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Each study had its limitations such as small sample size (lack of power) buy kamagra oral jelly 100mg without prescription, unknown statin doses safe kamagra oral jelly 100mg, unclear duration of statin or clopidogrel combination therapy cheap 100mg kamagra oral jelly, potential selection bias in database studies kamagra oral jelly 100 mg on-line, and unknown adherence to therapy; thus, the results should be interpreted carefully. We found 1 small retrospective review (N=13) that assessed the potential drug interaction with the combination of simvastatin to an efavirenz-based regimen in HIV-infected and non-infected patients. Efavirenz is a non-nucleoside reverse transcriptase inhibitor that has CYP 3A4 inductive effects and the combination with simvastatin, a 3A4 substrate, could potentially lead to less of a statin treatment effect. This study found small non- significant absolute differences in low-density lipoprotein and total cholesterol lowering effects between those using simvastatin-efavirenz and those using only statin therapy. There were no reports of myopathies or elevated liver transaminase and creatine kinase levels in the chart reviews. Potent inhibitors of CYP 3A4 are listed below: • Clarithromycin • Erythromycin • Cyclosporine • Protease inhibitors (indinivir, nelfinavir, ritonavir, saquinavir, amprenavir, lopinavir/ritonavir) • Delavirdine • Itraconazole • Fluconazole • Ketoconazole • Nefazodone • Grapefruit juice Published reports of rhabdomyolysis exist in patients receiving concomitant statin with Clarithromycin, Erythromycin, Cyclosporine, Itraconazole, and Nefazodone. Statins Page 65 of 128 Final Report Update 5 Drug Effectiveness Review Project Drugs known to inhibit metabolism via CYP 2C9 are listed below: • Amiodarone • Azole Antifungals • Cimetidine • Fluoxetine • Fluvoxamine • Metronidazole • Omeprazole • TMP/SMX • Zafirlukast Harms in organ transplant recipients. The main concern of statin therapy in organ transplant patients is the potential for increased musculoskeletal and hepato-toxicities from statin-drug interaction, especially for drugs that are substrates (simvastatin, lovastatin, atorvastatin) and inhibitors (cyclosporine) of the CYP 3A4 pathway. The risk for adverse events with statins in combination with cyclosporine appears to be dose-related. Long-term, single-drug treatment of hyperlipidemia with simvastatin at doses not exceeding 10 mg daily, respectively, has been shown to be well tolerated with minimal harms in 250, 251 cardiac and renal transplant patients receiving cyclosporine. Fluvastatin 20-80 mg daily and pravastatin at 20-40 mg daily have also been shown to be relatively safe in cyclosporine- 127, 252-255 managed cardiac and renal transplant recipients. A post hoc analysis of the ALERT trial, one of the largest renal transplant trials evaluating fluvastatin, found little statistical difference between fluvastatin and placebo-treated groups with or without diabetes with regards to changes in serum creatinine, creatinine clearance, proteinuria, serious renal adverse events 256 leading to study withdrawal, or incidence of graft loss. There was also little difference in the incidence of transplant rejection within the first post-transplantation year between pravastatin 257 and placebo-treated identified patients in a different retrospective study. Rosuvastatin 10 mg (average dose) was studied in a cohort study of 21 cardiac transplant recipients receiving 258 standard immunosuppressive therapy. The patients’ lipid levels were above target values on the highest tolerated doses of other statins. After 6 weeks, there were no statistically significant changes in creatine kinase levels or aspartate aminotransferase. There was no clinical evidence of myositis in any patient. One patient had myalgia and 2 patients were withdrawn because of mild elevation of creatine kinase (324 U/liter at 3 weeks and 458 U/liter at 6 weeks). In a premarketing study, cyclosporine had a clinically significant effect on the drug concentrations of rosuvastatin in heart transplant patients. The product label recommends limiting the dose of rosuvastatin to 5 mg in patients taking cyclosporine. Only 1 case of rhabdomyolysis was identified from a heart transplant registry which 259 included 210 patients managed with a variety of statins for 1 year. The patient with rhabdomyolysis was receiving simvastatin 20 mg daily. No rhabdomyolysis was seen in 39 patients receiving simvastatin 10 mg daily. A review of studies involving fluvastatin (up to 80 mg daily) in organ transplant patients receiving cyclosporine identified no cases of 260 261 rhabdomyolysis. One small study involving atorvastatin (10 mg/day) in 10 renal-transplant recipients taking cyclosporine observed a significant benefit with regard to lipid levels and no cases of myopathy or rhabdomyolysis. A small prospective, single-center cohort study found that 80% of heart transplant patients who were converted from cyclosporine and high-dose fluvastatin regimen to tacrolimus Statins Page 66 of 128 Final Report Update 5 Drug Effectiveness Review Project and atorvastatin 20-40 mg therapy tolerated the switch through 13 months. There were no reports 262 of myalgias, significant elevations in creatine kinase, myopathies, or liver toxicities. Harms in HIV-infected patients: Statins and protease-inhibitors. A significant proportion of HIV-infected patients receiving protease inhibitors developed hyperlipidemia as an adverse effect. As a result, these patients required lipid-lowering treatment. Because of the severity of the lipid elevation, statins are often prescribed to these patients but little is known about the harms observed in this population. To date, good-quality long-term clinical data evaluating the combination of the protease inhibitors with statins are limited. Pharmacokinetic studies have shown that when simvastatin or atorvastatin (CYP 3A4 substrates) are used in combination with potent CYP 3A4 inhibitors (such as ritonavir and/or saquinavir), increased drug concentrations of statins may lead to greater 263 potential risk for myopathies and rhabdomyolysis. Of these, 7 25 studied primarily pravastatin while 1 reported “combined statin” results. Of the 7 pravastatin studies, 3 randomized trials compared pravastatin 40 mg daily with placebo in HIV-infected patients receiving a protease-inhibitor (45% to 90% were prescribed 266, 269, 270 ritonavir). Over 8-12 week period, there were no reports of myopathy or rhabdomyolysis and no significant changes in aspartate aminotransferase, alanine aminotransferase, or creatine phosphokinase levels between treatment groups or across trials. Four cases of mild to moderate myalgias were found with pravastatin than with 1 case in the 266, 270 270 placebo group. Only 1 pravastatin-treated patient withdrew from a trial because of seizure and hospitalization, which 266 was not related to study treatment. There were no reports of myalgias or myositis during 48-72 weeks of follow-up and no significant elevations in creatine kinase or liver transaminases. All patients were using a protease inhibitor with about 27% to 88% using ritonavir. Totally daily doses of statins and fibrates studied were: pravastatin 10-20 mg, atorvastatin 10 mg, rosuvastatin 10 mg, fluvastatin 20-40 mg, fenofibrate 200 mg, gemfibrozil 1200 mg, and bezafibrate LA 400 mg. Two groups of experts have made recommendations regarding the use of statins in HIV- infected individuals receiving protease inhibitors, including the Adult AIDS Clinical Trials Research Group (AACTG) Cardiovascular Disease Focus Group and the Centers for Disease Control and Prevention/Department of Health and Human Services/Henry J Kaiser Foundation. Both groups have recommended avoidance of simvastatin and lovastatin in patients receiving protease inhibitors largely based on pharmacokinetic studies and suggest using low-to mid-level doses of atorvastatin, fluvastatin, or pravastatin as alternatives (http://wwwhivatis. Statins in HIV-infected patients with comorbidities. One small (N=80) retrospective chart review compared harms in HIV-positive and hepatitis C virus co-infection patients using statins compared with HIV-positive and hepatitis C virus/hepatitis B virus-negative patients using 25 statins. The purpose of the study was to evaluate whether statins increased hepatotoxicity Statins Page 67 of 128 Final Report Update 5 Drug Effectiveness Review Project between the 2 groups. Most patients were middle-aged men and about 45% were taking antiretroviral therapy with a protease inhibitor. Sixty-four percent of included patients were using atorvastatin, 29% pravastatin, 5% rosuvastatin, and 2. Overall, there were no major differences in the number of patients with liver enzymes ≥1. No patients discontinued statin therapy because of liver toxicities or modified their antiretroviral therapies due to drug interactions. The results from this study should be considered with caution due to poor internal quality. Harms of statin-fibrates combination (rhabdomyolysis and myopathy). Myopathy and rhabdomyolysis have also been reported in patients receiving monotherapy with fibrates, especially in patients with impaired renal function. Although the mechanism of the interaction is not completely known, it appears the combination of statins with fibrates, and to a lesser extent niacin, can result in a higher risk for myopathy or rhabdomyolysis. These adverse effects may 206, 224, 271 also be dose-related. The mechanism for the interaction is unclear but it is hypothesized that gemfibrozil inhibits glucuronidation of statins. Ten studies used bezafibrate, 2 used fenofibrate, 1 used clofibrate, 1 used ciprofibrate, 1 used both bezafibrate and ciprofibrate, 1 used bezafibrate or fenofibrate, and 1 used gemfibrozil or ciprofibrate. No reports of rhabdomyolysis were observed in the 1674 patients receiving statin-fibrate combination.
In-vivo dominant immune responses in aplastic anaemia: molecular 16 cheap kamagra oral jelly 100mg mastercard. Monocytes-macrophages that tracking of putatively pathogenetic T-cell clones by TCR beta-CDR3 express alpha-smooth muscle actin preserve primitive hematopoietic sequencing cheap kamagra oral jelly 100mg. Differential gene expression proﬁle associated Hematology 2014 75 with the abnormality of bone marrow mesenchymal stem cells in 59 order kamagra oral jelly 100mg fast delivery. Vascular endothelial cell growth factor is an autocrine aplastic anemia purchase kamagra oral jelly 100 mg free shipping. PTH expands short-term murine leukemia progenitor formation in myelodysplastic syndromes. Li JY, Adams J, Calvi LM, Lane TF, Weitzmann MN, Paciﬁci R. In vivo imaging of Treg cells bone marrow of myelodysplastic syndromes transforming to overt providing immune privilege to the haematopoietic stem-cell niche. Bone progenitor dysfunc- inducible gelatinase B/matrix metalloproteinase-9 in monocytes from tion induces myelodysplasia and secondary leukaemia. Kerbauy DM, Lesnikov V, Torok-Storb B, Bryant E, Deeg HJ. Mesenchymal stem cells from Shwachman-Diamond syndrome patients display normal functions and transplantation of hematopoietic and stromal cells. Establishment of a the reconstitution of exogenous hematopoietic stem cells in Fancg-/- xenograft model of human myelodysplastic syndromes. Kitagawa M, Yamaguchi S, Takahashi M, Tanizawa T, Hirokawa K, 65. Localization of Fas and Fas ligand in bone marrow cells expressed by marrow stroma inhibits differentiation of 32D cells demonstrating myelodysplasia. Tennant GB, Walsh V, Truran LN, Edwards P, Mills KI, Burnett AK. Effect of Abnormalities of adherent layers grown from bone marrow of patients intravenous coadministration of human stroma cell lines on engraftment with myelodysplasia. Insufﬁcient stromal support in MDS tors in bone marrow sinusoids can organize a hematopoietic microenvi- results from molecular and functional deﬁcits of mesenchymal stromal ronment. Murine xenogeneic models of myelodysplastic syn- 51. Preferential suppression of drome: an essential role for stroma cells. Perivascular support of human gous lymphocytes in patients with trisomy 8 myelodysplastic syndrome. Factors affecting mesenchymal stem cells in multiple human organs. Myelodysplastic cells in patients and reduced expression of activating NK receptors. Marcondes AM, Mhyre AJ, Stirewalt DL, Kim SH, Dinarello CA, Deeg 74. Dysregulation of IL-32 in myelodysplastic syndrome and chronic hematopoietic stem cell survival and accelerates hematopoietic recovery myelomonocytic leukemia modulates apoptosis and impairs NK func- after radiation injury. Therapeutic targeting of a stem esis of myelodysplastic syndrome. Evidence for a role of leukemias by the bone marrow microenvironment. Expression of TNF disease: early destruction of hematopoietic niche after MHC-mis- receptors and related signaling molecules in the bone marrow from matched hematopoietic stem cell transplantation. Flores-Figueroa E, Gutierrez-Espindola G, Montesinos JJ, Arana-Trejo syndrome-like disease in mice. In vitro characterization of hematopoietic microenviron- 79. NUP98-HOXD13 transgenic ment cells from patients with myelodysplastic syndrome. With the recent approval of disease-modifying agents, the appropriate timing of allogeneic HSCT needs to be addressed. Similarly, the optimal use of these disease-modifying agents before HSCT needs to be determined. In severe aplastic anemia, HSCT is a proven cure, but HLA-matched sibling donors are found in fewer than 25% of newly diagnosed patients. The use of early unrelated donor HSCT is an evolving concept that will become more accepted as improvements in HSCT outcomes continue. MDS and SAA in the context of alternative available therapies Interestingly, there did not appear to be a decrement in early survival in the transplantation arm, possibly dispelling the myth that early, up-front nonrelapse mortality is the price to be paid for the Introduction chance at cure with allogeneic HSCT. The broader generalizability Allogeneic hematopoietic stem cell transplantation (HSCT) is the of this retrospective review was limited by a 100% transplantation only known curative procedure for myelodysplastic syndrome rate in the donor group, which is not likely to be possible even with (MDS), which is currently the third most common indication for early recognition of potential transplantation candidates. HSCT, as reported to the Center for International Blood and Marrow Transplantation Research. Robin et al presented the results of a French study in abstract result, HSCT volumes for MDS continue to increase. In recent 4 format at the ASH Annual Meeting in 2013. In that study, subjects years, with the emergence of novel therapies to treat MDS, the role with high and intermediate-2 risk MDS [International Prognostic of HSCT has been called into question because these novel agents Scoring System (IPSS)], as well as subjects with intermediate-1 risk can improve hematologic parameters, reduce transfusion require- 2 MDS with poor cytogenetics or thrombocytopenia were enrolled ments, and even prolong survival. Subjects with transformed MDS or proliferative designed to determine the optimal timing of allogeneic HSCT for chronic myelomonocytic leukemia were also offered participation. These analyses and a During their donor search, non-HSCT therapy was offered at the discussion on the timing of HSCT for severe aplastic anemia (SAA) treating physician’s discretion. The primary comparison was between those subjects Transplantation for MDS: comparison with non-HSCT who were eligible for HSCT (with 10% BM blasts) and was therapy divided by the presence of a donor (n 129) or no donor (n 34). Retrospective reviews have often suggested that HSCT is Of those with a donor, 70. There was an superior to non-HSCT approaches for patients with advanced overall survival advantage for those subjects with a fully matched MDS who are eligible (based on age, comorbidity, and donor donor over those without a donor (P. However, the inherent bias of these analyses apparent after 2. There also appeared to be a makes them unreliable, and important secondary outcomes, such nonstatistical advantage in the no-donor group over HSCT using a as quality of life, cannot be ascertained retrospectively. Nonethe- 9/10 donor, although this comparison was limited by sample size less, more recent analyses have attempted to control for some of (P. In addition to this completed study, 2 larger prospective studies are being performed to demonstrate the relative advantage of HSCT Platzbecker et al compared allogeneic HSCT with DNA-hypomethy- over non-HSCT approaches. A German study will biologically lating therapy in patients 60-70 years of age in a donor versus no assign 250 newly diagnosed MDS patients age 55-70 years with donor analysis using a cohort who received therapy with azacytidine higher-risk MDS IPSS intermediate-2, high, or intermediate-1 with after an unsuccessful donor search or no search attempt (as a poor-risk cytogenetics) to HSCT or no HSCT on the basis of donor Hematology 2014 77 availability (www. All Given that the majority of patients with MDS are older, myeloabla- subjects enrolled will initiate therapy with azacitidine. After 4-6 tive HSCT usually cannot be used safely in this population. Those However, the role of RIC HSCT in MDS until recently has been less without a donor will continue to receive azacitidine. The trial is clear, largely because the approval of DNA-hypomethylating therapy powered to detect a meaningful difference in outcome if the 3-year has added options beyond supportive care for affected patients. In survival in the HSCT arm is 50% compared with 30% in the addition, prospective trials comparing these 2 approaches have not non-HSCT arm. A Blood and Marrow Transplantation Clinical Trials Network study We recently completed a decision analysis examining the role of (BMT-CTN 1102) has recently begun enrolling patients (www. This trial asks the more This analysis included data from over 500 patients aged 60-70 fundamental question of whether HSCT is of value at any time in the enrolled in clinical trials and prospectively registered in MDS disease course. Patients referred for transplantation will be biologi- databases. Given the therapeutic options previously unavailable to cally assigned to HSCT or non-HSCT therapy based on the patients with MDS, this analysis evaluated the role of best support- availability of a suitable matched sibling or 8/8 HLA-matched, ive care and/or erythropoiesis-stimulating agents in comparison unrelated donor and will be followed for overall survival without with RIC HSCT for patients with lower-risk MDS and evaluated the any mandate for the type of HSCT or non-HSCT therapy delivered. Both traditional Markov model- with the primary end point of overall survival being measured 3 ing and Monte Carlo simulation techniques were used, and quality years from the time of enrollment. Importantly, this trial will also of life was factored into the decision models.
This trial compared flavoxate 200 mg 3 times daily to placebo 100 mg kamagra oral jelly fast delivery. The difference between flavoxate and placebo in the mean change in frequency of micturitions was not statistically significant (–0 cheap kamagra oral jelly 100mg without a prescription. Four of them reported mean change in frequency of micturition and episodes of incontinence cheap 100 mg kamagra oral jelly with visa, with 3 finding significant 81 purchase 100mg kamagra oral jelly mastercard, 85, 92, 94 differences compared with placebo (Evidence Table 5). Two studies investigated the 85, 94 new extended-release formulation of trospium. Both were 12-week trials comparing trospium 60 mg once daily with placebo, and both found that trospium had better efficacy as measured by mean reduction in frequency of micturition and episodes of incontinence per day. One of the trials reported a mean reduction in number of daily incontinence and micturition episodes compared with placebo, –2. Similarly, the other placebo trial found a mean reduction in number of daily incontinence episodes and micturitions compared with placebo, –2. A very small placebo-controlled 2-week trial evaluating transdermal scopolamine in 20 women with detrusor instability showed greater improvements in daytime urinary frequency, 76 nocturia, urgency, and urge incontinence with scopolamine than placebo. A series of pooled analyses of subgroups of patients from 4 placebo-controlled trials studied the effects of solifenacin in patients with incontinence, without incontinence (dry overactive bladder), polyuria or nocturia, mixed urinary incontinence, or severe symptoms of 97-101 overactive bladder. In the subgroup with incontinence (n=1873), the proportions achieving continence at 12 weeks were 34% with placebo, 51% with solifenacin 5 mg daily, and 52% with 10 mg daily; the actual mean change in the number of incontinence episodes per day were –1. The authors also analyzed subgroups (age <65 or >65) within this subgroup, finding solifenacin to be superior to placebo in most cases. In patients without incontinence (n=975), the mean percent change in the number of urgency episodes per day was 46% with placebo and 75% with either 5 or 10 mg daily solifenacin, and the mean change in actual urgency episodes per day was –2. Micturition frequency was also significantly lower in the drug groups, with a mean percent change of 13% with placebo, 19% with solifenacin 5 mg daily, and 23% with solifenacin10 mg daily. An analysis of the effect of solifenacin on severe overactive bladder symptoms used 3 definitions of severity: more than 3 incontinence episodes per day (n=599), more than 8 urgency 99 episodes per day (n=741), and more than 13 micturitions per day (n=789). With all 3 Overactive bladder Page 23 of 73 Final Report Update 4 Drug Effectiveness Review Project definitions, the 10 mg daily dose of solifenacin was superior to placebo in the resolution of incontinence or urgency, normalization of micturition, and reduction in number of episodes of incontinence, micturition, or urgency per day. In contrast, the 5 mg dose was superior to placebo only for percent reduction in incontinence episodes per day and only among the patients who began with more than >13 micturitions per day. The impact on nocturia was not a reported outcome in this analysis. In the subgroup of patients with a history of mixed urinary incontinence (mixed stress and urge symptoms; n=1041), significantly more patients taking solifenacin achieved continence at 12 weeks (33% with placebo and 43% and 49% with solifenacin 5 and 10 mg daily, 98 respectively) These symptom improvements were associated with improvement in quality of life. Nocturia was not an outcome measured in this analysis. Two of these pooled subgroup analyses found that only the 10 mg dose of solifenacin 101 was statistically superior to placebo in reducing episodes of nocturia. A separate pooled analysis of only patients reporting nocturia at baseline (n=2534) found that solifenacin was superior to placebo in reducing nocturia in patients without polynocturia (unusually large 97 volumes of urine produced during sleep hours, as defined by Weiss and Blaivis). In this subgroup, 62% had polynocturia, with 602 patients who had data available for the analysis. Similarly, more patients in the drug groups than the placebo group achieved less than 1 episode of nocturia per night at 12 weeks; this difference was statistically significant. An analysis that pooled the results of the 2 placebo-controlled trials of transdermal 102 oxybutynin confirmed the efficacy finding of the individual trials. Median daily number of incontinence episodes was reduced by 3 with oxybutynin and by 2 with placebo patch; frequency of micturition was reduced by 2 with oxybutynin and by 1 with placebo. Dry mouth was experienced by 7% of patients using oxybutynin transdermal and by 5% using placebo. A post hoc subgroup analysis of a placebo-controlled trial of tolterodine extended-release 90 103 examined the subgroups of patients with and without incontinence at baseline. For both subgroups, this analysis found similar improvement of urgency symptoms with tolterodine over placebo. Among patients incontinent at baseline (40%), incontinence outcomes also were improved compared with placebo. Is there a difference in effectiveness between long-acting and short-acting formulations? We found 8 fair-quality studies comparing the efficacy of an extended-release formulation of an 22, 24, 25, 36, 46, anticholinergic drug for overactive bladder with an immediate-release formulation. In these studies oxybutynin doses ranged from 5 mg to 30 mg daily, tolterodine was dosed at 4 mg daily, and the darifenacin dose was either 15 mg or 30 mg daily. Of the 4 studies comparing extended-release oxybutynin with immediate-release oxybutynin, 1 was 6 weeks in duration and compared oxybutynin 10 mg daily, either as Overactive bladder Page 24 of 73 Final Report Update 4 Drug Effectiveness Review Project 25 extended-release 10 mg once daily or immediate-release 5 mg twice daily. The other 3 22, 24, 47 studies used a dose titration up to the threshold of either intolerable side effects (in which case the dose was reduced by 5 mg per day) or maximum efficacy. In 1 study the efficacy analysis was performed with only patients who completed ≥ 2 weeks at the optimal dose and had 24 no major protocol violations. All 4 studies were funded by or had authors from the companies that make the extended-release formulations. We found only 1 study comparing tolterodine extended-release (4 mg once daily) with 46 immediate-release (2 mg twice daily). A placebo arm was also included in this 12 week-study. This large study included over 500 patients per treatment arm, and it used an intention-to-treat analysis. A study comparing extended-release tolterodine with immediate-release oxybutynin 36 included 600 Japanese or Korean patients. Patients received daily doses of either tolterodine 4 mg or oxybutynin 9 mg. The manufacturer of extended-release tolterodine provided funding; the formulation of immediate-release oxybutynin used in this study is not available in the United States. One study compared extended-release oxybutynin (10 mg once daily) with immediate- 23 release tolterodine (2 mg twice daily) for 12 weeks. The funding was provided by Alza, the manufacturer of the extended-release form of oxybutynin, and the company employed one of the authors. Two studies compared solifenacin with tolterodine (one immediate-release and the other extended-release). The first, a fair-quality study, compared solifenacin 5 mg, solifenacin 10 mg, 50 immediate-release tolterodine 2 mg twice daily, and placebo. This study was not powered to show treatment differences between the active treatment arms. Thus, the authors did not conduct a statistical analysis of comparisons between drugs; however, they did perform statistical analyses of each drug compared with placebo. A fair-quality systematic review evaluated differences in tolerability, safety, and efficacy between oxybutynin, tolterodine, trospium, darifenacin, and solifenacin and concluded that based on 1 short-term trial, solifenacin had 16 greater efficacy for some clinical outcomes than tolterodine. The trial compared extended-release tolterodine 4 mg with a “flexible” dose of solifenacin (5 mg or 10 mg) over a total of 12 weeks. Patients were randomized to either tolterodine extended- release 4 mg or solifenacin 5 mg for the first 4 weeks. At week 4, solifenacin patients were allowed to increase their dose if they were not satisfied with treatment efficacy. The final dose was maintained for the remaining 8 weeks of the study. The investigators stated that use of flexible dosing allowed the trial to mirror clinical practice as closely as possible. One problem with this trial’s analysis should be noted: Data for both doses of solifenacin were combined in the analyses of efficacy and safety outcomes. Thus, it is not possible to determine which dose of solifenacin provided greater efficacy or whether the different doses caused a difference in rates of adverse events. Because the authors did not conduct a statistical analysis of the difference in adverse events between solifenacin and tolterodine, we did a statistical analysis of the adverse event rates of the STAR trial ourselves using the StatsDirect program. The investigators did a post hoc analysis of the STAR trial data to determine which drug most quickly led to 106 improvement. The analysis compared tolterodine with the initial dose of solifenacin (tolterodine extended-release 4 mg compared with solifenacin 5 mg over the first 4 weeks of the trial). Overactive bladder Page 25 of 73 Final Report Update 4 Drug Effectiveness Review Project In the final included study, darifenacin (15 mg and 30 mg doses) was compared with 105 immediate-release oxybutynin in a crossover study with 2 weeks in each treatment arm. Episodes of incontinence and frequency of micturition Short-acting compared with long-acting drugs 22, 47 Two fair-quality studies that titrated extended-release or immediate-release oxybutynin to adverse events or efficacy reported no significant difference between groups in the mean change in number of incontinence episodes per week.
Chem oregim en:D AY 1:cisplatin100m g/m 2andD AYS 1- 5 3:5-F U 1000m g/m 2 cheap 100mg kamagra oral jelly with visa. The deW it patientsoncisplatinwereinahighlyem etogenic category(definedby 2001 Hesketh 1997);butthepatientsoncyclophospham idehaddosages ≥ 500 N R m g/m 2 generic kamagra oral jelly 100mg amex,which canrangefrom m oderate(500-750m g/m 2and750-1500 5 m g/m 2)em etogenicitytohigh em etogenicity(≥ 1500m g/m 2)perHesketh 1997 order kamagra oral jelly 100mg visa. Antiemetics Page 34 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1 100mg kamagra oral jelly amex. C h em oth erapy:H ead-to-h ead trials A uth or Y ear A ge Setting A llow oth er G ender H esketh rating Design Subpopulation Intervention m edication R un-in/W ash -out Eth nicity allgiven dex am ethasone(dex ) 20m g ivasa15-m in DelF avero infusion45m inbefore 61 1995 D BR CT O ndansetroniv8m g kinetosis adm inistrationof N R /N R 68%m ale M ulticenter Parallel G ranisetroniv3m g cisplatin. Allpts N R 5 receivedD ex im and m etoclopram idepoon days2-4. Antiemetics Page 35 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Screened/ W ith drawn/ Setting Eligible/ L ostto fu/ H esketh rating Enrolled A nalyz ed O th erpopulationch aracteristics M ediandoseof cisplatin(m g persquarem eter):8% D oseof cisplatin: <90m g/m 2:63% ≥ 90m g/m 2:37% Perform anceStatus: 50-80:35% 90-100:65% Previousnon-cisplatinchem o: Yes7% N o92% DelF avero Prim arytum or: 1995 O vary:14% N R /N R /973 6/1/966 M ulticenter L ung:38% 5 Head-neck:12% Bladder:14% O ther:21% K inetosis: Yes:10% N o:89% Concom itantm edications: O pioids:4% H2antagonists:14% Benz odiaz epines:4% N SAID :9% Antiemetics Page 36 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating R esults Data givenas ond vs gran Com pleteresponse:acute:nonauseaandnovom iting,andnonausea+novom iting N onausea:acute:72. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating A dverse events C om m ents 15m inafterstudydrug adm inistrationfinished,cisplatininfusionbeganand wasgivenover30m in. Theotherchem oagentsweregivenim m ediately aftertheendof thecisplatininfusion. G ranandO ndgiventopatientsonday1only;soday1wasthe DelF avero weakness:2. G ran:1ptdiedduring first24hours; 2ptsfailedtoreceiveantiem etic therapyafterrandom iz ation;1ptwaslostto Antiemetics Page 38 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear A ge Setting A llow oth er G ender H esketh rating Design Subpopulation Intervention m edication R un-in/W ash -out Eth nicity Yes;allreceived dex am ethasone10m g F ox-G eim an O ndansetronpo24m g (8m g Q 8) ivqdwhilereceiving the 47 2001 D BR CT BM T;TBI O ndansetroniv32m g qd 5-HT3antagonist;also, N R /N R 28%m ale SingleCenter Parallel G ranisetronpo2m g (1m g Q 12) benz odiaz epineswere N R 5 allowedasneededfor sleep. Antiemetics Page 39 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Screened/ W ith drawn/ Setting Eligible/ L ostto fu/ H esketh rating Enrolled A nalyz ed O th erpopulationch aracteristics M eanweight,kg:78kg allogenic transplant3% autologoustransplant97% Inpatienttreatm entsetting 73% O utpatienttreatm entsetting 27% Historyof m oderate/severenausea72% Historyof vom iting:57% Historyof anticipatorynausea/vom iting 12% Conditioning regim ens:TBI-containing 26% Conditioning regim ens:Chem oonly74% F ox-G eim an preparativeregim en: 2001 N R /N R /102 6/0/102 STAM P V:33% SingleCenter TBI/VP/CY:25% 5 TAN C:15%; BU /CY:11% BE AM :4%; BCN U /VP/CY:2% ICE :2% Carboplatin/VP:2% Carboplatin/M TZ/CY:2% M M T:2% Thiotepa/CY:1% TBI/CY:1% Antiemetics Page 40 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating R esults O ndpo24vsO ndiv32vsG ranpo2 Com pleteresponse(CR :noorm ildnausea(ptabletoeat;reasonableintake)andnorescueantiem eticsused) D ay1:95% vs92% vs92%,N S D ay2:69% vs69% vs77%,N S D ay3:73% vs75% vs81%,N S D ay4:35% vs32% vs45%,N S D ay5:27% vs30% vs25%,N S D ay6::32% vs32% vs25%,N S D ay7:45% vs31% vs15%,N S D ay8:35% vs10% vs8%,N S Com positescore(overall-D ays1-8):48% vs49% vs47%,N S M ajorR esponsescore(1vom iting episodeorif novom iting,m oderatenausea(intakesignificantlydecreased;ptcaneat)with rescueallowed: F ox-G eim an N orm aliz edfor8days:82% vs81% vs84%,N S 2001 M ajorresponse(M R ):1episodeof vom iting orm oderatenausea(intakesignificantlydecreased,butpatientcaneat)with rescueallowed SingleCenter D ay1:2% vs6% vs8%,N S 5 D ay2:31% vs24% vs17%,N S D ay3:21% vs19% vs11%,N S D ay4:42% vs42% vs47%,N S D ay5:58% vs47% vs55%,N S D ay6:46% vs41% vs60%,N S D ay7:28% vs54% vs57%,N S D ay8:44% vs65% vs70%,N S F ailure(>4episodesof nausearegardlessof nauseaorrescueantiem etic use) Com positescore:4. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating A dverse events C om m ents PatientswerestratifiedbygenderandbyTBI-containing vs. Ptpopulationweretoreceivechem oor chem oradiotherapytreatm entspriortostem celltransplantation. Chem o TotalpoptsvsO ndIV regim ens:Preparativeregim ensincludedSTAM P V;TBI/etoposide Totalwithdrawals:7. Theadditional5 totalAU C = 30;carboplatine/m itox antrone(M TZ)/CY;M M T (paclitax el150 withdrawals"refusedtocontinuetheprotocolduetopoornauseaand/or m g/m ^2perdaycontinuousIV infusion[CIV]over96hoursondays-6,-5,- em esiscontrol. Antiemetics Page 42 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear A ge Setting A llow oth er G ender H esketh rating Design Subpopulation Intervention m edication R un-in/W ash -out Eth nicity G ebbia 59 1994a O penR CT ondansetroniv24m g none N o N R /N R 64%m ale SingleCenter Parallel granisetroniv3m g N R 5 G ebbia 56 1994b O penR CT ondansetroniv16m g none N o N R /N R 21%m ale SingleCenter Parallel G ranisetroniv3m g N R 3 Antiemetics Page 43 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Screened/ W ith drawn/ Setting Eligible/ L ostto fu/ H esketh rating Enrolled A nalyz ed O th erpopulationch aracteristics D elayed:91% Prim arytum or: headandneck47% lung 16% G ebbia urinarybladder7% 1994a ovary7% N R /N R /182 16/0/166 SingleCenter stom ach 6% 5 endom etrium 6% vulva7% breast3% testis1% sarcom a1% Prim aryTum or: Breast60% G ebbia L ung 15% 1994b N R /N R /164 8/0/158 O vary8% SingleCenter Stom ach 6% 3 N on-Hodgkinlym phom a9% M elanom a1% Antiemetics Page 44 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating R esults O ndansetronvsG ranisetron Acuteem esisresponserates:com plete,m ajor,m inor,andfailure M ajorresponse:29% vs24%,N S M inorresponse:14% vs12%,N S F ailure:5% vs15%,N S Com pleteresponse:noem esis(acute):52% vs49%,N S G ebbia D elayedem esisresponserates:com plete,m ajor,m inor,andfailure 1994a Com pleteresponse :39% vs36%,N S SingleCenter M ajorresponse:24% vs22%,N S 5 M inorresponse:21% vs28%,N S F ailure:16% vs14%,N S N auseaseverity N onausea:acute:74% vs79%,N S N oorm ildnausea:delayed:53% vs45%,N S Com pleteresponseinptsundergoing fractionatedchem o N oem esisinptsundergoing fractionatedchem o:D ays2-5:43% vs35%,N S O ndansetronvsgranisetron Acuteem esisresponserates:Com plete,m ajor,m inor,failure F ailure:≥ 6em etic episodes:3% vs4%,N S M inorresponse:3-5em etic episodes:6% vs10%,N S G ebbia M ajorresponse:1-2em etic episodes:22% vs19%,N S 1994b Com pleteresponse:noem etic episodes:69% vs67%,N S SingleCenter D elayedem esisresponserates:Com plete,m ajor,m inor,failure 3 M ajorresponse,days2-5:15% vs20%,N S Com pleteresponse:noem esisdays2-5:45% vs52%,N S Ptsex periencing nonausea: Acute:50% vs45%,N S D elayed:31% vs37%,N S Antiemetics Page 45 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating A dverse events C om m ents G ebbia Ptsstratifiedaccording tolength of chem o(singledayvs. Ptswith fractionatedchem o Headache:9% vs4%,N S SingleCenter receivedO ndpo8m g bid(total= 16m g)orG raniv3m g onthedayswith Constipation:17% vs7%,N S 5 chem oafterday1. Allptswererequiredtoreceiveepidox orubicin ≥ 75m g/m 2,dox orubicin≥ 40m g/m 2,cyclophospham ide ≥ 600m g/m 2iv,IF X ≥ 3g/m 2(study2). In G ebbia Study2,m ostpatientsreceivedaCM F regim en(cyclophospham ide600 1994b m g/m 2,m ethotrex ate40m g/m 2,and5-fluorouracil[5-F U ]600m g/m 2), SingleCenter F AC/F E C regim en(5-F U 600m g/m 2,cyclophospham ide600m g/m 2, 3 epidox orubicin75-90m g/m 2ordox orubicin40-60m g/m 2),orifosfam ide3- 5g/m 2plusvinorelbine25-30m g/m 2. Antiemetics Page 46 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear A ge Setting A llow oth er G ender H esketh rating Design Subpopulation Intervention m edication R un-in/W ash -out Eth nicity Corticosteroids (dex am ethasoneor m ethylprednisolone) couldbegivenas replacem entor G ralla O ndansetroniv32m g +dex orm - m aintenancetherapy 61. Antiemetics Page 47 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Screened/ W ith drawn/ Setting Eligible/ L ostto fu/ H esketh rating Enrolled A nalyz ed O th erpopulationch aracteristics M eanbodyweight= 74kg G ralla M eanalcoholunits/week= 6. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating R esults O ndansetronvsG ranisetron Totalcontrol(noem esis,nonauseaof anyseverity,andnouseof antiem etic rescuem edication)over24h postcisplatinadm inistration) F orallpatients:58. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating A dverse events C om m ents PatientswererequiredtoreceiveIV cisplatinof ≥ 60m g/m 2overaperiod notex ceeding 3hours. N oadditionalcisplatinwasadm inistereduntil24 O ndansetronvsG ranisetron hourshadelapsed. Thetim ing of allpost-chem oassessm entsand Asthenia:18. Thisstudyonlyreportednum bersforAE s Patientsex periencing anyAE :85. Thetwom ostcom m onlyused Both drugs antiem etic rescuem edicationsusedwereprochlorperaz ineand W ithdrawalsduetoAE s:notstratifiedbydrug:0. Antiemetics Page 50 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear A ge Setting A llow oth er G ender H esketh rating Design Subpopulation Intervention m edication R un-in/W ash -out Eth nicity H errington Yes:studydrug given 60. Antiemetics Page 51 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Screened/ W ith drawn/ Setting Eligible/ L ostto fu/ H esketh rating Enrolled A nalyz ed O th erpopulationch aracteristics Prim aryTum or-Breast:63%; H errington L ym phom a:20%;M ultiplem yelom a:7%; 2000 O ther:12% 65/61/61 0/0/61 M ulticenter Chem o:cyclophospham ide-dox orubicin:66%; 4 cyclophospham ide:21%; dox orubicin:7%; other:7% PreviousChem o:yes:70% PreviousChem o:no:30% Breastcancer:64% G astrointestinalcancer:16% L ym phom a:9% L ung cancer:4% Headandneckcancer:2% M esotheliom a:2% Jantunen O therm alignancies:2% 1993 Chem o:CM F :34% N R /N R /166 34/2/130 M ulticenter Chem o:F AC/F E C:14% 3,4 Chem o:C+m itox antrone+5-F U :5% Chem o:othercyclophospham idecontaining:7% Chem o:A/E +M TX +5-F U :14% Chem o:otheranthracycline-containing:9% Chem o:carboplatin-containing:5% Chem o:M itom ycin+M TX m itox antrone:5% Chem o:D TIC-containing:2% Chem o:cisplatin Chem o:other:4% Antiemetics Page 52 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating R esults ondpo16vsgranpo1 Totalcontrolof nauseaandem esis Totalcontrolof nauseaandem esis(over24hours):45% vs46%,N S Severityof nausea Severe:9% vs14%,N S H errington M ild:18% vs25%,N S 2000 M oderate:15% vs14%,N S M ulticenter N one:58% vs46%,N S 4 E m etic episodes N one:76% vs82%,N S 1:12% vs14%,N S 2-3:3% vs4%,N S 4orm ore:9% vs0%,N S R escueantiem eticsadm inistered:42% vs54%,N S O ndansetronvsG ranisetronvsTropisetron Controlof vom iting during thefirst24h (forCycle1of 3) Jantunen Com pletecontrol:novom iting orretching;Cycle1(N = 161of 166)(p-valuegranvs. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating A dverse events C om m ents ondansetronvsgranisetron O verallAE s H errington constipation:3. C= cyclophospham ide;M = m ethotrex ate;F or5-F U = 5-fluourouracil;A = dox orubicin;E = epirubicinM TX -m ethotrex ate;D TIC -ductualcarcinom a insitu. W ithdrawalinform ation:Incycle1,datawasgivenfor161of 166 Jantunen O ndansetronvsG ranisetronvsTropisetron pts(noreasonsgivenastowhythose5notaccountedfor);forall3cycles, 1993 Headache therewere36ptstotalwhocouldnotevaluated inthecross-overanalysis M ulticenter (no. O f these,18hadtheirchem ochangedduetoprogressive 3,4 35% vs35% vs34%, diseaseandnolongerfittheinclusioncriteria;4hadchem odose reductionsduetolow bloodcounts;5hadincom pletedataonem esis;4 requestedtobewithdrawnafterCycle1duetoinadequatecontrolof em esis(2inO nd,2inTrop);2em igratedandwerelosttoF /u;1didnotfit inclusioncriteria (astrocytom a);1receivedTrop 2X which wasconsideredtobe am ajorviolationof studyprotocol;1requestedtobewithdrawnafterrandom Antiemetics Page 54 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear A ge Setting A llow oth er G ender H esketh rating Design Subpopulation Intervention m edication R un-in/W ash -out Eth nicity K alaycio G ranisetroniv0. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Screened/ W ith drawn/ Setting Eligible/ L ostto fu/ H esketh rating Enrolled A nalyz ed O th erpopulationch aracteristics Prim aryTum or:Breast:100% K alaycio Chem otherapyN on-N aïve:100% 1998 Historyof alcoholuse:18% 48/48/48 3/45/45 N R Historyof em esis:38% 5 Historyof ondansetron:62% Historyof granisetron:31% Patientsreceiving m oderatelyem etogenic chem o:41% Ptsreceiving highlyem etogenic chem otherapy:59% L eonardi E CO G Perform anceStatus0-3:100% 1996 N R /N R /118 3/0/118 Breastcancer:36% M ulticenter L ung cancer:24% 3,4,5 Hodgkinsornon-Hodgkinslym phom a:16% O therm alignancies:24% Antiemetics Page 56 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating R esults G ranisetronvsO ndansetron K alaycio M eannum berof salvageanti-em etics:15. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating A dverse events C om m ents G ranisetronvsO ndansetron Allptsreceivedaninfusionof autologousstem cells3daysafterthechem o K alaycio headache:36% vs39%,N S regim enwascom plete. Allptsreceivedhem atopoietic growth factorsafter 1998 diarrhea:36% vs39%,N S ASCT untilengraftm entwasachieved. M oderatelyem etogenic (M E )chem o:aregim encontaining Adriam ycin>25 m g/m 2orepidox orubicin>40m g/m 2and/orcyclophospham ide>500 D eath:Both drugs:1. Highlyem etogenic (HE )chem o:aregim encontaining cisplatin>50m g/m 2aloneorin L eonardi O ndansetronvsG ranisetron associationwith otherantiblastic agents. D ataispresentedasaresultof 1996 Headache:24% vs23%,N S cycles,notpatients;O ndwasfirstadm inisteredin65patientsandG ranin M ulticenter L ightheadedness:13% vs18%,N S 53patients. Therewereatotalof 233cycles(3patientsdidnotcom pletea 3,4,5 Constipation:11% vs6%,N R secondcycle-2diedbeforethesecondcyclebeganandonerefuseda O therAE s(notspecified):6% vs6%,N R secondcycle)evaluatedforthe118patients. Therewere93HE cycles N um berof cycleswithoutanyAE s:62% vs68%,N S (40%)and140M E cycles(60%);andtherewere116cycleswith O ndand 117with G ran. Antiemetics Page 58 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear A ge Setting A llow oth er G ender H esketh rating Design Subpopulation Intervention m edication R un-in/W ash -out Eth nicity M antovani O ndansetroniv24m g N otex plicitlystated 58. N R 5 M artoni N ootherantiem etic 62 1995 O penR CT O ndansetroniv24m g drugsallowed, none N R /N R 75%m ale SingleCenter Crossover G ranisetroniv3m g including N R 5 corticosteroids.