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O. Oelk. North Carolina Wesleyan College.

In the PERISCOPE trial (N=543) 400 mg levitra plus for sale erectile dysfunction test, greater improvement in HbA1c was reported for subjects treated with pioglitazone (−0 generic levitra plus 400 mg without a prescription erectile dysfunction treatment abu dhabi. Change in HbA1c for pioglitazone compared with sulfonylureas in adults with type 2 diabetes HbA1c (%) HbA1c (%) change from P value change from baseline of baseline (mean, SD) between- Author, year (mean, SD) for for active group Quality Intervention pioglitazone control difference Glipizide: start 5 mg daily; mean 125 Agarwal 2005 maximal dosage 41 mg daily −0. Change in HbA1c for pioglitazone compared with metformin in adults with type 2 diabetes HbA1c (%) change from HbA1c change P value of baseline (mean, from baseline between- Author, year SD) for (mean, SD) for group Quality Intervention pioglitazone active control difference 140 Pio 15 mg daily Kato 2009 -1. Rosiglitazone compared with an active control Characteristics of studies We included 14 active-control trials comparing rosiglitazone with an active control (Tables 32 141-154 144, 148, 149, 152-154 and 33). Six of these are new to this section in this report. There were 4 147, 148 monotherapy trials comparing rosiglitazone to metformin or rosiglitazone to a 145, 147, 149 sulfonylurea. The combined therapy trials compared rosiglitazone to a sulfonylurea 141-144, 152, 154 with both groups receiving metformin or insulin or compared rosiglitazone to 151 146 metformin with both groups receiving sulfonylureas or various hypoglycemic agents. Kadoglou and colleagues compared the addition of rosiglitazone with increasing the dose of metformin for people with inadequately controlled diabetes while taking metformin 850mg daily. Across active-control studies, rosiglitazone dosing was either 4 or 8 mg daily. Follow-up 147 142, intervals ranged from 24 weeks to 4 years, with 7 trials having follow-up of 1 year or more. Characteristics of rosiglitazone active-control trials with sulfonylurea in adults with type 2 diabetes a Age (years) (SD) a % Female a % White a Author, Sample size (N) % Hispanic year Follow-up Other population Combination Quality (weeks) characteristics Intervention therapy 58. Data shown are mean (SD) unless otherwise indicated. Characteristics of rosiglitazone active-control trials with metformin or other in adults with type 2 diabetes a Age (years) (SD) a % Female a % White a Sample size (N) % Hispanic Author, year Follow-up Other population Combination Quality (weeks) characteristics Intervention therapy 146b 58. Data shown are mean (SD) unless otherwise indicated. Efficacy results HbA1c results for active-control trials of rosiglitazone are presented in Tables 34 and 35. One of 147 the 14 trials, A Diabetes Outcomes Progression Trial (ADOPT), reported a statistically significantly greater improvement in HbA1c for subjects treated with rosiglitazone than those 143 treated with active controls and one reported greater improvement for the active control than for rosiglitazone. The other 12 trials reported no statistically significant difference between groups. ADOPT was a large (N=4360), multicenter, double-blind, randomized controlled trial designed to evaluate monotherapy with rosiglitazone, metformin, or glyburide. The trial reported greater improvement in HbA1c at 4 years for subjects treated with rosiglitazone than for those treated with metformin (treatment difference −0. Garber and colleagues reported greater improvement in glycemic control for subjects treated with a combination of glibenclamide 5 mg/metformin 1000 mg (once or twice daily) than for those treated with rosiglitazone 4-8 mg daily combined with metformin 1500-2000 mg daily (between-group 143 difference in HbA1c 0. Among the monotherapy trials, ADOPT (N=4360) was designed to evaluate monotherapy with rosiglitazone, metformin, or glyburide among subjects recently diagnosed (within 3 years) with type 2 diabetes and who had failed lifestyle therapy but had not started on 147 oral hypoglycemic agents. The primary outcome was monotherapy failure defined as fasting plasma glucose level of >180 mg/dL. Median duration of treatment with rosiglitazone was 4 years. The cumulative incidence of monotherapy failure at 5 years was 15% with rosiglitazone, 21% with metformin, and 34% with glyburide (P<0. The results of 2 smaller rosiglitazone monotherapy trials were similar to the results from ADOPT when the appropriate follow-up intervals were compared. Hanefeld and colleagues 145 found no significant difference between glibenclamide and rosiglitazone at 52-week follow-up and Pop-Busui and colleagues found no significant difference between glyburide and 149 rosiglitazone at 26 weeks. Likewise, Kiyici and colleagues reported similar changes from 148 baseline in HbA1c for subjects treated with rosiglitazone and those treated with metformin. Among the combination therapy trials where rosiglitazone was added to ongoing metformin therapy compared with adding various sulfonylureas to ongoing metformin, 4 trials 141, 142, 144, 152 did not show significant differences between rosiglitazone and active comparators. Combination therapy studies comparing rosiglitazone to metformin with both groups 146, 151 receiving other oral agents did not show significant differences between treatment groups. Rosiglitazone was superior to repaglinide (each as monotherapy; no statistics provided). Subjects taking metformin at study entry were randomized to add-on sulfonylurea. Change in HbA1c in rosiglitazone active-control trials with sulfonylurea in adults with type 2 diabetes HbA1c (%) HbA1c (%) change change from from baseline baseline (mean, P value of Author, year (mean, SD) for SD) for active between-group Quality Intervention rosiglitazone control difference Rosi: start 4 mg daily 141 Bakris 2006 −0. Change in HbA1c in rosiglitazone active-control trials with metformin or other in adults with type 2 diabetes HbA1c (%) HbA1c (%) change change from from baseline baseline (mean, P value of (mean, SD) for Author, year SD) for active between-group rosiglitazone Quality Intervention control difference SU (background Rosi + metformin: metformin) vs. TZDs compared with newer diabetes drugs Characteristics of studies We found 4 trials comparing rosiglitazone with a newer diabetes drug of primary interest to this 36, 40, 67, 84 report (Table 36). One compared the addition of rosiglitazone with the addition of 36 sitagliptin to ongoing metformin; one compared the addition of rosiglitazone with the addition 84 of liraglutide to ongoing glimepiride; one compared the addition of colesevelan, rosiglitazone, 40 or sitagliptin to ongoing metformin; and one compared the addition of exenatide, rosiglitazone, 67 or exenatide and rosiglitazone to ongoing metformin. Characteristics of TZD interclass head-to-head trials in adults with type 2 diabetes a Age (years) (SD) a % Female a % White a Author, year Sample size (N) % Hispanic Country Follow-up Other population Combination Quality (weeks) characteristics Intervention therapy Rosiglitazone 8 mg daily 56 (10) DeFronzo, 67 137 51 Added to 2010 Exenatide 20 mcg daily 20 61 metformin Fair 23 Exenatide and Rosiglitazone 54. Data shown are mean (SD) unless otherwise indicated. Efficacy results HbA1c results for these are presented in Table 37. One 18 week trial (N=273) found no significant difference in reduction of HbA1c between those treated with the addition of 36 rosiglitazone and those treated with the addition of sitagliptin. The trial that randomized subjects to add-on either rosiglitazone, sitagliptin, or colesevelam to ongoing metformin found 40 no statistically significant difference between the rosiglitazone- and sitagliptin-treated subjects. One 26 week trial (N=1040) comparing the addition of rosiglitazone with the addition of liraglutide (to ongoing glimepiride treatment) reported greater reduction in HbA1c with 84 liraglutide (−1. One 20-week trial comparing exenatide to rosiglitazone with all participants on background metformin therapy, found no significant difference in improvement in HbA1c 67 between the exenatide and rosiglitazone arms (-0. Change in HbA1c in TZD interclass head-to-head trials in adults with type 2 diabetes HbA1c (%) HbA1c change change from from baseline Author, year baseline (mean, (mean, SD) for P value of Country SD) for active between-group Quality Intervention rosiglitazone comparator difference Rosiglitazone 8 mg daily DeFronzo, 67 Exenatide 20 mcg 2010 -1. We do not report those results in this table to avoid double-counting subjects. Detailed Assessment of TZDs Compared with Placebo Placebo-controlled trials of pioglitazone For this report, we did not update the comparisons of pioglitazone or rosiglitazone compared with placebo. This information was included in the 2008 Drug Effectiveness Review Project 18 drug class review on TZDs. We briefly summarize the findings of that report here. In the original report, 16 trials comparing pioglitazone to placebo in at least 1 study arm were identified.

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Beclomethasone (BDP) + Formoterol (FM) compared with Beclomethasone (BDP) Three fair RCTs (982 subjects) meeting our inclusion/exclusion criteria compared BDP+FM 188 order levitra plus in united states online erectile dysfunction caused by spinal cord injury, 189 purchase levitra plus 400 mg line testosterone associations with erectile dysfunction diabetes and the metabolic syndrome, 199 with a higher dose of BDP alone. All 3 enrolled adults ≥18 that were not controlled on 188 ICSs. Two compared BDP+FM in a single inhaler device and one tested the combination 189 188, 189 delivered by separate inhalers. Two studies reported statistically significantly better symptom and rescue medicine use outcomes for subjects treated with BDP+FM than those 199 treated with FM alone (Evidence Tables A and B). Two studies found a trend toward fewer exacerbations in those treated 189, 199 with BDP+FM. Controller medications for asthma 105 of 369 Final Update 1 Report Drug Effectiveness Review Project 6. Fluticasone (FP) + Salmeterol (SM) compared with Budesonide (BUD) 192 190, 191 One good 12-week RCT (N = 349) and one fair 24-week RCT (N = 353) meeting our inclusion/exclusion criteria compared FP+SM with a higher relative dose of BUD alone. The 12- week trial compared FP/SM (200/100) with BUD (800) and the 24-week trial compared FP/SM (500/100) with BUD (1600). Both were multinational trials that enrolled subjects ≥ 12 years of age. The 12-week trial found no statistically significant difference between treatment groups in symptoms, exacerbations, or rescue medicine use. The 24-week trial reported fewer symptoms, less rescue medicine use, and greater improvement in quality of life for those treated with FP+SM than those treated with BUD alone, but no significant difference in exacerbations. Budesonide (BUD) + Formoterol (FM) compared with Fluticasone (FP) One 12-week fair RCT meeting our inclusion/exclusion criteria compared BUD+FM in a single 193 inhaler with a higher relative dose of FP alone in 344 adults with moderate persistent asthma. The trial reported no statistically significant difference in symptoms or nocturnal awakenings. But, those treated with BUD+FM had fewer exacerbations and required less rescue medicine compared to those treated with FP alone. Fluticasone (FP) + Salmeterol (SM) compared with Triamcinolone (TAA) We found one fair RCT meeting our inclusion/exclusion criteria that compared FP+SM (in 53 separate inhalers) with a higher relative dose of TAA alone. This trial is also included above in this section for the FP+SM compared with FP comparison because there was an FP-only arm as well. It enrolled 680 adults and adolescents ≥ 12 years of age with persistent asthma not adequately controlled on ICS. They reported greater improvement in symptoms, nocturnal awakenings, and rescue medicine use for those treated with FP+SM than for those treated with TAA alone. Controller medications for asthma 106 of 369 Final Update 1 Report Drug Effectiveness Review Project Table 19. Characteristics of head-to-head studies comparing ICS+LABA (in one or separate inhalers) with higher dose ICS Study Design Country N Population Comparison Quality Study Duration Setting (total daily dose in mcg) Rating Fluticasone + salmeterol compared with fluticasone 53 Baraniuk et al. Characteristics of head-to-head studies comparing ICS+LABA (in one or separate inhalers) with higher dose ICS Study Design Country N Population Comparison Quality Study Duration Setting (total daily dose in mcg) Rating 24 weeks Multicenter (36) de Blic et al. RCT, DB, DD 12 European Countries FP (100) + SM (200) Fair 195 2009 Vs. RCT, DB, DD Germany FP/SM DPI (100/ 200) Fair 200 2009 Vs. Characteristics of head-to-head studies comparing ICS+LABA (in one or separate inhalers) with higher dose ICS Study Design Country N Population Comparison Quality Study Duration Setting (total daily dose in mcg) Rating double-counting. RCT USA FP DPI (500) Fair 197 2010 182 Age 6-17 years, mild-to-moderate asthma uncontrolled on low- FP/SM DPI (200/100) dose ICS 48 wks (3 cross-over FP (200) DPI + ML (5-10mg) periods of 16 wks each) Childhood Asthma Research and Education Network Centers 127 Peters et al. Characteristics of head-to-head studies comparing ICS+LABA (in one or separate inhalers) with higher dose ICS Study Design Country N Population Comparison Quality Study Duration Setting (total daily dose in mcg) Rating Budesonide + formoterol compared with budesonide Bisgaard et al. Controller medications for asthma 110 of 369 Final Update 1 Report Drug Effectiveness Review Project Table 19. RCT USA BUD (640) + FM (18) Fair 198 2008 BID (160/4. BUD (640) BID All delivery devices - pMDI 179 Pauwels, et al. Characteristics of head-to-head studies comparing ICS+LABA (in one or separate inhalers) with higher dose ICS Study Design Country N Population Comparison Quality Study Duration Setting (total daily dose in mcg) Rating 187 Woolcock et al. RCT Russia, France, Poland, Romania, Hungary, Belgium BDP/FM pMDI (400/24 Good 199 2009 Vs. Characteristics of head-to-head studies comparing ICS+LABA (in one or separate inhalers) with higher dose ICS Study Design Country N Population Comparison Quality Study Duration Setting (total daily dose in mcg) Rating Sweden) compared with 349 BUD DPI (800) Age ≥ 12, mild to moderate persistent asthma, uncontrolled on 12 weeks previous therapy (~80% ICS), excluded smokers or those with > 10 pack-year smoking history Multicenter Budesonide + formoterol compared with fluticasone 193 Bateman et al. Africa) compared with 344 FP DPI (500) Age ≥ 18; moderate persistent asthma, previous use of 12 weeks constant dose of ICS > 30 days, 5-7% smokers in each group Multicenter (37) Fluticasone + salmeterol compared with triamcinolone 53 Baraniuk et al. This study is also listed 680 Age ≥ 12, uncontrolled with low-dose ICS, severity NR, FP MDI (440) above under FP+SM smokers excluded vs. Symbol use: Drug X > Drug Y = statistically significant difference in outcomes favoring Drug X; Drug X > Drug Y trend = point estimate favors Drug X, but the difference is not statistically significant or tests of statistical significance were NR; No difference = no statistically significant difference or tests of statistical significance were not reported and outcomes are similar. Controller medications for asthma 114 of 369 Final Update 1 Report Drug Effectiveness Review Project 3. ICS+LABA compared with ICS (same dose) (addition of LABA to ICS compared with continuing same dose ICS) Summary of findings 166, 168, 203 135- We found 3 systematic reviews with meta-analyses and 32 RCTs (37 publications) 137, 139, 140, 142-144, 157, 173, 179, 180, 185, 198, 199, 204-225 that included head-to-head comparisons of an ICS+LABA and the same dose ICS meeting our inclusion/exclusion criteria (Table 20). These trials compared the addition of a LABA to an ICS with continuing the same dose of the ICS. Eighteen of the 32 (56%) administered the ICS and LABA in a single inhaler, 10 (31%) administered them in separate inhalers, and 4 studies (13%) administered them both as a single inhaler and in separate inhalers to different study groups. Overall, results from large trials up to one year in duration support greater efficacy with the addition of a LABA to an ICS over continuing the current dose of ICS alone for patients with poorly controlled persistent asthma (high strength of evidence, Appendix H, Table H-12). Our meta-analysis shows statistically significantly greater improvement in rescue medication-free days (SMD 0. Results were 203 generally consistent with a previously published meta-analysis which also reported fewer exacerbations in those treated with the addition of a LABA to ICS (RRR 23% with LABA) (N = 6808, RR = 0. Detailed Assessment Description of Studies 166, 168, 203 Of the included studies (Table 20), the 3 systematic reviews with meta-analyses compared the addition of any LABA to any ICS (ICS+LABA) with the addition of placebo and 203 continuing the same dose of the ICS. The largest review included 77 trials (16,623 adults and 4,625 children). Of the 32 RCTs that met our inclusion/exclusion criteria, 16 (50%) compared budesonide + formoterol with budesonide (one used eformoterol), 9 (28%) compared fluticasone + salmeterol with fluticasone, 3 (9%) compared an ICS (not specified) + salmeterol with an ICS, 2 (6%) compared an ICS (not specified) + formoterol with an ICS, 1 (3%) compared beclomethasone + salmeterol with beclomethasone, and 1 (3%) compared beclomethasone + formoterol with beclomethasone. We also found one study of ICS+LABA compared with the same dose of ICS, however the patient population included both steroid naïve and current ICS 150 users, therefore this study is not included in the analyses for this section. The most commonly used delivery devices were DPIs: 18 studies (56%) delivered all study medicines via DPIs, 7 studies (22%) delivered all via MDIs, and 7 studies (22%) used both MDIs and DPIs. Eighteen of the 32 (56%) administered the ICS and LABA in a single inhaler, 10 (31%) administered them in separate inhalers, and 4 studies (13%) administered them both as a single inhaler and in separate inhalers to different study groups. Controller medications for asthma 115 of 369 Final Update 1 Report Drug Effectiveness Review Project Study Populations The 32 head-to-head RCTs included a total of 14,737 subjects (Table 20). Nine studies (28%) included pediatric populations under 12 years 185, 212, 214, 215, 218-222 of age. The majority of trials were multinational (17 trials, 53%); 10 (31%) were conducted in the United States, 2 (6%) were conducted in the UK, and one in each of the following: Canada, Sweden, and the Netherlands. All subjects were poorly controlled on ICS therapy prior to randomization in all but three 135, 137, 213 trials.

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To improve oxygenation in patients with reduced or increased RBC mass discount levitra plus 400 mg amex erectile dysfunction without pills, RBC administration (simple transfusion) or RBC removal (RBC depletion) is performed 400 mg levitra plus fast delivery natural treatment erectile dysfunction exercise, respectively. However, for patients with abnormal Hb, RBCs containing abnormal Hb are removed and replaced by healthy volunteer donor RBCs by red cell exchange (RCE). RCE can be performed by manual exchange or by automated exchange using a blood cell separator (erythrocytapheresis). In this review, indications for RCE in sickle cell disease using the evidence-based American Society for Apheresis categories1 are presented and the rationale for RCE in each disorder are discussed. Simple transfusion versus RCE and manual RCE versus automated RCE are compared. Finally, this review briefly presents some of the challenges of performing erythrocytapheresis in small children and discusses various choices for central venous access during RCE. In this review, RCE refers to both manual and ● To describe indications for RCE automated RCE; however, when only automated RCE is used in a ● To define goals for RCE for stroke prophylaxis in sickle cell study, this will be referred to as erythrocytapheresis. Readers are disease referred to excellent reviews on RCE. Indications for RCE RCE is used exclusively in treating complications of sickle cell Introduction disease (SCD), but is rarely used in non-SCD disorders. In this The primary goal of therapeutic red cell exchange (RCE) is to review, RCE as acute or chronic transfusion therapy in only remove abnormal or excess RBCs from a patient. The 3 indications SCD-related complications is presented and the rationale for RCE in for RCE are: (1) polycythemia or erythrocytosis, (2) hemochromato- a specific complication entity will be discussed. The American sis, and (3) the presence of abnormal RBCs due to intrinsic RBC Society for Apheresis (ASFA) classifies indications for therapeutic disorders or acquired RBC disorders resulting from systemic causes 9 apheresis into 4 categories on the basis of evidence. For the first 2 indications, categories are defined in Table 1. Table 2 summarizes the indica- RCE is performed to deplete RBCs or the iron store with non-RBC tions for RCE in SCD. Indications for RCE in non-SCD disorders replacemenst. The hallmark of erythrocytosis and polycythemia is are listed in Table 3 using the ASFA indication categories without increased hematocrit (Hct) with hyperviscosity of whole blood with further review. The first prospective randomized trial in hereditary hemochromatosis to achieve the causing RBCs to become rigid, adherent, and deformed, leading to target serum ferritin level 50 g/L showed that erythrocytaphere- microvasculature occlusion, which results in tissue hypoxia and sis is highly effective in reducing iron overload and lowering the infarction. In addition to impairment of RBC rheology due to rigid total number of procedures by at least 50% compared with RBCs, many other factors are responsible for the pathophysiology phlebotomy, and it also shortens treatment duration. At the present time, the standard common adverse events or progression of preexisting organ dysfunction. To practice for treating SCD-related complications is transfusions of date, the advantages of RCE, especially compared with simple donor RBCs to increase the oxygen-carrying capacity of the blood transfusion, and the relative benefit of manual versus automated by reducing HbS concentration and increasing the Hb level. Indications for therapeutic apheresis: ASFA 2010 categories9 Category Description I Disorders for which apheresis is accepted as first-line therapy, either as a primary standalone treatment or in conjunction with other modes of treatment. II Disorders for which apheresis is accepted as second-line therapy, either as a standalone treatment or in conjunction with other modes of treatment. III Optimum role of apheresis therapy is not established. IV Disorders in which published evidence demonstrates or suggests apheresis to be ineffective or harmful. Institutional review board approval is desirable if apheresis treatment is undertaken in these circumstances. For acute complications of SCD, the goal of transfusion therapy is to (3) erythrocytapheresis can be performed safely under isovolemia. Rapid ment of acute stroke because treatment goals for postexchange Hct lowering of HbS levels can only be achieved by acute RCE. Category I indication Acute stroke (cerebrovascular accident) Category II indications Cerebrovascular accident is one of the most devastating complica- Acute chest syndrome tions of SCD. Stroke occurs in both children and adults and, without Acute chest syndrome (ACS) is defined by the National Acute Chest preventive therapy, 11% of patients experience stroke by 20 years Study Group as a new infiltrate on chest X-rays accompanied by at of age. ACS is the most common cause of death in adults with to maintain HbS 30%. Acute simple transfusion raises the Hb SCD and the second most common cause of hospitalization. The level, which improves oxygen delivery to the brain, but will not management of ACS includes antibiotics, respiratory therapy, and sufficiently reduce the HbS level without raising the Hb level much RBC transfusion. A retrospective cohort study of 137 children with SCD and first In a retrospective study of 32 episode of ACS in 32 children, all strokes showed that children receiving simple transfusion at the 23 children who received transfusion within 24 hours after time of stroke presentation had a 5-fold greater relative risk of hospital admission had improved outcomes, whereas 5 of the 9 having a second stroke than those receiving RCE. There have been no prospective random- SCD, 65% of episodes were treated with transfusion (simple ized trials comparing different methods of transfusion as an initial transfusion, RCE, and simple transfusion followed by whole treatment for stroke. The transfusions significantly improved oxygen- ation, but there was no significant difference in clinical manifes- Compared with simple transfusion, acute erythrocytapheresis has tations and duration of hospital stay between the transfused and several distinctive advantages in patients with SCD and overt nontransfused groups. Indications for RBC exchange in non-SCD to a predetermined level without raising the Hb level 10 g/dL, and ASFA indication 1 category Table 2. Indications for RBC exchange in SCD Acute Nonacute or ASFA indication category Disease RCE chronic RCE Acute Nonacute or Babesiosis, severe I SCD-related complications RCE chronic RCE Babesiosis, high-risk population II Acute stoke I Malaria, severe II Acute chest syndrome, severe II Hematopoietic stem cell transplantation– III Multiorgan failure III apheresis with minor ABO incompatibility Severe intrahepatic cholestasis III Polycythemia vera I I Priapism III Erythrocytosis, secondary III III Stoke prophylaxis with prevention II Hemochromatosis, hereditary I of iron overload Drug/chemical overdose, tacrolimus III Vaso-occlusive pain III Cyclosporine A III* Presurgery III High-oxygen affinity hemoglobin, preoperatively III* Pulmonary hypertension III* Carbon monoxide poisoning III* End-stage renal disease III* Methhemoglobinemia, severe III* *NoASFAindicationcategoryassigned. Hematology 2014 451 In a multicenter prospective study of 671 episodes of ACS in 538 included simple transfusion, RCE, or a combination of both. SCD patients in the United States, 72% of the patients were Currently, the standard care for prevention of primary and second- transfused for a worsening clinical course, with both simple ary stroke is to maintain the target HbS at 30% by indefinite transfusion and RCE associated with improved oxygenation, which long-term transfusion regardless of the method of transfusion. In suggested that limited transfusions alleviate organ dysfunction. At this center, Long-term transfusion therapy is associated with potentially serious transfusion was administered only in the most severe cases, which complications, among them transfusional iron overload. Both oral were defined as patients with early acute respiratory failure or those and parenteral iron chelation are effective in treating iron overload, with mild respiratory distress that worsened after 3 days. It is not but treatment failure is common due to poor compliance, drug clear whether deaths in the transfused group were attributed to more toxicity, and/or intolerability. The investigators concluded that restricting transfusions to the most In an effort to prevent transfusional iron overload, chronic transfu- severe ACS cases does not seem to increase the mortality rate, so sion therapy has been modified by raising the target HbS level to transfusions should be restricted to the more severely affected cases. In the mid-1980s, when the blood cell The effects of chronic transfusion therapy on the prevention of new separator for erythrocytapheresis became available, manual RCE and recurrent episodes of ACS in 27 children with SCD were was switched to automated RCE (erythrocytapheresis). Comparing target HbS 50% prevented or markedly reduced transfusional iron simple transfusion with RCE in 40 adults with ACS using a overload in 14 patients with SCD. To reduce blood require- erythrocytapheresis for worsening respiratory function demon- ments, Kim et al modified the standard erythrocytapheresis proce- strated that clinical respiratory scores were improved within 24 dure by incorporating RBC depletion with isovolemic hemodilution hours after exchange. Furthermore, prompt RCE over iron overload, particularly erythrocytapheresis over manual RCE, simple transfusion should be considered in selective patients with which is an acceptable therapy on an adjunctive basis for prevention ACS including those with: (1) rapidly worsening respiratory of both recurrent stroke and transfusional iron overload (Table 2). Pain is the most common manifestation of vaso-occlusive events in patients with SCD, requiring frequent emergency department visits and To date, there have been no prospective randomized controlled trials hospitalizations.

The trial used a triple cross-over Controller medications for asthma 139 of 369 Final Update 1 Report Drug Effectiveness Review Project design cheap 400mg levitra plus amex are erectile dysfunction drugs tax deductible. Subjects with uncontrolled asthma while receiving FP (100 twice daily) were randomized to FP (250 twice daily) purchase levitra plus 400 mg overnight delivery erectile dysfunction zinc deficiency, FP (100 twice daily) plus salmeterol, or FP (100 twice daily) plus montelukast for 16 weeks of each treatment (total of 48 week treatment phase). The primary outcome was a composite of exacerbations, number of asthma control days, and FEV1. The response to LABA step-up therapy was most likely to be the best response compared with LTRA step-up (relative probability, 1. One hospitalization for asthma- related symptoms occurred in each of the three treatment groups. A total of 120 prednisone bursts were prescribed for exacerbations (30 during treatment with FP+SM compared with 43 during treatment with FP+ML, P = NR). We do not describe all of the other included RCTs in detail because they generally found results consistent with the overall conclusions of the meta-analysis. For all of our outcomes of interest, most trials reported favorable results for subjects treated with ICS+LABA; the others reported no statistically significant differences (Evidence Tables A and B). Controller medications for asthma 140 of 369 Final Update 1 Report Drug Effectiveness Review Project Table 23. Characteristics of head-to-head studies comparing ICS+LABA with ICS+leukotriene modifiers Study design N Comparison Quality Study Duration Study population (total daily dose) rating LTRA plus ICS compared with LABA plus ICS Ducharme et al. Systematic Review 1 trial in children; 10 in adults LABA (salmeterol 100 mcg or formoterol 24 mcg) plus Good 235 2006 with meta-analysis ICS vs. Multinational (37 countries - eastern Europe) ML (10mg) plus FP (200 mcg) Good RCT vs. Age 15 – 72, mild to severe persistent asthma IMPACT 1490 SM (100 mcg) plus FP (200 mcg) currently uncontrolled on low dose ICS, smoking 48 weeks status NR Same Low dose ICS Multicenter (148) 237 Fish et al. Age 15 and older, moderate to severe persistent 948 ML plus baseline ICS (10mg) asthma despite low to high dose ICS, smoking 12 weeks status NR Same Low to High dose ICS Multicenter (71) 238 Ilowite et al. Age 14 – 73, mild to severe persistent asthma 1473 ML (10 mg) plus FP (220 mcg) uncontrolled on ICS, smoking status NR 48 weeks Unspecified whether ICS dose changed from baseline Multicenter (132) to study low dose ICS Lemanske et al. Age 6-17 182 FP/SM (200 mcg/100 mcg) BADGER Multicenter vs. Characteristics of head-to-head studies comparing ICS+LABA with ICS+leukotriene modifiers Study design N Comparison Quality Study Duration Study population (total daily dose) rating 239 Nelson et al. Age 15 and older, moderate to severe persistent 447 FP (200 mcg) plus ML (10 mg) asthma uncontrolled don low dose ICS, smoking 12 weeks status NR Same Low dose ICS Multicenter 240 Pavord et al. Age 18 – 50, mild to moderate persistent 66 FP (200 mcg) plus ML (10 mg) asthma uncontrolled on medium dose ICS, 12 weeks excluded smokers Decrease to Low dose ICS Multicenter 241 Ringdal et al. Age 15 and older, mild to severe persistent 805 FP (200 mcg) plus ML (10 mg) asthma on low to high dose ICS at baseline, 12 weeks excluded patients with a 10 pack-year history of Decreased to Low dose ICS and had to remain smoking uncontrolled. Multicenter (114) Montelukast plus budesonide compared with formoterol plus budesonide 242 Ceylan et al. Age 15 – 60, moderate persistent asthma 48 BUD (400 mcg) plus ML (10 mg) uncontrolled on unspecified ICS dose, excluded 8 weeks smokers Unspecified change from baseline to Low dose ICS University based clinics Abbreviations: BUD = Budesonide; CI = confidence interval; DPI= Dry Powder Inhaler; FM = Formoterol; FP = Fluticasone Propionate; ICS = Inhaled Corticosteroids; LABAs = Long- Acting Beta-2 Agonists; LTRAs = Leukotriene receptor antagonists; MA=meta-analysis; ML = Montelukast; NR = not reported; NS = not statistically significant; OR= odds ratio; QOL = quality of life; RCT= randomized controlled trial; SM = Salmeterol;; SR=systematic review. Symbol use: Drug X > Drug Y = statistically significant difference in outcomes favoring Drug X; Drug X > Drug Y trend = point estimate favors Drug X, but the difference is not statistically significant or tests of statistical significance were NR; No difference = no statistically significant difference or tests of statistical significance were not reported and outcomes are similar. Controller medications for asthma 142 of 369 Final Update 1 Report Drug Effectiveness Review Project 7. LTRA+LABA compared with ICS+LABA Summary of findings We found one fair quality RCT comparing LTRA plus LABA with ICS plus LABA (Appendix 243 H, Table H-16 and Table 24). The fair-rated, placebo-controlled, multi-center RCT (N = 192) compared ML (10mg/day) plus SM (100 mcg/day) plus placebo ICS (N = 98) compared with low dose BDP (160 mcg/day) plus SM (100 mcg/day) plus placebo LTRA (N = 92) for 14 243 weeks, washout for 4 weeks, then crossover for another 14 weeks. Subjects age 12 to 65 with moderate asthma were enrolled from multiple sites in the United States. There was a 4-week run- in period that involved a single-blind treatment with both BDP (160 mcg/day) and ML (10 mg/day). The primary objective of the study was to assess time until treatment failure. The trial was terminated early because the Data and Safety Monitoring Board determined that the primary research question had been answered. Those treated with LTRA+LABA had significantly shorter time to treatment failure than those treated with ICS+LABA (P = 0. Controller medications for asthma 143 of 369 Final Update 1 Report Drug Effectiveness Review Project Table 24. Characteristics of head-to-head studies comparing ICS+LABA with LTRA+LABA Study design Country N Study population Comparison Study Duration Setting (total daily dose) Quality rating Montelukast plus salmeterol compared with beclomethasone plus salmeterol Deykin et al. United States ML (10mg) + SM (100 mcg) plus placebo ICS vs. Fair 243 RCT 2007 BDP (160 mcg) + SM (100 mcg) plus placebo LTRA 192 Age 12 to 65 Low dose ICS 14 weeks, washout for 4 weeks, then Multicenter crossover for 14 weeks Abbreviations: BDP = Beclomethasone dipropionate; ICS = Inhaled Corticosteroids; LABAs = Long-Acting Beta-2 Agonists; LTRAs = Leukotriene receptor antagonists; ML = Montelukast; RCT= randomized controlled trial; SM = Salmeterol. Symbol use: Drug X > Drug Y = statistically significant difference in outcomes favoring Drug X; Drug X > Drug Y trend = point estimate favors Drug X, but the difference is not statistically significant or tests of statistical significance were NR; No difference = no statistically significant difference or tests of statistical significance were not reported and outcomes are similar. Controller medications for asthma 144 of 369 Final Update 1 Report Drug Effectiveness Review Project Key Question 2. Adverse Events What is the comparative tolerability and frequency of adverse events for controller medications used to treat outpatients with persistent asthma? Inhaled Corticosteroids Summary of Findings 22, 23, 244-248 27-33, 35-50, 52-55, 58-70, 249-258 We found seven systematic reviews, 50 RCTs and 12 259-269 observational studies reporting the tolerability or frequency of adverse events for inhaled corticosteroids meeting our inclusion/exclusion criteria (Table 7 and Evidence Tables A and B). Few RCTs were designed to assess adverse events as primary outcomes; most published studies designed to assess adverse events were observational studies. The overall incidence of adverse events and withdrawals due to adverse events are similar for equipotent doses of ICSs; results from head-to-head RCTs suggest no significant differences between ICSs (moderate strength of evidence). Overall summaries for specific adverse events are described below in the specific adverse events section. Most of the data for specific adverse events comes from placebo-controlled trials or observational studies, rather than from head-to-head comparisons. Detailed Assessment Description of Studies Most studies that examined the efficacy of one ICS relative to another (described in Key Question 1) also reported tolerability and adverse events. Six head-to-head RCTs that did not 249-252, 257, 258 report efficacy met our inclusion/exclusion criteria for tolerability or adverse events. Placebo-controlled RCTs and observational studies are described below in their respective specific adverse event sections. Methods of adverse events assessment differed greatly. Few studies used objective scales such as the adverse reaction terminology from the World Health Organization (WHO). Most studies combined patient-reported adverse events with a regular clinical examination by an investigator.

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