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There were some baseline differences among groups in vaginal irritation and itching (more severe in placebo group) and vaginal dryness (greater in placebo and 100 mcg vaginal ring groups) cheap malegra dxt plus 160 mg otc. There was significant improvement in vaginal dryness at 4 and 8 weeks in the E2 vaginal ring 100 mcg group buy 160 mg malegra dxt plus visa, and significant improvement in pain during intercourse at week 4 in both E2 groups and at week 13 in the E2 100 mcg group discount 160 mg malegra dxt plus amex. There was a nonsignificant trend toward greater improvement of other urogenital symptoms in both E2 groups compared with placebo malegra dxt plus 160 mg discount. In a subgroup of 60 women (18% of total) with signs and symptoms of vaginal atrophy at baseline, the maturation index was improved in both E2 groups compared with placebo at week 13. A trial of transdermal E2, utilizing responses on the McCoy Sex Scale Questionnaire, 95 indicated improvement in responses to five of nine items compared to placebo. A correlation between improved sexual life and a quality-of-life questionnaire was also reported in this study. These findings were supported by another trial of transdermal E2 that indicated improvement in 76 sexual problems and dysfunction as measured with the McCoy Sex Scale compared to placebo. Another trial of transdermal E2 indicated improvement in vaginal dryness, but not dyspareunia, 96 frequent urination, dysuria, stress incontinence, and nocturia, compared to placebo. Another trial comparing transdermal E2 and placebo indicated no differences between groups for 73 symptoms of vaginal discomfort, loss of libido, and incontinence. There are two brief reports from one head-to-head study that measured sexual functioning and sexual quality-of-life in 186 women randomized to transdermal E2 or oral E2. One of these 97 98 is an abstract and the other a poster presentation. On some, but not all, measures of sexual function and sexual quality of life, there was more improvement in women who used transdermal E2 compared with oral E2. This study is not published in full-text form and the brief reports do not provide sufficient detail to assess quality. A trial of CEE reported significantly improved vaginal dryness and urinary frequency, but no significant improvement on six other items related to sexual function on a General Health 61 Questionnaire compared to placebo. The HERS trial found that women with at least one episode of incontinence per week at baseline who received CEE/MPA had worsening 99 incontinence after approximately 4 years of follow up compared to women taking placebo. The WHI reported on genital symptoms, as noted above under the section ‘Hot 81 flashes/flushes’. In Update #3, the ULTRA study found no differences between treatment with low-dose 30 39 transdermal estradiol on vaginal dryness or on urinary incontinence. There was a reduction in Hormone therapy Page 38 of 110 Final Report Update 3 Drug Effectiveness Review Project investigator-assessed vaginal atrophy, dryness, and friability for estradiol acetate compared with 37 placebo (p<0. A Cochrane systematic review compared efficacy and safety of intra-vaginal estrogen preparations (creams, pessaries, tablets, and estradiol-releasing ring) for the relief of symptoms 100 of vaginal atrophy (vaginal dryness, itching, discomfort, and painful sexual intercourse). Overall, the author concluded that the preparations appear to be equally effective for the symptoms of vaginal atrophy. CEE cream caused more side effects compared to estradiol tablets (uterine bleeding, breast pain, and perineal pain) or estradiol vaginal ring (endometrial overstimulation). For the comparison of the estradiol ring to CEE vaginal cream, there was no difference between groups in patient assessment of vaginal dryness or withdrawals due to adverse events, but there was more improvement in pruritis with the ring. For the comparison of estradiol ring versus estradiol tablet, vaginal dryness was improved more with tablets, but there was no difference between groups in genital pruritis or withdrawals due to adverse events. Symptom improvement was similar for tablet versus cream, but there were fewer withdrawals due to adverse effects with tablets compared with cream. There was no difference among all treatment comparisons for dysuria, nocturia, urgency, urge incontinence, participant symptom improvement in dryness, soreness, and irritation, loss of libido, and vaginitis. Quality-of-life A head-to-head comparison of CEE vs. A trial comparing oral E2 and intravaginal ring E2 found significant improvement on the Greene Climacteric Scale among 102 both treatment groups but no between-group differences. One trial of oral E2 conducted in HRT-naive women in Thailand observed no difference in mean Greene score 83 improvement compared with placebo after 12 months of treatment. A trial of low-dose oral E2 103 (1 mg per day) reported significant improvement from baseline at 6 and 12 weeks on six of nine domains of the Women’s Health Questionnaire (vasomotor symptoms, sexual behavior, depressed mood, somatic symptoms, anxiety/fear, and sleep problems). There was no difference between control and treatment groups on the memory concentration, menstrual symptoms, and attractiveness items of the scale. Seven trials of transdermal E2 and placebo indicated improved health related quality-of- life and well-being measured by various instruments: Nottingham Health Profile, Psychological General Well-Being Index, Women Health Questionnaire, Kupperman’s index, McCoy Sex 68, 70, 73, 74, 76, 96, 104 Scale, and psychological general well-being index. One trial indicated that women with high well-being and no vasomotor symptoms at baseline had no improvement with 105 treatment as measured by the Psychological General Well-Being Index. The HERS trial (CEE), using non-validated quality of life instruments (Duke Activity Status Index, RAND Mental Health Inventory, among others), found that quality of life scores were significantly lower among women who were older, had diabetes, hypertension, chest pain, 91 or heart failure, and that use of CEE had little effect. One trial found a significant decrease in 59 Kupperman’s index among women treated with E2V compared with placebo. A trial of Hormone therapy Page 39 of 110 Final Report Update 3 Drug Effectiveness Review Project esterified estrogens reported improvement in the Quality of Life Menopause Scale compared to 106 placebo. Health-related quality of life (HRQL) measures were collected on a subgroup of women 85 enrolled in the WHI randomized to CEE plus MPA or to placebo (n=16,608). Quality of life and functional status were assessed using the RAND 36-item Health Survey, which includes items about general health, physical functioning, limitations on usual role-related activities due to physical health problems, bodily pain, energy and fatigue, limitations on usual role-related activities due to emotional or mental problems, social function, and emotional or mental health. At 1-year follow-up, there were small but statistically significant positive effects of CEE/MPA on physical functioning (0. There were no differences from placebo in any other HRQL measure and by 3 years of follow-up (n=1511) there were no significant differences from placebo on any HRQL measure. Subgroup analyses detected no statistically significant interactions between baseline age, race, ethnicity, body mass index, or menopausal symptoms and HRQL. In a post hoc analysis of women 50 to 54 years of age who reported moderate-to-severe vasomotor symptoms at baseline, there was a positive effect on sleep disturbance, but no effect on other HRQL measures, despite significant improvement in vasomotor symptoms. At 1-year follow-up, there was a small positive effect of CEE on sleep disturbance (0. At 1- year follow-up of women who had moderate-to-severe vasomotor symptoms at baseline, 72. In a subsample (n=1,189) examined at 3-year follow-up there were no significant differences in any HRQL measure between treatment groups. For Update #3, none of the three new studies reporting HRQL or related outcomes showed significant effects between the treatment and placebo groups. The ULTRA study of 78 low-dose transdermal estrogen reported no significant improvements in the SF-36 subscales of 29 physical and mental function. The findings of Dayal and colleagues were similar in that conjugated equine estrogen did not improve vitality, general health status, or quality of life at 12- week follow-up. A third study of women over 70 years randomized to oral estradiol or placebo 26 also did not report significant changes in a “SF-36 score. What is the comparative effectiveness of different hormone therapy preparations when used by postmenopausal women or women in the menopausal transition stage for preventing low bone density and fractures? Outcomes include bone density measurements at lumbar spine, forearm, and hip sites and/or fracture data from one or more sites. Numbers of included studies are summarized in Table 7 below; trials are described in Evidence Tables 5 (head-to-head trials) and 6 (placebo- controlled trials), and quality ratings are presented in Appendix F. Quality ratings of studies added for Update #3 are shown in Appendix G.

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Several protein tyrosine kinases (red symbols) and the lipid kinase PI3K (green symbol) transmit survival and proliferation signals and regulate cell maturation and migration purchase malegra dxt plus 160 mg with mastercard. Small-molecule inhibitors of select kinases in the BCR pathway that have demonstrated significant clinical activitgips2 indAR ed purchase 160 mg malegra dxt plus mastercard. Here cheap malegra dxt plus 160mg with visa, I briefly BCR signaling in CLL review the BCR signaling pathway and its role in CLL buy discount malegra dxt plus 160 mg, summarize Comparative analysis of CLL cells isolated from the blood and the clinical experience with these targeted agents, and provide an lymph nodes provided direct evidence for ongoing antigen- outlook on their possible future role in the therapeutic approach to dependent signaling through the BCR in vivo and suggested that CLL and LPL. This conclusion is also supported by the BCR and Toll-like receptor (TLR) signaling in CLL observations of a reversible down-modulation of surface IgM and LPL expression on CLL cells and the anergic state of some CLL cells. Consis- immunoglobulin heavy chain variable (IGHV) region genes, which 13,14 tent with these in vitro data, the degree of BCR activation in CLL encode the antigen-binding domains of the BCR. Naive B cells cells in vivo correlates with increased tumor proliferation and acquire these IGHV mutations after antigen biding as part of a 20 shorter time to progression. The presence or absence of somatic mutations in the clonal The transduction of signals from the BCR involves a network of IGHV gene distinguishes 2 major CLL subtypes; IGHV mutated kinases and adaptor molecules that connect antigen stimulation to (M-CLL) and IGHV unmutated (U-CLL, which has 98% se- 29 1 intracellular responses (Figure 1). In vivo, additional elements quence homology to the germline IGHV). M-CLL cells appear to present in the tissue microenvironment cooperate with the BCR and be “anergic,” that is, in a state of hyporesponsiveness to BCR may influence the cellular response. The term “microenvironment” activation that can result from frequent BCR stimulation. Extensive in vitro studies identified many pathways and is a more rapidly progressive disease with inferior survival com- factors that enhance CLL cell survival and promote limited prolifera- pared with M-CLL indicates that the degree of BCR activation tion, including TLRs, cytokines, chemokines, CD40, B-cell- and/or the type of antigen may be important. LPL cells derive from a activating factor of tumor necrosis factor family (BAFF), integrins, postgerminal center B cell and typically express mutated IGHV and components of the extracellular matrix. Select inhibitors of kinases in the BCR pathway in clinical trials Target Drug, company Notes SYK Fostamatinib (R788),83 Rigel Oral prodrug of R406, an inhibitor of SYK and several other kinases. Common adverse effects: fatigue, diarrhea, hypertension, cytopenias. CLL: ORR 55% GS-9973,90,91 Gilead Highly selective for SYK; common AEs in phase 2: fatigue, diarrhea, transaminase elevations. BTK Ibrutinib (PCI-32765),53,64 Pharmacyclics First FDA-approved BTK inhibitor for second-line treatment of CLL and MCL. Covalent binding to Cys481 leads to irreversible inhibition. ORR 71% in relapsed/refractory CLL patients, additional 18% with PRL. CC-292 (AVL-292),103 Celgene Covalent binding to Cys481 leads to irreversible inhibition. ONO-4059,104 Ono Pharma Covalent binding to Cys481 leads to irreversible inhibition. Orally once a day, preliminary ORR in relapsed/refractory CLL comparable to ibrutinib. ACP-196, Acerta Pharma Covalent binding to Cys481 leads to irreversible inhibition. PI3K Idelalisib (GS-1101, CAL-101),52,63 Gilead Selective inhibitor of PI3K. Single-agent ORR in relapsed/refractory CLL patients, 39% plus 33% PRL; in SLL, 61%; in LPL, 80%. In combination with rituximab, ORR 81% and PFS at 6 months 93%. IPI-145,105 Infinity Selective inhibitor of PI3K and PI3K. To what degree such tumor-extrinsic effects contrib- to estimate to what degree any single factor or pathway may be ute to efficacy or to adverse events are becoming an important area necessary or sufficient for CLL pathogenesis. Davide 2 months before gradually resolving, but there is considerable Rossi in this publication. A subset of patients may show persistent lymphocytosis for many months to years on monotherapy and this does not appear to be a harbinger of treatment failure. Most advanced in their clinical development are inhibi- increase in ALC was also recorded in patients with indolent tors of BTK, PI3K, and SYK (Table 1). Many of these inhibitors non-Hodgkin’s lymphoma (NHL) treated with idelalisib, mostly in were initially developed for use in inflammatory diseases. Preclini- SLL (64% of patients), and less commonly in follicular lymphoma cal in vitro and in vivo studies identified these kinases as promising (18%). Treatment-induced lymphocytosis was not seen in patients with LPL. Characteristic clinical observations in CLL patients treated Ibrutinib with kinase inhibitors Ibrutinib (formerly PCI-32765) is an orally bioavailable BTK Treatment-induced lymphocytosis inhibitor that irreversibly inactivates the kinase by covalently binding to a cysteine residue (Cys481) near the active site. Loss-of-function mutations in BTK block B-cell maturation at the Due to redistribution of cells out of the lymph node (tissues) into the pre-B-cell stage and cause X-linked agammaglobulinemia (also blood. Although BTK is Mostly well tolerated oral agents and limited myelosuppression. Rate of infection higher in relapsed/refractory patients, appears to be due to underlying disease. Ibrutinib was approved by the FDA in November 2013 for the Ibrutinib: frequent grade 1 ecchymosis, rare grade 3 bleeding (avoid treatment of relapsed MCL and in February 2014 for relapsed/ Coumadin, hold drug for invasive procedures). BCR activation in B cells is inhibited with an IC50 Idelalisib: grade 3 diarrhea, colitis, and pneumonitis. Typically rapid improvement in cytopenias and disease symptoms. Durable responses despite the presence of residual disease. Due to its covalent binding to BTK, ibrutinib can be given once Inhibition of BCR signaling paralleled by decreased tumor daily despite the short half-life of the drug. Full BTK occupancy, a surrogate of complete kinase inhibition, was observed at 4 hours after administration of doses of 2. On day 8, the pre-dose occupancy of BTK at the 420 mg tantly, these targeted agents do not just redistribute the disease, dose level ranged from 60% to 99%, with no correlation between because the increase in ALC does not match the decrease in nodal the degree of inhibition and best objective response. Ibrutinib was very well tolerated and treatment discontinua- found that, upon starting ibrutinib, the frequency of dead or dying tion because of side effects rare. The most common side effects cells in the circulation doubled from baseline. Accordingly, ibruti- were grade 1-2, including diarrhea (47% of patients), upper nib inhibits proliferation and increases the rate of cell death, respiratory tract infections (33%), fatigue (28%), cough (31%), resulting in a gradual attrition of the tumor burden over time that arthralgia (27%), rash (27%), pyrexia (22%), and peripheral edema matches well with the observed clinical response. Grade 3 or 4 anemia, neutropenia, or thrombocytopenia conclusion has been reached using mathematical modeling.

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Both trials used valsartan 160 mg daily as their treatment dose quality 160mg malegra dxt plus, 95 85 but ramipril doses ranged from 5 mg daily to 10 mg daily order malegra dxt plus 160 mg otc. Neither of these 2 trials reported mortality purchase malegra dxt plus 160mg otc, end stage renal disease order malegra dxt plus 160mg free shipping, or quality of life outcomes. Both trials reported changes in proteinuria among participants receiving these 2 treatments. One group examined both mean protein to creatinine ratio and mean proteinuria on 85 24 hour urine collection after treatment. They found no statistically significant difference in either of these measures between valsartan and ramipril. This trial additionally reported no significant differences in blood pressures between treatment groups. The other study examined 95 changes in proteinuria by examining pre and post treatment proteinuria values. In their analysis they noted a more significant decline in proteinuria with ramipril (–53% change) compared with valsartan (–38%) (P=0. Within that study, however, systolic blood pressure and diastolic blood pressure were also significantly lower in the ramipril group as compared with the valsartan group (P=0. Esnault and colleagues found no significant differences in serum creatinine levels after treatment with either valsartan or ramipril. Yilmaz and colleagues DRIs, AIIRAs, and ACE-Is Page 56 of 144 Final Report Drug Effectiveness Review Project similarly found no significant difference in pre and post treatment glomerular filtration rate among those treated with valsartan compared with ramipril. One trial did report a subgroup analysis examining antiproteinuric outcomes among diabetics compared with non-diabetics. Diabetics were found to have a statistically greater degree of proteinuria at baseline compared with non-diabetics (P=0. No significant difference in reduction in protein to creatinine ratio was found comparing any treatment groups within this diabetic subgroup. One study reported 14 withdrawals, all of which were 95 related to adverse events; the remaining study reported 2 withdrawals, 1 of which was related 85 to an adverse event. One trial looked specifically for hypotension, and they note that there was no difference in the number of occurrences of hypotensive events within each treatment arm (specific numbers of events and statistical analysis 85 are not reported). That group additionally reported 1 event of laryngeal edema with ACE-I. The remaining trial noted 8 adverse events in the ramipril group and 6 adverse events in the valsartan 95 group, but specific types of adverse events were not delineated by group. Telmisartan Telmisartan compared with enalapril 87 One multi-center trial from France compared telmisartan to enalapril (N=71). This double- dummy, parallel group, active control trial received a quality rating of fair and followed participants for 12 weeks. Participants were required to have a creatinine clearance of between 30-80 ml/min (average at baseline was 50 ml/min), but types of chronic kidney disease among participants were not reported. Baseline proteinuria among participants ranged from 1. Starting doses of telmisartan 40 mg daily and enalapril 10 mg daily were utilized, with dose increase to telmisartan 80 mg daily and enalapril 20 mg daily if diastolic blood pressure remained between 90-110 mmHg. If diastolic blood pressure remained elevated on maximum dose of study medication, then furosemide could be added as a once daily dose of 40 mg. Eligible efficacy/effectiveness outcomes from this study included changes in creatinine clearance and proteinuria. Mean change in proteinuria between those treated with telmisartan (– 26. Median percent decline in creatinine clearance also showed no statistically significant difference between groups. Blood pressure control was statistically similar between groups. Harms were reported for multiple categories, but no statistical analysis comparing groups was reported. Hypotension, dizziness, asthenia, pain, cough, uremia, and dysuria each reported zero to 1 event for telmisartan and enalapril. Abdominal pain and nausea was reported 4 times for enalapril, compared with zero times for telmisartan. Additionally, 2 withdrawals for acute renal failure were reported; treatment groups for that adverse event were not specified. Irbesartan Irbesartan compared with fosinopril 86 One single-center study in Switzerland compared the use of irbesartan to fosinopril (N=11). This study received a quality rating of fair, and followed participants for 32 weeks. Participants DRIs, AIIRAs, and ACE-Is Page 57 of 144 Final Report Drug Effectiveness Review Project had a range of glomerulonephritides including focal segmental glomerulosclerosis, IgA nephropathy and membranoproliferative glomerulonephritis and were required to have proteinuria of greater than 1. The baseline mean creatinine clearance at baseline was 77 ml/min. This trial utilized fosinopril at 20 mg per day and irbesartan at 150 mg per day; additional diuretics were allowed if needed for edema management. The only eligibility/efficacy outcome of interest reported from this study was percent decline in proteinuria. Participants in the irbesartan group were noted to have a 37% decline in proteinuria (from 7. No statistical analysis comparing changes in proteinuria between groups was reported, but confidence intervals are noted to overlap suggesting no significant difference between groups (although this may also be influenced by very small sample size). There were no statistically significant differences in blood pressure control between groups. This trial did report 1 withdrawal, which was not related to an adverse event. This trial reported adverse events by treatment groups, but did not provide statistical analysis for comparison between groups. No participants in the fosinopril or irbesartan arm experienced either cough or dizziness. Two participants in the fosinopril group experienced acute renal failure, compared with zero in the irbesartan group. Two in the fosinopril group experienced a potassium level greater than 5 milli-equivalents per liter, as compared with only 1 in the irbesartan group. Combination therapy: Inter-class comparison of effectiveness, efficacy and harms between AIIRA and ACE-I Proteinuric Chronic Kidney Disease We included 16 trials that compared the combination of an AIIRA and an ACE-I with either or 84-86, 89, 90, 93, 94, 103-105, 107-112 both as montherapy. Four trials were rated poor quality and will not be 92, 96, 98, discussed in this analysis, but additional information can be found in Evidence Table 10. The former 113 provided no significant information on adverse events; the latter had a very small sample size 98 (19, nine of whom withdrew). The COOPERATE trial and its sub-study were rated as poor for 92, 96 reasons discussed previously. The majority of trials (11 of 16) provided 6 months or more of 84-86, 89, 90, 93, 104, 105, 109, 110, 112 111 follow-up , the longest of which was 36 months (3 years).

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