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Statins Page 75 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 1 100 mg zenegra. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Results (mean changes in lipoprotein levels) Harms/Comments Wolffenbuttel et al zenegra 100mg. ADEs were similar between groups and no serious ADEs or withdrawal from 1998 LDL-c reduction from baseline: groups as a result of ADEs were reported zenegra 100 mg. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Funding Source Wolffenbuttel et al 100mg zenegra. Supported by Parke- 1998 Davis; one author R , OL , MC . Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Inclusion Criteria/ Patient Clinical Trial Population Exclusion criteria Intervention Fluvastatin vs . Mean baseline LDL-c 187 mg/dl Davidson et al , 2003 Men and women >20 years with TG Patients with myocardial infarction , coronary bypass surgery, or Fluva 20 or 40 mg qd or lova 10, 20, or 40 R, DB, MC, PC, level < 4. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Results (mean changes in lipoprotein levels) Harms/Comments Berger et al. Withdrawals due to AEs: R, OL, MC, ITT LDL-c reduction from baseline: 8 fulva vs. HDL-c increase from baseline at 6 weeks (NS): fulva 20 mg: 3. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Funding Source Berger et al. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Inclusion Criteria/ Patient Clinical Trial Population Exclusion criteria Intervention Nash 1996 Men or women previously 363 patients screened, 137 patients randomized. Mean baseline LDL-c Not reported Statins Page 81 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 1. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Results (mean changes in lipoprotein levels) Harms/Comments Nash 1996 Efficacy analysis for 137 patients. R, OL, MC, ITT LDL-c reduction from baseline at 8 weeks: fulva: men and women 26% Musculoskeletal abnormalities existed significantly more often as a 137 patients randomized lova: men 29%, women 26% (NS) background medical condition in the lova group. No lova: men 7%, women 4% details on what dose of fulva patients experienced these ADEs. Trigs reduction from baseline at 8 weeks: fulva: men 14%, women 10% lova: men 12%, women 20% Achieved LDL-c goal (<160 mg/dl) at 4 weeks: fulva: 85% lova: 91% (NS) Achieved LDL-c goal (<160 mg/dl) at 8 weeks: fulva: 89% lova: 91% (NS) Statins Page 82 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 1. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Funding Source Nash 1996 Funded by Sandoz R, OL, MC, ITT Pharmaceuticals. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Inclusion Criteria/ Patient Clinical Trial Population Exclusion criteria Intervention Fluvastatin vs. Analysis included both on treatment and intention to 6-week dietary/placebo run-in phase then, R, DB, MC, both ITT and LDL>160 mg/dl and trigs <400 treat population. Severe forms of hypercholesterolemia and those randomization to: on treatment analysis mg/dl with impaired renal function were excluded. No details provided on fulva 40 mg qd or numbers and reasons for excluding patients. Statins Page 84 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 1. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Results (mean changes in lipoprotein levels) Harms/Comments Jacotot et al. No patient R, DB, MC, both ITT and LDL-c reduction from baseline at 16 weeks: withdrew due to myopathic complaints or liver ADEs. More GI ADEs in fulva on treatment analysis fulva 40 mg bid: 29. No patient experienced clinically significant elevation in ALT, AST or parva 40 mg qd: 26. Trigs reduction from baseline at 16 weeks: Fluvastatin 40 mg bid ≈ pravastatin 40 mg qd. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Funding Source Jacotot et al. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Inclusion Criteria/ Patient Clinical Trial Population Exclusion criteria Intervention Fluvastatin vs. Simvastatin Bevilacqua M, et al Men and women with T2DM, Surgery, myocardial infarction, angioplasty in last 6 months, poorly 4 week dietary run-in; fluvastatin extended- 2005 triglycerides > 2. Analysis for LDL-c reduction did not include 4-week dietary/placebo run-in, then R, DB, MC, ITT less and a total cholesterol >250 17 patients due to missing or inappropriately done labs. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Results (mean changes in lipoprotein levels) Harms/Comments Bevilacqua M, et al LDL-c change from baseline at 8 weeks: No severe AEs reported, Data = NR 2005 fulva -51% vs. Number of patients reporting ADEs similar across all groups. GI ADEs were R, DB, MC, ITT LDL-c reduction from baseline at 6 weeks: more frequent in fulva vs. HDL-c increase from baseline at 6 weeks: Fluvastatin 40 mg qd = simvastatin 10 mg qd for NCEP goal reached. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Funding Source Bevilacqua M, et al NR 2005 RCT, OL, SC, ITT 94 patients randomized (n = fulva 48, simva 46) 8 weeks Ose et al. R, DB, MC, ITT 432 patients randomized 6 weeks Statins Page 89 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 1. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Inclusion Criteria/ Patient Clinical Trial Population Exclusion criteria Intervention Schulte et al. Active 4-week dietary run-in phase and R, DB LDL-c >185 mg/dl and trigs <300 liver or gallbladder disease, elevated aminotransferases or other randomized to: mg/dl. Patients with concomitant conditions such as myocardial infarction or 8-week dietary and 2 week-placebo run-in R, DB, MC, not ITT CVA within the past 6 months, planned angioplasty or coronary phase, then randomized to: Mean baseline LDL-c bypass surgery during the previous 6 months, unstable angina, fulva 20 mg qd or 113 patients randomized 185-187 mg/dl cardiac or renal failure, hepatic disease, uncontrolled hypertension, simva 20 mg qd 16 weeks partial ileal bypass, secondary hypercholesterolemia, or for 16 weeks. Statins Page 90 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 1. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Results (mean changes in lipoprotein levels) Harms/Comments Schulte et al. One patient in each group had R, DB LDL-c reduction from baseline at 4 and 10 weeks: elevations in AST or ALT >3x ULN. No clinically significant increase in CK was fulva 40 mg: 23. HDL-c increase from baseline at 4 and 10 weeks: Fluvastatin 80 mg qd = simvastatin 40 mg qd. ADEs similar between groups, with a trend to more GI ADEs in the fulva vs. R, DB, MC, not ITT LDL-c reduction from baseline at 16 weeks: simva group (8 vs. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Funding Source Schulte et al. R, DB 120 patients randomized 10 weeks Sigurdsson et al. Statins Page 92 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 1. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Inclusion Criteria/ Patient Clinical Trial Population Exclusion criteria Intervention Lovastatin Extended Release vs. Lovastatin Immediate Release Lukacsko et al, 2004 Men and women ages 21 to 70 with a History of underlying hepatic disease or elevation of serum alanine Lovastatin 20mg ER once daily vs lovastatin TG level less than 350 mg/dL and aminotransferase (ALT) or aspartate aminotransferase (AST) above 1. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Results (mean changes in lipoprotein levels) Harms/Comments Lukacsko et al, 2004 Efficacy analysis for 179 patients. No apparent trends by treatment in the incidence of treatment emergent signs LDL-c reduction from baseline at week 12 (from baseline to endpoint and symptoms. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Funding Source Lukacsko et al, 2004 Funded by Andrx Laboratories, and all 179 patients randomized authors employed by (n= 90 lova ER, 89 lova same. IR) 12 weeks; crossover Statins Page 95 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 1. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Inclusion Criteria/ Patient Clinical Trial Population Exclusion criteria Intervention Lovastatin vs. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Results (mean changes in lipoprotein levels) Harms/Comments McPherson et al. R, DB, MC, not ITT LDL-c reduction from baseline at 8 weeks: lova 20 mg: 28% Difference in LDL-c lowering greater at 4 weeks in lova vs. Trigs reduction from baseline at 8 weeks: lova 20 mg: 6. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Funding Source McPherson et al. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Inclusion Criteria/ Patient Clinical Trial Population Exclusion criteria Intervention Strauss et al. The Lovastatin Men and women 25-75 years with Patients aged <25 or >75 yrs, secondary hypercholesterolemia, 7-week dietary/placebo run-in phase Pravastatin Study hypercholesterolemia triglyceride level >300mg/dl, women who could not conceive and DM, followed by randomization to: Group 1993 lova 20 mg qd (n=339) or R, DB, MC, not ITT Mean baseline LDL-c parva 10 mg qd (n=333) 194-196 mg/dl for 6 weeks. Statins Page 99 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 1. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Results (mean changes in lipoprotein levels) Harms/Comments Strauss et al. No cases of myopathy or R, SB, Crossover, not LDL-c reduction from baseline at 4 weeks: clinical significant elevation in ALT or AST observed. ITT lova: 24% parva: 19% (NS) Dose equivalence 31 patients randomized HDL-c increase from baseline at 4 weeks: Lova 10 mg = parva 10 mg qd. Liver transaminase levels >3x ULN occurred in one lova vs. Group 1993 LDL-c reduction from baseline at 6, 12 and 18 weeks: R, DB, MC, not ITT lova 20 mg: 28% vs. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Funding Source Strauss et al. Group 1993 R, DB, MC, not ITT 672 patients randomized 18 weeks Statins Page 101 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 1. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Inclusion Criteria/ Patient Clinical Trial Population Exclusion criteria Intervention Weir et al. Statins Page 102 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 1. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Results (mean changes in lipoprotein levels) Harms/Comments Weir et al. No difference in quality of life between R, DB, MC, not ITT LDL-c reduction from baseline at 12 weeks: groups. Trigs reduction from baseline at 12 weeks: lova: 6% parva: 8. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Funding Source Weir et al. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Inclusion Criteria/ Patient Clinical Trial Population Exclusion criteria Intervention Lovastatin vs. Current treatment with other investigational drug, hypersensitivity to HMG-CoA reductase inhibitors, concurrent use of cimetidine, use of antacids or immunosuppressive agents, drug or alcohol abuse, overweight and with poor mental function. Statins Page 105 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 1. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Results (mean changes in lipoprotein levels) Harms/Comments Farmer et al. Withdrawal for clinical or laboratory R, DB, MC, not ITT LDL-c reduction from baseline at 24 weeks: ADEs not different between groups. Patients in Stratum 2 experienced more laboratory ADEs in lova group vs. R, DB, MC, not ITT LDL-c reduction from baseline at 18 weeks: simva group (8. There were said to be minor and well within normal ranges. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Funding Source Farmer et al. Merck coordinated data and 298 patients randomized biostatistics groups. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Inclusion Criteria/ Patient Clinical Trial Population Exclusion criteria Intervention Pravastatin vs. Men and women 22-75 years with Patients with plasma triglyceride levels >4. Simva 219 mg/dl Statins Page 108 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 1. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Results (mean changes in lipoprotein levels) Harms/Comments Douste-Blazy et al. Two patients in each group 1993 LDL-c reduction from baseline at 6 weeks: stopped the statin due to ADEs and were not serious. No patient withdrew due R, DB, MC, not ITT parva: 25% to a laboratory ADE. No clinically important changes in liver transaminases simva: 6. Trigs reduction from baseline at 6 weeks: parva: 10. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Funding Source Douste-Blazy et al. R, DB, MC, not ITT 273 patients randomized 6 weeks Lambrecht et al.

Im m ediate R elease (ER vs IR ) O xybutyninER v Tolterodine IR Appell Patientreported O verall7 zenegra 100 mg. R CT = R andom ControlledTrial 100 mg zenegra,U TI = U rinary TractInfection 100mg zenegra,N S = N ostatisticaldifference Overactive bladder 209 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 10 zenegra 100mg. Sh ort-term com parative studies:A dverse effects A uth or N um berEnrolled Y ear Setting Interventions (drug ,regim en ,duration) Extended R elease vs . E nrolled= 608 2003 O x y IR 3m g threetim esdaily x 12wks TolE R = 240 O x y IR = 246 Pla= 122 Extended R elease vs . Tolterodine ER Chapple F lex ibledosing ,W eeks0-4: F ullanaly sisset(F AS):1177 2005 Sol5m g qd STAR trial TolE R 4m g qd Stable-dosephase ,W eeks5-12: Sol5m g qd(Sol5) Sol10m g qd (Sol10) TolE R 4m g qd(Tol4) *Padtest= patientfillsbladderto300m l,thenperform saseriesof m aneuvers,i. R CT = R andom ControlledTrial,U TI = U rinary TractInfection,N S = N ostatisticaldifference Overactive bladder 210 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 10. Sh ort-term com parative studies:A dverse effects A uth or Y ear W ith drawals due to Q uality rating and Setting N um berofadverse effects adverse events C om m ents Extended R elease vs. O x y 93% undefined; N odeathsandnoclinically significantchangesinlab orE CG values. Tolterodine ER Chapple AE evalutedateach clinic visitinresponsetoquestioning by theinvestigatororvolunteeredby W ithdrawalsdueto 2005 patient AE s: STAR trial Sol:3. R CT = R andom ControlledTrial,U TI = U rinary TractInfection,N S = N ostatisticaldifference Overactive bladder 211 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 10. Sh ort-term com parative studies:A dverse effects A uth or N um berEnrolled Y ear Setting Interventions (drug,regim en,duration) Extended R elease vs. Im m ediate R elease (ER vs IR ) DarifenacinIR and DarifenacinER vs. E nrolled790 2003 TolE R 4m g/day x 12wks O x y E R = 391 O PE R A TolE R = 399 *Padtest= patientfillsbladderto300m l,thenperform saseriesof m aneuvers,i. R CT = R andom ControlledTrial,U TI = U rinary TractInfection,N S = N ostatisticaldifference Overactive bladder 212 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 10. Sh ort-term com parative studies:A dverse effects A uth or Y ear W ith drawals due to Q uality rating and Setting N um berofadverse effects adverse events C om m ents Extended R elease vs. Im m ediate R elease (ER vs IR ) DarifenacinIR and DarifenacinER vs. O xybutyninIR ChappleandAbram s C oh ort1% (Dar:# ofpts;O xy:# ofpts)vs. C oh ort3% (D:#;O :#) D iscontinueddueto 2005 AllAE s:43% (D :5,O 8)vs73% (D :16;O ;19)vs98% (D :22;O :24) AE s:3. Tol19/399 D atacollectedateach O PE R A m ild:ox y 87/391(22. R CT = R andom ControlledTrial,U TI = U rinary TractInfection,N S = N ostatisticaldifference Overactive bladder 213 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 10. Sh ort-term com parative studies:A dverse effects A uth or N um berEnrolled Y ear Setting Interventions (drug,regim en,duration) Transderm alvs. O xybutyninIR D avila Starting doseassigneddepending onpriororal E nrolled76 2001 ox y buty nindoseof /= O x y TD = 38 20m g daily : O x y IR = 38 O x y TD 2. R CT = R andom ControlledTrial,U TI = U rinary TractInfection,N S = N ostatisticaldifference Overactive bladder 214 of 217 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 10. Sh ort-term com parative studies:A dverse effects A uth or Y ear W ith drawals due to Q uality rating and Setting N um berofadverse effects adverse events C om m ents Transderm alvs. O x y IR O x y IR :1(dry m outh) F air 2001 D ry m outh:15(39%)vs. Anticholinergic sideeffects(% only ,num bersN R ) TolSR = 2/123(1. R CT = R andom ControlledTrial,U TI = U rinary TractInfection,N S = N ostatisticaldifference Overactive bladder 215 of 217 Final Report Update 4 Drug Effectiveness Review Project 1 Evidence Table 11. C linically significantdrug interactions F lavoxate Trospium O xybutyninC h loride Tolterodine Tartrate Darifenacin SolifenacinSuccinate H ydroch loride C h loride Drugs affecting N otreported N otreported N o significant N o dose adjustm ent 5 N otreported F urth erstudies needed. N o action needed forC Y P2D6 and (C Y P 450) 2 m oderate C Y P3A 4 required. F luoxetine N otreported N otreported N o dose adjustm ent N otreported N otreported N otreported required. M ay increase concentrationof 2 tolterodineby fourfold. Diuretics N otreported N otreported N o significant N otreported N otreported N otreported 1 interactions. O ral N otreported N otreported N o significant N otreported N otreported N otreported C ontraceptives interactions. A nticoagulants N otreported N otreported N o significant N otreported N otreported N otreported 2 interactions. Increased N otreported N otreported N otreported N otreported sedationwith CN S 2 depression. Increased N otreported N otreported N otreported N otreported 2 anticholinergic effects. M acrolide N otreported 2 N otreported N otreported N otreported N otreported Inform ationnotavailable. C linically significantdrug interactions F lavoxate Trospium O xybutyninC h loride Tolterodine Tartrate Darifenacin SolifenacinSuccinate H ydroch loride C h loride A z ole antifungal N otreported N o significantinteraction. Co-adm inistration N otreported agents Serum concentrationsof required. M ay inhibit with asingle10m g ox y buty ninincreasedthree m etabolism of tolterodine. Reports are not usage guidelines, nor should they be read as an endorsement of, or recommendation for, any particular drug, use or approach. Oregon Health & Science University does not recommend or endorse any guideline or recommendation developed by users of these reports. McNally, MPH, MA Sujata Thakurta, MPA:HA Original report: Susan L. Burda Oregon Evidence-based Practice Center Oregon Health & Science University Mark Helfand, MD, MPH, Director Copyright © 2008 by Oregon Health & Science University, Portland, Oregon 97239. Final Report Update 1 Drug Effectiveness Review Project TABLE OF CONTENTS INTRODUCTION.......................................................................................................................... Pharmacokinetics, indications and dosing of included drugs................................................. Quick-relief medications for asthma: included citations: efficacy, effectiveness, and safety.. Albuterol compared with levalbuterol: Demographic and study characteristics in adults (studies with effectiveness outcomes only)........................................................................................... Albuterol compared with levalbuterol: Demographic and study characteristics in children (studies with effectiveness outcomes only)........................................................................................... Albuterol compared with levalbuterol: Effectiveness outcomes.............................................. Albuterol compared with pirbuterol: Demographic and study characteristics of included efficacy and effectiveness studies......................................................................................................... Albuterol compared with fenoterol: Demographic and study characteristics of included studies (studies with effectiveness outcomes only)........................................................................................... Albuterol compared with fenoterol: Effectiveness outcomes of included studies.................... Albuterol compared with terbutaline: Demographic and study characteristics of included studies (studies with effectiveness outcomes only)............................................................................... Albuterol compared with terbutaline: Effectiveness outcomes of included studies............... Fenoterol compared with terbutaline: Demographic and study characteristics of studies with effectiveness outcomes......................................................................................................................... Fenoterol compared with terbutaline: Effectiveness outcomes............................................. Quality assessment methods for drug class reviews for the Drug Effectiveness Review Project.................................................................................................................................................... Cochrane systematic reviews related to beta -agonists. Quick-relief medications for asthma Page 4 of 113 Final Report Update 1 Drug Effectiveness Review Project Suggested citation for this report: Norris S, McNally T, Thakurta S. Drug class review: Quick-relief medications for asthma. These organizations selected the topic and had input into the Key Questions for this review. The content and conclusions of the review are entirely determined by the Evidence-based Practice Center researchers. The authors of this report have no financial interest in any company that makes or distributes the products reviewed in this report. Quick-relief medications for asthma Page 5 of 113 Final Report Update 1 Drug Effectiveness Review Project INTRODUCTION Asthma Asthma is a chronic inflammatory disorder of the airways. In susceptible individuals this inflammation causes recurrent episodes of wheezing, breathlessness, cough, and other symptoms. These episodes are usually associated with widespread and variable airflow obstruction. This obstruction is often reversible, either spontaneously or with treatment. Airway inflammation also increases bronchial hyper-responsiveness to a variety of stimuli, resulting in increased susceptibility to bronchospasm. In addition to bronchospasm and inflammation, some patients also experience airway remodeling, which leads to more severe and persistent disease. Airway 1, 2 reversibility may be incomplete in some patients. Asthma is diagnosed when 1) the patient has episodic symptoms of airflow obstruction; 2) airflow obstruction is at least partially reversible; and 3) alternative diagnoses are excluded. Asthma most often begins in childhood and in these children is frequently associated with atopy. Asthma can, however, develop at any time in life and can be related to allergens or can be 2 nonallergic (or intrinsic). In 1996 new measures of asthma prevalence were adopted. These measures suggest that prevalence 3 of asthma remained relatively stable from 1997 to 2004. Asthma medications fall into 2 general classes: medications for long-term control and 1, 2 medications for quick relief of airflow obstruction and symptoms. Persons with persistent asthma require long-term controller and quick relief medications. Long-term controller medications include corticosteroids, cromolyn sodium and nedocromil, methylxanthines, 1, 2 leukotriene modifiers, and long-acting beta -agonists. Medications for quick relief of2 bronchoconstriction and acute symptoms include short-acting beta -agonists and2 anticholinergics. Exercise-induced asthma Exercise-induced asthma is characterized by coughing, wheezing, shortness of breath, and chest 4 tightness during or after exercise. Exercise-induced asthma is associated with airway obstruction after exercise, as indicated by a decrease in the volume of air forcefully expired in 1 second (forced expiratory volume in 1 second, FEV ). In exercise-induced bronchospasm exercise1 4 precipitates airway obstruction, but lung function is normal at rest. The term exercise-induced asthma sometimes refers to persons who have exacerbation of their chronic asthma during exercise. We use the term exercise-induced asthma to encompass both this condition and 1 exercise-induced bronchospasm. The mechanisms underlying exercise-induced asthma are not well understood. The hyperosmolarity hypothesis proposes that water loss from the airway causes hypertonicity of 4 airway cells, leading to release of inflammatory mediators and subsequent bronchoconstriction. Another hypothesis suggests that hyperventilation leads to cooling of airway cells, and after Quick-relief medications for asthma Page 6 of 113 Final Report Update 1 Drug Effectiveness Review Project exercise the rewarming process leads to dilatation of bronchiolar vessels accompanied by fluid exudation, mediator release, and bronchoconstriction. Exercise-induced asthma can affect elite and recreational athletes. Prevalence is reported 4 as 17% in athletes participating in winter Olympics, 35% among athletes competitive in cold 4 4 weather sports, and 9% among school children. Treatment focuses on avoidance of the particular activities that precipitate bronchospasm, adequate warm-up periods, and pharmacologic therapy. The last of these usually consists of an 4 inhaled short-acting beta -agonist 15 minutes prior to exercise. Additional, daily therapy may be2 required for management of underlying chronic asthma. Inhaled beta2-agonists Beta -agonists act mainly to relax airway smooth muscle by stimulating beta -receptors, which in2 2 2 turn increase cyclic AMP and produce functional antagonism to bronchoconstriction. Beta -2 5 agonists may also have anti-inflammatory properties, as suggested by in vitro experiments. The short-acting beta -agonists2 relax airway smooth muscle and increase airflow within 1 30 minutes and last 4 to 5 hours. They are the drug of choice for treating acute asthma symptoms and exacerbations and are used for preventing exercise-induced bronchospasm. The 1 short-acting beta -agonists are not recommended for regularly scheduled, daily use.

In a small 12-month trial (N=85) of olanzapine and immediate-release quetiapine 100 mg zenegra, no significant differences were found between the drugs based on 83 the SIP or the GAF scale after 12 months zenegra 100 mg. In a study of olanzapine compared with ziprasidone in patients with “schizophrenia or schizoaffective disorder and who had prominent depressive symptoms as defined by a score of 16 or higher (mild depression) on the Montgomery- Asberg Depression Rating Scale (MADRS) and a score of 4 or higher (pervasive feelings of sadness or gloominess) on item 2 (reported sadness) of the MADRS” 100mg zenegra, olanzapine was found to be superior on improvement in GAF zenegra 100mg. Olanzapine was found superior to risperidone after 6 months in a large , prospective 146 , 243 cohort study , with a difference in improvement of 2 . Another much 146 smaller study (N=42) did not find differences between the drugs at 6 months follow-up . Among patients with first-episode schizophrenia , 2 observational studies found no difference 174 between olanzapine and risperidone in GAF scores after 6 months (subgroup analysis) and 2 208 years. GAF was not a primary outcome measure in these studies. Atypical antipsychotic drugs Page 45 of 230 Final Report Update 3 Drug Effectiveness Review Project Violent behavior Three studies have evaluated the comparative effects of atypical antipsychotics on violent 178, 244, 245 behavior in patients who are primarily in the outpatient setting. While the highest quality of these was the CATIE study, this analysis did not make direct comparisons among the atypical antipsychotic drugs, and violent behavior was not a primary outcome. The method of determining violent behavior was also limited to the MacArthur Community Violence Interview tool, which is based on patient self-report and family interviews at the time the patient 245 discontinued their Phase 1 assigned drug. In the intent-to-treat analysis (N=1445) the atypical antipsychotics were not found different to perphenazine, with changes in score ranging from -14. In the analysis of those who continued for 6 months (N=653), the change in score was more pronounced and varied more (range -5. A subgroup of the Schizophrenia Care and Assessment Program that included 124 patients used 3 sources of data to identify violent episodes: MacArthur Community Violence Interview tool, inpatient and 244 outpatient medical records, and the North Carolina Criminal Justice database. Based on modeling techniques to estimate the effects of olanzapine and risperidone on violence, a switch to olanzapine within the last 6 months was found to be associated with the highest risk of violence, with a predicted probability of violence of 23% compared with 8% in those who remained on olanzapine for at least 12 months, 12% for those who switched to risperidone in the last 6 months, and 10% for those remaining on risperidone for at least 12 months. The comparison of these groups indicated a statistically significant difference between the 2 olanzapine groups, but not compared with either risperidone group. However, if a term for compliance with medication was added to the model, none of the comparisons were significant, suggesting that compliance was a key factor. The European SOHO study recorded physician 244 ratings of physical hostility/aggression at baseline and follow-up visits. At 6 months, the proportions with reports of hostility were significantly lower with olanzapine (9%) and risperidone (11%) compared with clozapine (17%), with odds ratios of improvement of hostility over time of 1. In this observational study baseline severity of symptoms of schizophrenia were slightly higher in the clozapine group (CGI 3. However, there were no significant differences among these drugs in the proportion with hostile behavior at baseline, and with inclusion of the factors younger age, male gender, early age of onset, and comorbid substance use disorders, logistic regression analysis were reported to not change the results. Persistence Persistence refers to the duration of time a patient continues to take a prescribed drug. In the setting of a study, this may also be referred to as early discontinuation or withdrawal from treatment during the trial period and can be assessed as a rate or the time to discontinuation. Because the reasons for discontinuing the assigned drug treatment encompass inadequate efficacy as well as intolerable side effects, discontinuation is considered a good measure of overall effectiveness. Discontinuation rates were higher among patients with schizophrenia than is typical in other diseases, with rates of 50% or more being common. As noted above, the Atypical antipsychotic drugs Page 46 of 230 Final Report Update 3 Drug Effectiveness Review Project CATIE study used this outcome as the primary measure of effectiveness along with time to discontinuation. Rate of discontinuation Data from discontinuation rates from 79 head-to-head trials were used in a mixed treatment comparisons analysis (also known as a network meta-analysis; Table 3). This analysis included data from all phases of the CATIE study. With 1493 patients enrolled in Phase 1, this study constituted the largest study among the 79 included in the analysis. The mixed treatment comparisons analysis used both direct and indirect comparisons based on the head-to-head trials and found that olanzapine was superior to aripiprazole, asenapine, iloperidone, immediate- release quetiapine, risperidone, and ziprasidone in rates of all-cause discontinuation of assigned drug across all the trials. Clozapine was found superior to iloperidone, immediate-release quetiapine, risperidone, and ziprasidone. Risperidone was also found superior to iloperidone, based on limited evidence. A difference between clozapine and olanzapine was not found. Statistically significant differences between paliperidone and other drugs were also not found, likely due to the very low numbers of studies with direct comparisons to other atypical antipsychotics. This analysis controlled for between-study heterogeneity, dose level within study (low, medium, or high), and study duration using the fixed-effects model. It did not control for within-study heterogeneity for those studies with more than 2 drug arms. Dose comparisons were an issue in this set of studies, with early studies using doses that were not considered clinically optimal now. For example, early studies of risperidone often used doses well above those used today and clozapine and olanzapine studies used doses below those used today. There were fewer comparative data available for the newer drugs, particularly asenapine, iloperidone, and paliperidone, and results for these drugs should be interpreted with caution. Sensitivity analyses stratifying studies by shorter and longer durations did not alter the results in meaningful ways. For example, the odds ratio for olanzapine compared with risperidone for studies 6 months or less (N=58) was 0. Atypical antipsychotic drugs Page 47 of 230 Final Report Update 3 Drug Effectiveness Review Project a Table 3. Mixed-treatment comparisons analysis of discontinuations from trials Asenapine Clozapine Iloperidone Olanzapine Quetiapine Paliperidone Risperidone Ziprasidone 1. Atypical antipsychotic drugs Page 48 of 230 Final Report Update 3 Drug Effectiveness Review Project For olanzapine, these results compared with the results of CATIE Phase 1 as shown in Table 4, below. In comparing olanzapine with ziprasidone, the mixed-treatment comparisons analysis found a larger magnitude of effect favoring olanzapine than CATIE found. In CATIE Phase 1, risperidone, immediate-release quetiapine, and ziprasidone were not statistically significantly different from each other. Olanzapine was also found to have lower rates of discontinuations due to lack of efficacy or patient decision, and significantly longer duration of successful treatment than immediate-release quetiapine. The numbers needed to treat with olanzapine for discontinuation due to lack of efficacy were 7. A statistically significant difference was not found between risperidone and quetiapine or between risperidone and ziprasidone for either lack of efficacy or due to the patient’s decision. Analyses of discontinuation rates of olanzapine compared with other atypical antipsychotic drugs Comparison CATIE Phase 1 Number Mixed-treatment Number atypical Hazard ratio needed comparisons needed antipsychotic (95% CI) to treat N Odds ratio (95% CI) to treat N Quetiapine 0. An analysis of 31 trials directly comparing olanzapine with risperidone is represented in Figure 4, below. The graph indicates that olanzapine had lower rates of early discontinuation of drug compared with risperidone. This group of studies represented the largest body of direct comparison evidence in this report. Atypical antipsychotic drugs Page 49 of 230 Final Report Update 3 Drug Effectiveness Review Project Figure 4. Relative risk of early discontinuation of olanzapine compared with risperidone (symbol size represents sample size) 100 Olanzapine % 75 50 25 0 0 25 50 75 100 Risperidone % Fourteen retrospective studies, utilizing databases of medical and/or prescription claims 156, 166, 169, 170, 175, 176, 180, 181, 185, 197, 203, 204, 210, 212 or electronic medical records and the European and 218, 247 Intercontinental SOHO studies (Table 5), reported comparative evidence on rate and/or 175 time to discontinuation of atypical antipsychotics. Overall, the findings of these studies were consistent with the trials in that clozapine was found to have lower discontinuation rates than other atypical antipsychotic drugs and olanzapine was found to have lower rates than the rest of the atypical antipsychotic drugs, with few exceptions. New evidence on risperidone long-acting injection indicated that oral atypical antipsychotics may have lower rates of discontinuation over longer periods of follow-up (18 months). Findings were also consistent that olanzapine resulted in a longer time to discontinuation compared with other antipsychotics, with the exception of clozapine. Clozapine was found to have a lower discontinuation rate than other atypical antipsychotics studied (olanzapine, immediate-release quetiapine, risperidone, risperidone long- 203, 212, 247 acting injection). Of 10 studies comparing olanzapine with risperidone, 6 found the rate 166, 169, 175, 176, 218, 247 of discontinuation lower with olanzapine, while the others did not find a 181, 197, 204, 212 statistically significant difference. Olanzapine was not found to have statistically significantly different rates of discontinuation compared with aripiprazole or ziprasidone in a 204 study of Maryland Medicaid data. Immediate-release quetiapine was found to have higher 204, 218, 247 rates of discontinuation than olanzapine in 3 of 4 studies, and no difference was found Atypical antipsychotic drugs Page 50 of 230 Final Report Update 3 Drug Effectiveness Review Project 210 compared with aripiprazole in a single study. Risperidone long-acting injection was studied in a large study of United States Veterans (N=11 821), where the injection was found to have higher rates of discontinuation over an 18-month follow-up period compared with aripiprazole, clozapine, olanzapine, immediate-release quetiapine, and risperidone (oral), but no difference 203 with ziprasidone. In a small study of electronic medical records of patients in a Scottish 210 county, aripiprazole and quetiapine discontinuation rates were similar. Atypical antipsychotic drugs Page 51 of 230 Final Report Update 3 Drug Effectiveness Review Project Table 5. Discontinuation of atypical antipsychotics in observational studies Prospective Time to discontinuation (days) Dossenbach 2005 Olanzapine 233; Risperidone 142; 1 year; N=6662 HR, 0. Atypical antipsychotic drugs Page 52 of 230 Final Report Update 3 Drug Effectiveness Review Project Time to discontinuation In CATIE Phase 1, time to discontinuation for any reason was significantly longer with olanzapine than risperidone (hazard ratio, 0. Although differences among risperidone, immediate-release quetiapine, and ziprasidone were found to be statistically significant, the clinical significance was limited, as the Kaplan-Meier analysis of time to discontinuation for the 3 drugs was 4. Olanzapine was also found to have a significantly longer duration of successful treatment (hazard ratio, 0. Successful treatment was defined as CGI-S score of at least 3 (mildly ill) or by a score of 4 (moderately ill) with an improvement of at least 2 points from baseline. The duration of successful treatment was significantly longer in the risperidone group than in the immediate-release quetiapine group (hazard ratio, 0. Time to discontinuation due to lack of efficacy was statistically significantly longer for olanzapine compared with immediate- release quetiapine (hazard ratio, 0. Differences between immediate-release quetiapine, risperidone, and ziprasidone were not statistically significant. In Phase 1B, time to discontinuation was statistically significantly longer with immediate-release quetiapine (median 9. Time to discontinuation was longer with clozapine (10. Statistically significant differences were not found between the other atypical antipsychotics, although the small sample size may have resulted in inadequate power to find differences where they may exist. Further analysis of the time to discontinuation due to lack of efficacy indicated that clozapine was superior to all 3 of the other drugs. Time to discontinuation in Phase 2T was statistically significantly longer with risperidone (7 months) and olanzapine (6. Further analysis of data from Phase 1 indicated that olanzapine and risperidone had significantly longer time to discontinuation due to lack of efficacy than immediate-release quetiapine did. Olanzapine was also statistically superior to ziprasidone for this outcome. Twelve retrospective observational studies also reported time to discontinuation with 156, 166, 169, 170, 175, 176, 180, 197, 210, 212, 248, 249 comparisons of atypical antipsychotics. The mean time to discontinuation with olanzapine compared with risperidone was significantly longer with olanzapine in 7 studies (mean of 251 days to discontinuation for olanzapine and 173 days for 166, 169, 170, 175, 176, 180, 197 risperidone), while differences were not found in 3 studies (mean of 235 156, 185, 249 days to discontinuation for olanzapine and 228 for risperidone). Pooling these results indicated a statistically significant difference of up to 66 days (95% CI, 59 to 73) longer with olanzapine. Removal of a single study with much longer duration of treatment than the others indicated a smaller, but statistically significant, difference of 46 days (95% CI, 43 to 49). Comparisons of aripiprazole, olanzapine, or risperidone with immediate-release 185, 210, 249 quetiapine had mixed results with no consistent finding of a superiority or inferiority. Comparisons of ziprasidone with olanzapine or risperidone did not find statistically significant 156, 249 differences in the time to discontinuation. Atypical antipsychotic drugs Page 53 of 230 Final Report Update 3 Drug Effectiveness Review Project Inpatient outcomes While many studies described patients as being hospitalized initially, many were unclear about 25, 28, 29, 34, 39, 40, 46, 48, 59, 61, 62, 65, 70, 75, 81, 84, the disposition of patients later in the course of the study. Even for those that described patients as inpatient for the entirety of the study, outcomes reported related to improvements in the intermediate measures of symptom scales. The impact of the atypical antipsychotics on the course of an inpatient stay was, therefore, unclear. Of these 19 head-to-head trials, 5 were poor quality due to problems with randomization/allocation concealment, differences at baseline between groups, lack of intention 40, 46, 48, 61, 81 to treat, and unclear reporting of discontinuations. The remaining 14 fair-quality 28, 59 29, 84, 250, 253 trials compared clozapine with olanzapine or risperidone, aripiprazole with 34, 70 65 125 39 risperidone, olanzapine, or aripiprazole, risperidone with immediate-release quetiapine, 75 252 olanzapine with ziprasidone, clozapine with olanzapine or risperidone, olanzapine with 25, 251 risperidone or immediate-release quetiapine, and aripiprazole, olanzapine, risperidone, and 62 ziprasidone in trials ranging from 3 to 26 weeks in duration. For the most part, these studies did not find differences among the groups based on intermediate efficacy measures; with the exception that ziprasidone was not found to be non-inferior to aripiprazole on the Brief Psychiatric Rating Scale (BPRS) in one study. We also found 9 fair-quality retrospective 135-140, 147, 254 studies reporting outcome relating to the inpatient stay. Aggressive behavior 59, 252 Two studies evaluated acts of aggression during hospitalization. Acts of aggression were 252 assessed using the Overt Aggression Scale (OAS) in 1 study and the Modified Overt 59 Aggression Scale (OAS-M) in the other. In the first study (N=157), similar rates of aggressive acts were seen among patients on clozapine, risperidone, and olanzapine when evaluating the entire 14-week period. Subsequent analysis indicated that when incidents occurring during the first 24 days were removed (to allow full dosing of clozapine to be reached), clozapine was superior to haloperidol. The second study used rating scale measures of aggressive acts over a 12-week period and found clozapine to be superior to olanzapine in total score (P<0. Secondary analyses of aggression against 59 property and verbal aggression did not find differences between the drugs. Length of stay 62, 253 135-140, Two fair-quality randomized controlled trials and 9 fair-quality retrospective studies 147, 254 of patient records and pharmacy or billing databases reported outcomes related to duration of inpatient stay, rate of switching to another drug, and timing of overall response rates after being prescribed either olanzapine or risperidone. Three of the retrospective studies were part of the Risperidone Olanzapine Drug Outcome Studies (RODOS) in Schizophrenia. One reported 147 combined results from 61 hospitals in 9 countries, 1 reported results from 11 centers in the 138 135 United Kingdom, and 1 reported data from 6 centers in Ireland. Two trials, 1 a retrospective study and the other a randomized controlled trial, were studies of patients admitted to state 140, 253 psychiatric hospitals.

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