Early versus later response to treatment in patients with community-acquired pneumonia: analysis of the REACH study.

BACKGROUND: Key goals in the treatment of CAP include early response to treatment and achievement of clinical stability. The US FDA recommends early response endpoints (72 hours after initiation of treatment) in clinical trials for the treatment of community-acquired bacterial pneumonia. REACH (REtrospective Study to Assess the Clinical Management of Patients With Moderate-to-Severe Complicated Skin and Soft Tissue Infections [cSSTI] or CAP in the Hospital Setting) was a retrospective observational study, providing current data on the clinical management and resource burden of CAP in real-life settings in European hospitals. This analysis reviews the characteristics and outcomes of patients showing early positive response to treatment (time to clinical stability [TCS] ≤4 days, as assessed by Halm's criteria) compared with patients with later positive response (TCS >4 days). METHODS: Patients were adults, hospitalized with CAP (2010-2011) and requiring in-hospital treatment with intravenous antibiotics. RESULTS: Of the 2039 patients included in REACH, 585 (28.7%) had TCS assessed by Halm's criteria: 332 (56.8%) showed early response (median 3.0 days), and 253 (43.2%) showed later response to treatment (median 7.0 days). Use of Halm's criteria varied across participating countries, ranging from 0% (Belgium) to 49.1% (UK). Patient characteristics and relevant medical history were similar between the two groups. There were no notable differences in initial antibiotic therapy between groups, except that more early responders had been treated with amoxicillin-clavulanate and amoxicillin monotherapy (22.6%; 7.5%, respectively) than later responders (5.9%; 1.2%, respectively). Initial treatment modification and re-infection or recurrences were less frequent in early responders compared with later responders (14.2% and 3.3% vs. 34.8% and 5.9%, respectively). Early responders had a shorter duration of hospitalization (mean 9.4 ± SD 7.0; median 8.0 days vs. mean 15.6 ± SD 10.5; median 12.0 days, respectively), lower rate of ICU admission (3.3% vs. 21.3%) and shorter duration of ICU stay (mean 6.2 ± SD 5.7; median 4.0 days vs. mean 10.4 ± SD 10.1; median 8.0 days, respectively) compared with later responders. Mortality was low in both groups. CONCLUSIONS: Achieving early clinical stabilization in CAP (≤4 days) is associated with improved outcomes, lower requirement for initial treatment modification or readmission and lower resource use, compared with a later response. TRIAL REGISTRATION: NCT01293435.

Sleep parameters and health-related quality of life with bazedoxifene/conjugated estrogens: a randomized trial.

OBJECTIVE: The effects of bazedoxifene (BZA)/conjugated estrogens (CE) on sleep and health-related quality of life (HRQoL) were evaluated in nonhysterectomized postmenopausal women who were enrolled in a randomized, double-blind, placebo- and active-controlled phase 3 trial. METHODS: The sleep/HRQoL substudy enrolled 459 women with bothersome moderate to severe vasomotor symptoms who were randomized to BZA 20 mg/CE 0.45 mg, BZA 20 mg/CE 0.625 mg, BZA 20 mg, CE 0.45 mg/medroxyprogesterone acetate (MPA) 1.5 mg, or placebo for 1 year. On months 3 and 12, sleep parameters were evaluated using the Medical Outcomes Study sleep scale, and HRQoL was assessed using the Menopause-Specific Quality of Life (MENQOL) questionnaire. RESULTS: BZA/CE and CE/MPA significantly improved sleep and HRQoL compared with placebo. On month 3, most Medical Outcomes Study sleep parameter improvements with BZA/CE and CE/MPA versus placebo were not significant. On month 12, both BZA/CE doses and CE/MPA significantly improved time to fall asleep and sleep disturbance (P < 0.05 vs. placebo); BZA 20 mg/CE 0.625 mg and CE/MPA also showed significant improvements in sleep adequacy and sleep problem indices I and II (P < 0.01 vs placebo). Both BZA/CE doses and CE/MPA significantly improved MENQOL vasomotor function score versus placebo at 3 and 12 months (P < 0.001). At 3 months, total MENQOL score was significantly improved with BZA 20 mg/CE 0.625 mg and CE/MPA versus placebo (P < 0.05); at 12 months, both BZA/CE doses and CE/MPA showed significant improvements (P < 0.001). CONCLUSIONS: Symptomatic postmenopausal women who are treated with BZA/CE for 1 year demonstrate significant improvements in sleep and HRQoL, similar to women treated with CE/MPA.

Evaluation of the direct and indirect effects of bazedoxifene/conjugated estrogens on sleep disturbance using mediation modeling.

OBJECTIVE: Mediation modeling was used to evaluate the direct effects of bazedoxifene (BZA)/conjugated estrogens (CE) on sleep, compared with its indirect effects via improvements in hot flushes, in postmenopausal women enrolled in the SMART (Selective estrogens, Menopause, And Response to Therapy)-2 and SMART-5 trials. METHODS: Statistical mediation modeling estimated the direct effects of BZA/CE on sleep disturbance (Medical Outcomes Study sleep scale) and its indirect effects via hot flush improvement (item 1 of the Menopause-Specific Quality of Life questionnaire). In SMART-2, a total of 318 women with moderate to severe vasomotor symptoms (VMS) received BZA 20 mg/CE 0.45 mg, BZA 20 mg/CE 0.625 mg, or placebo; in SMART-5, a total of 1,843 women seeking menopausal symptom treatment received BZA 20 mg/CE 0.45 mg, BZA 20 mg/CE 0.625 mg, CE 0.45 mg/medroxyprogesterone acetate 1.5 mg, BZA 20 mg, or placebo. The SMART-5 sleep substudy enrolled 459 women with bothersome VMS and sleep disturbances. RESULTS: In SMART-2, BZA 20 mg/CE 0.45 mg and BZA 20 mg/CE 0.625 mg had a primarily direct effect on sleep in symptomatic women (64% and 66%, respectively; P < 0.001). Conversely, in the overall SMART-5 population, effects were primarily indirect (82% and 75% for BZA 20 mg/CE 0.45 mg and BZA 20 mg/CE 0.625 mg, respectively; P < 0.01), suggesting that sleep improvement was largely mediated via hot flush improvements. In a subpopulation of SMART-5 (participants with bothersome VMS), BZA 20 mg/CE 0.45 mg and BZA 20 mg/CE 0.625 mg affected sleep disturbance directly (82% and 76%, respectively; P < 0.0001). CONCLUSIONS: BZA/CE improves sleep in postmenopausal women with moderate to severe and milder VMS. This study suggests that improvements occur directly in women with moderate to severe VMS and indirectly in less symptomatic women.

Evaluation of the efficacy and safety of bazedoxifene/conjugated estrogens for secondary outcomes including vasomotor symptoms in postmenopausal women by years since menopause in the Selective estrogens, Menopause and Response to Therapy (SMART) trials.

BACKGROUND: Bazedoxifene/conjugated estrogens (BZA/CE), a novel tissue-selective estrogen complex (TSEC), has been evaluated in the Selective estrogens, Menopause And Response to Therapy (SMART) trials. Secondary outcomes from these trials were evaluated to determine whether the effects of BZA/CE are influenced by years since menopause (YSM). METHODS: SMART-1 and SMART-2 were randomized, double-blind, placebo (PBO)-controlled phase 3 trials in nonhysterectomized postmenopausal women. Outcomes were evaluated for women <5 or ≥5 YSM in SMART-1 (BZA 20 mg/CE 0.45 mg, n=433; BZA 20 mg/CE 0.625 mg, n=414; PBO, n=427) and SMART-2 (BZA 20 mg/CE 0.45 mg, n=127; BZA 20 mg/CE 0.625 mg, n=128; PBO, n=63). Hot-flush frequency and severity, health-related quality of life (HRQoL), sleep, treatment satisfaction, cumulative amenorrhea, and breast pain were assessed for each study individually, using defined statistical analysis protocols. RESULTS: For <5 and ≥5 YSM subgroups, BZA 20 mg/CE 0.45 and 0.625 mg showed significant decreases in hot-flush frequency and severity at 3 months compared with PBO (p<0.05 for both). Both BZA/CE doses showed significant improvements compared with PBO in HRQoL scores, sleep parameters, and satisfaction with treatment at 3 months irrespective of YSM (p≤0.05 vs. PBO for all). Similar to PBO, BZA/CE showed high proportions of cumulative amenorrhea (SMART-1) and low incidences of breast pain (SMART-1 and SMART-2) for women <5 and ≥5 YSM. CONCLUSIONS: The positive effects of BZA/CE on secondary outcomes were consistent among women <5 or ≥5 YSM.

Cost-effectiveness of bazedoxifene versus raloxifene in the treatment of postmenopausal women in Spain.

BACKGROUND: The purpose of this study was to assess the cost-effectiveness of bazedoxifene and raloxifene for prevention of vertebral and nonvertebral fractures among postmenopausal Spanish women aged 55-82 years with established osteoporosis and a high fracture risk. METHODS: A Markov model was developed to represent the transition of a cohort of postmenopausal osteoporotic women through different health states, ie, patients free of fractures, patients with vertebral or nonvertebral fractures, and patients recovered from a fracture. Efficacy data for bazedoxifene were obtained from the Osteoporosis Study. The perspective of the Spanish National Health Service was chosen with a time horizon of 27 years. Costs were reported in 2010 Euros. Deterministic results were presented as expected cost per quality-adjusted life-year (QALY), and probabilistic results were represented in cost-effectiveness planes. RESULTS: In deterministic analysis, the expected cost per patient was higher in the raloxifene cohort (€13,881) than in the bazedoxifene cohort (€13,436). QALYs gained were slightly higher in the bazedoxifene cohort (14.56 versus 14.54). Results from probabilistic sensitivity analysis showed that bazedoxifene has a slightly higher probability of being cost-effective for all threshold values independent of the maximum that the National Health Service is willing to pay per additional QALY. CONCLUSION: Bazedoxifene was shown to be a cost-effective treatment option for the prevention of fractures in Spanish women with postmenopausal osteoporosis and a high fracture risk. When comparing bazedoxifene with raloxifene, it may be concluded that the former is the dominant strategy.

Impact of the severity of vasomotor symptoms on health status, resource use, and productivity.

OBJECTIVE: The current study characterizes health-related quality of life, work productivity, and resource use among postmenopausal women by severity of vasomotor symptoms (VMS). METHODS: Participants were selected from the 2010 US National Health and Wellness Survey. Women aged 40 to 75 years who did not report a history of menstrual bleeding or spotting for 1 year were eligible for analysis (N = 3,267). Cohorts of women with no VMS (n = 1,740), mild VMS (n = 931), moderate VMS (n = 462), and severe VMS (n = 134) were compared after controlling for demographic and health characteristics. Outcome measures were assessed using linear models and included health status, work productivity within the past 7 days, and healthcare resource use within the past 6 months. RESULTS: The mean age of women experiencing severe VMS was 57.92 years. After demographic and health characteristics had been controlled for, women experiencing severe and moderate VMS reported significantly lower mean health status scores compared with women with no symptoms (P < 0.0001). The mean number of menopause symptom-related physician visits was significantly greater among women with severe, moderate, or mild symptoms than among women with no symptoms (P < 0.0001). Among employed women experiencing VMS, women with severe and moderate symptoms had adjusted presenteeism of 24.28% and 14.3%, versus 4.33% in women with mild symptoms (P < 0.001), and activities of daily living impairment of 31.66% and 17.06%, versus 6.16% in women with mild symptoms (P < 0.0001). CONCLUSIONS: In postmenopausal women, a greater severity of VMS is significantly associated with lower levels of health status and work productivity, and greater healthcare resource use.