icturitions/d)and ≥1U rgencyepisodes/24h during 3-dayvoiding diaryperiod Darifenacinvs. O xybutinin *Padtest= patientfillsbladderto300m l,thenperform saseriesof m aneuvers,i. R CT = R andom ControlledTrial,U TI = U rinaryTractInfection,N S = N ostatisticaldifference Overactive bladder 105 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. C om parative clinicaltrials A uth or, Interventions (drug,regim en, O th erinterventions/ M eth od ofO utcom e A ssessm entand Tim ing of Y ear duration) m edications A ssessm ent Chapple,etal. Stabledosing phase:(W eeks0-4) nonereported 3-daym icturitiondiarypresentedatscheduledvisitsat 2005 Solifenacin5m g once/d wks4,8and12. Sym ptom sassessedinclude: STAR TolterodineE R 4m g once/d m icturitionfrequency(prim aryendpoint),episodesof (datafrom F lex ible-dosing phase:(W eeks5-12) urgency,incontinencewith andwithouturgency, uncorrectedproof) Solifenacin5m g once/d(Sol5) nocturia,padusage/24h,volum evoidedperm icturition. Solefenacin10m g once/d (Sol10) Health relatedQ oL :validated6-pointcategoricalscaleto TolterodineE R 4m g once/d(Tol4) assessPerceptionof BladderCondition. Chappleetal Stabledosing phase:(W eeks0-4) nonereported 3-daym icturitiondiarypresentedatscheduledvisitsat 2007 Solifenacin5m g once/d wks4,8and12. Sym ptom sassessedinclude: STAR post-hoc TolterodineE R 4m g once/d m icturitionfrequency(prim aryendpoint),episodesof N odoseincrease(N D I)phase:(W eeks5- urgency,incontinencewith andwithouturgency, 12) nocturia,padusage/24h,volum evoidedperm icturition. Solifenacin5m g once/d(Sol5) Health relatedQ oL :validated6-pointcategoricalscaleto TolterodineE R 4m g once/d(Tol4) assessPerceptionof BladderCondition. O xybutinin *Padtest= patientfillsbladderto300m l,thenperform saseriesof m aneuvers,i. R CT = R andom ControlledTrial,U TI = U rinaryTractInfection,N S = N ostatisticaldifference Overactive bladder 106 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. C om parative clinicaltrials N um berscreened/ A ge O th erpopulation A uth or, eligible/ G ender ch aracteristics N um berwith drawn/ Y ear enrolled Eth nicity (diagnosis,etc) lostto fu/analyz ed Chapple,etal. O xybutinin *Padtest= patientfillsbladderto300m l,thenperform saseriesof m aneuvers,i. R CT = R andom ControlledTrial,U TI = U rinaryTractInfection,N S = N ostatisticaldifference Overactive bladder 107 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. C om parative clinicaltrials A uth or, Y ear O utcom es Chapple,etal. Prim aryendpoint:m icturitionfrequencySecondaryendpoints:episodesof urgency,incontinencewith 2005 andwithouturgency,nocturia,padusage/24h,volum evoidedperm icturition. Health relatedQ oL : STAR validated6-pointcategoricalscaletoassessPerceptionof BladderCondition. Health relatedQ oL : STAR post-hoc validated6-pointcategoricalscaletoassessPerceptionof BladderCondition.
Cardiovascular events There were no episodes of congestive heart failure during the FDCP trial generic plaquenil 200 mg. Three patients in the monotherapy arms (2 on pioglitazone and 1 on metformin) showed clinically significant worsening ECG results from baseline to end of follow-up cost of plaquenil. One pioglitazone patient was found to have coronary artery disease and myocardial infarction; the other was diagnosed with arterial branch block best purchase plaquenil. The metformin patient was determined to have myocardial ischemia. Gastrointestinal events Diarrhea and gastrointestinal events were reported less frequently in patients taking Actoplus Met (9. In the dual therapy trial, 5 patients in the metformin arm withdrew due to gastrointestinal events. Edema Incidence of peripheral edema in the FDCP trial was highest for pioglitazone alone (4. Weight change In the FDCP trial, patients on Actoplus Met reported less weight gain (0. In the dual therapy study, 3 pioglitazone monotherapy patients withdrew from the study due to excessive weight gain. While weight change itself was not reported for this trial, dual therapy and metformin were associated with significant decreases in body mass index, compared to an increase in the pioglitazone group. Total cholesterol Neither the FDCP trial nor the dual therapy trial reported outcomes related to cholesterol. Other adverse events In the FDCP trial, headache was reported more frequently with than Actoplus Met (5. In the same trial, bone fractures occurred in 1 metformin monotherapy patient (traffic accident) and 1 patient on Actoplus Met (unspecified cause). Adverse events of Actoplus Met or pioglitazone plus metformin dual therapy in adults with type 2 diabetes 139 a188 Perez 2009 Derosa 2009 Actoplus Met Pio Met Pio + Met Pio Met Overall incidence of AEs (%) 50. One randomized controlled trial including dual therapy with sitagliptin and metformin met inclusion criteria. This 31 trial resulted in 3 publications; one reporting results after 24 weeks (N=1,091), one reporting 32 33 results after 54 weeks, and the other after a total of 104 weeks No comparative cohort studies, case-control studies or systematic reviews were identified reporting long-term benefits. Table 69 summarizes adverse events of metformin/sitagliptin dual therapy in adults with type 2 diabetes. Incidences of adverse events were generally similar between treatment arms over the 104-week study period. One patient in the higher-dose dual therapy group died of an electrical shock during the continuation phase, and 1 patient withdrew from the lower-dose metformin monotherapy arm due to esophageal carcinoma and died during the study period. There was slightly more variation in the incidence of severe adverse events between groups. At 24 weeks, fewer patients in the higher-dose dual therapy arm reported serious events (0. After 104 weeks, sitagliptin monotherapy was associated with the highest rate of serious adverse events (7. Incidence of severe events in both dual therapy arms was 6% and 6. Seventy-one percent of patient in the lower-dose combination arm reported adverse effects. Hypoglycemic events were rare across treatment groups at 24, 54 and 104 weeks and were of mild or moderate severity. At both points of measurement, more higher-dose dual therapy patients reported hypoglycemia (2. After 104 weeks, rates of hypoglycemia across the 3 monotherapy arms ranged from 1. Patients in either dual therapy arm reported adverse gastrointestinal events more frequently than patients on sitagliptin monotherapy or lower-dose metformin. Nausea / vomiting and abdominal pain were reported most frequently in the higher-dose metformin monotherapy group, and diarrhea was reported most frequently by higher-dose dual therapy patients. After 104 weeks, there was no change in weight from baseline for the sitagliptin monotherapy patients. Body weight decreased by small but statistically significant amounts in the other arms, ranging from 0. The only arm in which total cholesterol changed significantly from baseline was higher- dose dual therapy; total cholesterol decreased by 3. Adverse events of metformin/sitagliptin dual therapy in adults with type 2 diabetes 31 32a 33a Goldstein 2007 Williams-Herman, 2009 Williams-Herman, 2010 Sita Sita Sita Sita Sita Sita 100 + 100 + 100 + 100 + 100 + 100 + Sita Met Met Met Met Sita Met Met Met Met Sita Met Met Met Met 100 1,000 2,000 1,000 2,000 100 1,000 2,000 1,000 2,000 100 1,000 2,000 1,000 2,000 Withdrawals due to 2. Williams-Herman et al, 2010 is an extension of Goldstein et al, 2007. Are there subgroups of patients based on demographics (age, racial groups, gender), comorbidities (drug-disease interactions, obesity), or other medications (drug-drug interactions) for which newer diabetes medications differ in efficacy/effectiveness or frequency of adverse events? Newer Drugs for the Treatment of Diabetes Mellitus: Amylin Agonists, DPP-4 Inhibitors, and GLP-1 agonists Summary of Findings for Newer Drugs • We found insufficient evidence to draw any firm conclusions about whether there are subgroups of patients based on demographics, comorbidities, or other medications for which newer diabetes medications differ in efficacy/effectiveness or frequency of adverse events. Detailed Assessment for Newer Drugs Pramlintide for type 1 diabetes There was insufficient evidence to perform subgroup analyses based on age, sex, race, ethnicity, or baseline HbA1c in individual studies. One randomized controlled trial conducted subgroup analyses that were not all 21, 304 prespecified, and 1 post hoc pooled-analyses was identified. Results from these hypothesis- generating analyses should be used with caution. Further prospective research with larger sample sizes will need to be conducted to verify these findings. Baseline body mass index 2 Pramlintide appeared to inhibit weight gain in patients with baseline body mass index ≤ 23 kg/m 2 while producing mild weight loss for patients with body mass index > 23 kg/m (baseline to 21 week 26). Baseline HbA1c < 8% Data from 3 studies that included patients with baseline HbA1c between 7% and 8. Two of the 19, 21 3 studies were identified and included in our review. The third study was in abstract form and was excluded. The pooled publication reported results up to 26 weeks. In this subgroup, the pooled change in HbA1c was −0. There was no overall increased risk in hypoglycemia. The improvement in HbA1c in this pooled subgroup analysis was similar to the change in HbA1c noted for all subjects (across a range of HbA1c) in the original studies. Thus, it appears that patients with good but not optimal baseline HbA1c of 7% to 8. Pramlintide for type 2 diabetes Age, sex, total daily insulin dose, and prior use of oral hypoglycemic agents None of the randomized controlled trials conducted subgroup analyses evaluating whether pramlintide had differential effects in these populations. Race and ethnicity 305 25, 26 A post hoc analysis of two 52-week trials pooled subjects of various ethnic groups.
Altogether buy plaquenil 200 mg without a prescription, the evidence is inconclusive to determine whether second-generation antidepressants differ between patients with diverse ethnic backgrounds purchase plaquenil 200mg otc. Sex Two pooled-data analyses did not find significant associations between sex and efficacy 294 order online plaquenil, 295, 303 outcomes in patients treated for MDD. A pooled analysis of data from four sertraline- RCTs conducted in populations with panic disorder reported better responses of female than 301 male patients on some outcome measures. A fair trial comparing bupropion and paroxetine showed a significant difference in anti- depressant related sexual dysfunction in men but not in women. Paroxetine-treated men reported a worsening of sexual function while bupropion-treated men had no significant change in sexual function. A meta-analysis of RCTs found significant gender-related adverse events of antidepressants. Citalopram, fluoxetine, paroxetine, sertraline, and venlafaxine caused higher 304 rates of desire and orgasm dysfunction in men and higher arousal dysfunction in women. A pooled data analysis indicated higher rates of vomiting in women than in men treated with 303 desvenlafaxine. Concomitant medications A fair retrospective cohort study found evidence of increased breast cancer mortality in women treated with tamoxifen for breast cancer and concurrent use of paroxetine. No evidence of increased risk was found with concurrent use of fluoxetine, sertraline, citalopram, fluvoxamine, 306 or venlafaxine. Evidence is insufficient to determine the influence of concomitant medications on the effectiveness or harms of SSRIs, SNRIs, or other second-generation antidepressants. Second-generation antidepressants 104 of 190 Final Update 5 Report Drug Effectiveness Review Project 5. Comorbidities We found no prospective study directly comparing the efficacy, effectiveness and tolerability of SSRIs, SNRIs, and other second-generation antidepressants in a population with a specific comorbid condition to a population without that same condition. A meta-analysis with a subgroup analysis yielded good evidence that overall, SSRIs were superior to placebo at 6 to 8 months for patients without comorbidities compared with patients with comorbidities (analyzed 307 as a combined category). However, we could not identify further studies analyzing outcomes after a follow-up of similar duration. The majority of studies we identified are limited to depressive disorders in patients with a variety of disorders. Overall, evidence of treatment efficacy across various disease conditions and second-generation depressants is mixed. For other conditions, however, such as methadone-maintained opioid addiction, cocaine 312, 313, 322, 324, 326-328 abuse, HIV, multiple sclerosis, arthritis, diabetes, or cancer, comorbid alcohol 311 use disorder in depressed adolescents or substance abuse in adolescents with comorbid 314 conduct disorder, second-generation antidepressants were unable to achieve response or remission rates that were statistically significantly better than placebo. For some comorbid conditions the evidence was inconclusive. For depression with 308-310 comorbid alcoholism, evidence of treatment efficacy of a SSRI compared with placebo, 317, 319 318 lack of such an effect, or differential effect only for women in the treatment group were identified. Also, treatment efficacy for post-stroke depression was not uniform across studies, 331, 333 with two trials showing second-generation antidepressant superior to placebo yet one 336 trial lacking a significant treatment effect. Inconclusive also the findings of trials with second- generation-antidepressants for Alzheimer’s depression, with one study showing a treatment 320 effect, a second trial, however, lacking such an effect but with more adverse events in the 321 treatment group. Interventions, numbers of patients, and quality ratings in controlled trials assessing efficacy and effectiveness in subgroups Quality Author, Year Interventions N Results rating Age Escitalopram compared No significant difference in response 65 Kasper et al. They include bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, and venlafaxine. From a total of 4,850 citations identified, we ultimately included 275 studies of good or fair quality. Of these, 170 were randomized controlled trials (RCTs) and the remaining 105 studies were meta-analyses or systematic reviews, observational studies and studies of other designs. Seventy-two studies that met the eligibility criteria were later rated as poor quality for internal validity and excluded from the analysis. Overall, the new evidence (59 new studies) that we found during the update of the report from 2008 did not lead to changes in our main conclusion from that review—namely, that no substantial differences in efficacy exist among second-generation antidepressants for the treatment of MDD. Strength of the Evidence Table 23 summarizes principal findings and the strength of the underlying evidence. The strength of the evidence for the comparative efficacy for the treatment of MDD was generally good to fair. The strength of the evidence for other depressive disorders, such as dysthymia, subsyndromal depression, or seasonal affective disorders was poor with no comparative data available. Similarly, the strength of the comparative evidence for the treatment of MDD in children and adolescents was poor. For anxiety disorders the strength of the comparative evidence was fair for some comparisons but poor for most others. For premenstrual dysphoric disorder, no comparative evidence could be found and the strength of the evidence was rated poor. Good evidence indicates that second-generation antidepressants have similar adverse events profiles. Fair to good evidence also suggests that differences for some specific adverse events exist among some antidepressants. For example, mirtazapine causes higher rates of weight gain, venlafaxine leads to higher rates of nausea and vomiting, and sertraline has an increased risk of diarrhea than other antidepressants. Except for lower rates of sexual dysfunction for bupropion than for comparator drugs, the evidence on the comparative risks of serious adverse events such as suicidality, seizures, and others was rated poor. Fair evidence indicates that no differences in efficacy for subgroups based on age. For all other subgroups the evidence on the comparative efficacy and harms was rated poor. Limitations As with other types of research, the limitations of this systematic review are important to recognize. These can be divided into 2 groups, those relating to applicability of the results and those relating to methodology within the scope of this review. The applicability of the results are limited by the scope of the key questions and inclusion criteria and by the applicability of the studies included. Most studies included narrowly defined populations of patients who met strict Second-generation antidepressants 111 of 190 Final Update 5 Report Drug Effectiveness Review Project criteria for case definition, had few comorbidities, and used few or no concomitant medications. Minorities, older patients, and the most seriously ill patients were underrepresented. Methodological limitations of the review within the defined scope included the exclusion of studies published in languages other than English and lack of a specific search for unpublished studies. Unfortunately, for many drugs, there are few or no effectiveness studies and many efficacy studies. As a result, clinicians must make decisions about treatment for many patients who would not have been included in controlled trials and for whom the effectiveness and tolerability of the different drugs are uncertain.
Controller medications for asthma 235 of 369 Final Update 1 Report Drug Effectiveness Review Project Appendix G order plaquenil 200mg otc. Excluded studies at full-text level The following full-text publications were considered for inclusion for the update report but failed to meet the criteria for this report discount 200mg plaquenil with mastercard. In addition to the references listed below there were 45 studies excluded because they were not published in English (2) or they were not an eligible study design (43) plaquenil 200 mg with mastercard. A list of studies excluded from the original report is available as an appendix to that report. Exclude Reasons 2 = Ineligible outcome(s) 3 = Ineligible drug 4 = Ineligible population 6 = Ineligible design (e. A retrospective database study comparing treatment outcomes and cost associated with choice of fixed-dose inhaled corticosteroid/long-acting beta-agonists for asthma maintenance treatment in Germany. Short-term lower-leg growth rate and urine cortisol excretion in children treated with ciclesonide. Ciclesonide (
There was also a significant difference in stenosis diameter between groups at 6 months (P=0 buy cheapest plaquenil. The available data provided no information on the comparative effectiveness of pioglitazone and rosiglitazone on macro- and microvascular outcomes when used as monotherapy or when added to or substituted for other oral hypoglycemic agents order 200 mg plaquenil mastercard. Dormandy and 177 colleagues addressed the question of combined therapy as pioglitazone was added to other 168 anti-diabetic therapy in 96% of patients buy plaquenil 200mg. In the study by Wang and coauthors monotherapy and combined therapy patients were aggregated, so conclusions cannot be drawn about each of these 2 approaches. In the updated review several additional trials provided evidence on macrovascular outcomes and on mortality, with 5 trials providing additional evidence on pioglitazone. The primary endpoint was the change in carotid artery intima-media thickness after 72 weeks. Secondary endpoints included the composite of cardiovascular mortality, non-fatal myocardial infarction, or nonfatal stroke, and the composite of these outcomes plus coronary revascularization, carotid endarterectomy/carotid stenting, hospitalization for unstable angina, or hospitalization for heart failure. There were few events reported, and no cardiovascular deaths. There were 2 instances of the first composite endpoint in the glimepiride group and none in the pioglitazone group. On the second composite endpoint, there were 10 events in the glimepiride group (8 of which were coronary revascularization) and 4 in the pioglitazone group (3 coronary revascularization). PERISCOPE was another trial of pioglitazone compared to glimepiride designed to 128 measure progression of atherosclerosis in patients with type 2 diabetes. After 18 months of follow-up, there was no difference between groups in the occurrence of clinical endpoints, including the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (2. There were 3 cardiovascular deaths in the pioglitazone group and 1 in the glimepiride group (P=0. In a small, fair-quality, randomized controlled trial (N=47), patients with impaired glucose tolerance or type 2 diabetes (combined in the analysis) in addition to nonalcoholic steatohepatitis, received either pioglitazone 45 mg daily or placebo, in addition to a weight loss 180 intervention. Glycemic control improved with pioglitazone compared with placebo (P<0. Plasma aspartate and alanine aminotransferase levels and hepatic fat content all decreased with treatment compared with placebo (P<0. Histologic changes in the liver also improved significantly with pioglitazone. At 6- months follow-up these researchers demonstrated that late luminal loss was less in the pioglitazone group than in the control group (P=0. Major cardiac events (myocardial infarction or revascularization of the target lesion) were significantly decreased in the pioglitazone group at 6 months compared with the control group (7. Takagi and colleagues compared pioglitazone with placebo in 44 patients with type 2 182 diabetes who had undergone coronary stent implantation. After 6 months of follow-up, angiographic in-stent restenosis (19% compared with 46%; P=0. There was no difference in HbA1c levels at follow-up in this study (See Key Question 1). The updated search identified several important recent trials of rosiglitazone reporting 146, 157 147 vascular or mortality outcomes: the RECORD trial and ADOPT. The RECORD trial was an open-label, multicenter, noninferiority, randomized controlled trial (N=4447). Subjects who were already taking metformin or a sulfonylurea were randomized to add-on rosiglitazone 4 mg daily (titrated up to 8 mg daily) or to metformin (titrated up to 2550 mg daily) plus a sulfonylurea (glyburide, gliclazide or glimepiride, depending on physician preference). The primary outcome for the RECORD study was time to first occurrence of cardiovascular hospitalization or cardiovascular death. The hazard ratio for rosiglitazone (plus metformin or a sulfonylurea) compared with metformin plus a sulfonylurea was 0. Heart failure causing admission to the hospital or death occurred in 61 people in the rosiglitazone group and 29 in the active control group(hazard ratio 2. Subjects with significant renal or hepatic disease, unstable or severe angina, or congestive heart failure of any New York Heart Association class were excluded. Approximately half of subjects 156 had hypertension, 81% had metabolic syndrome, and 45% were smokers. The number of deaths from all causes was similar across the 3 groups, but more cardiovascular events were reported in the rosiglitazone group (4. Congestive heart failure events were higher with rosiglitazone than with glyburide (further details are presented in Key Question 8). The lower rates of cardiovascular events in the glyburide group were primarily due to lower rates of nonfatal myocardial infarction and congestive heart failure in this group. Several additional, smaller rosiglitazone trials were also identified in the updated 174, 176 search. In a very small (N=16), poor-quality, randomized controlled trial, subjects with coronary stent implantation were randomized to rosiglitazone 4-8 mg daily or placebo for 6 months. Rosiglitazone did not reduce in-stent restenosis and there were no differences in cardiac 174 events between the groups. Fixed-dose Combination Products (FDCPs) or Dual Therapy Summary of findings for FDCPs or Dual Therapy Evidence in children • We did not find any evidence meeting inclusion/exclusion criteria for children (insufficient strength of evidence). Evidence in adults • We found no studies that focused on health outcomes as the primary outcomes for any available FDCP. Two studies reported health outcomes among other secondary outcomes 183, 184 or in the adverse events section. Overall evidence was insufficient to determine how FDCPs compare with other treatments for their impact on health outcomes. Detailed Assessment for FDCPs and Dual Therapy 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. For this report, dual therapy was defined as using the individual components of a FDCP in separate pills/tablets. Studies were required to randomize subjects to the components of a FDCP or to monotherapy with one of the components of the FDCP to be eligible for this report. No studies were identified that used the fixed-dose combination tablets comprised of 189 190 pioglitazone/glimepiride (Duetact ) or sitagliptin/metformin (Janumet ). The efficacy and safety of Duetact and Janumet have been established based on trials using the co- administration of their separate components. The majority of the trials were 4- to 6-month evaluations of glycemic control and general adverse events with FDCPs or dual therapy compared to component monotherapy when used as initial treatment for patients with type 2 diabetes. Studies that compared type 2 diabetes combination tablet products to co-administration of their components were few, nonrandomized, 191-193 and limited to analyses based on refill data from pharmacy claims databases. We found no evidence to address the effectiveness of combination tablet products in improving long-term health. Throughout this section, meta-analyses were not performed due to an insufficient number of studies or heterogeneity of study populations, outcomes, and designs.