Purpose In the absence of head-to-head trial data, network meta-analysis (NMA) was used to compare trastuzumab emtansine (T-DM1) with other approved treatments for previously treated patients with unresectable or metastatic HER2-positive breast cancer (BC). Methods Systematic reviews were conducted of published controlled trials of treatments for unresectable or metastatic HER2-positive BC with early relapse (≤ 6 months) following adjuvant therapy or progression after trastuzumab (Tras) + taxane published from January 1998 to January 2018. Random-effects NMA was conducted for overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and safety endpoints. Results The NMA included regimens from seven randomized controlled trials: T-DM1 and combinations of Tras, capecitabine (Cap), lapatinib (Lap), neratinib, or pertuzumab (Per; unapproved). OS results favored T-DM1 over approved comparators: hazard ratio (HR) (95% credible interval [95% CrI]) vs Cap 0.68 (0.39, 1.10), LapCap 0.76 (0.51, 1.07), TrasCap 0.78 (0.44, 1.19). PFS trends favored T-DM1 over all other treatments: HR (95% CrI) vs Cap 0.38 (0.19, 0.74), LapCap 0.65 (0.40, 1.10), TrasCap 0.62 (0.34, 1.18); ORR with T-DM1 was more favorable than with all approved treatments. In surface under cumulative ranking curve (SUCRA) analysis T-DM1 ranked highest for all efficacy outcomes. Discontinuation due to adverse events was less likely with T-DM1 than with all comparators except neratinib. In general, gastrointestinal side effects were less likely and elevated liver transaminases and thrombocytopenia more likely with T-DM1 than with comparators. Conclusions The efficacy and tolerability profiles of T-DM1 are generally favorable compared with other treatments for unresectable or metastatic HER2-positive BC.

2019) Efficacy of emicizumab prophylaxis versus factor VIII prophylaxis for treatment of hemophilia A without inhibitors: network meta-analysis and sub-group analyses of the intra-patient comparison of the HAVEN 3 trial, ABSTRACT Objectives: To compare the efficacy of emicizumab prophylaxis with that of factor VIII (FVIII) prophylaxis in patients with hemophilia A without inhibitors using two approaches: network meta-analyses (NMA) and additional sub-group analyses from the HAVEN 3 trial. Methods: The NMA used data from trials identified using a systematic literature review and compared bleed rates in patients receiving emicizumab prophylaxis and patients receiving FVIII prophylaxis using a Bayesian, random effects generalized linear model with log link Poisson likelihood. Additional subgroups of the HAVEN 3 trial included here were defined as patients whose dose-taking behavior met either European label or World Federation of Hemophilia guidelines. A negative binomial regression model was used to conduct an intra-patient comparison of bleed rates within the sub-groups, during treatment with FVIII prophylaxis before entering HAVEN 3 and treatment with emicizumab prophylaxis during HAVEN 3. Results: Four studies were included in the base-case NMA. Evidence showed that the total treated bleed rate was lower with emicizumab prophylaxis compared with FVIII prophylaxis (rate ratio [RR] ¼ 0.36 [95% credible interval (CrI) ¼ 0.13-0.95]). Similar associations were observed in sensitivity analyses. The additional HAVEN 3 analyses also showed lower rates of treated bleeds with emicizumab prophylaxis than with FVIII prophylaxis (RRs [95% confidence interval (CI)] ¼ 0.380 [0.186-0.790] and 0.472 [0.258-0.866] in two sub-groups). These results confirm the original HAVEN 3 intra-patient comparison findings. Conclusions: Combined findings from NMA and additional sub-group analyses of HAVEN 3 support the superiority of emicizumab prophylaxis over FVIII prophylaxis in patients with hemophilia A without inhibitors. ARTICLE HISTORY

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RATIONALE Drug resistance in pneumonia (DRIP) score, among other prediction models, performed significantly better in detecting the risk of pneumonia due to drug-resistant pathogens (DRP). The use of this clinical prediction score may have the potential to decrease the use of unwarranted extended spectrum antibiotics in patients with low risk of pneumonia due to DRP. Furthermore, It can likewise select patients who will benefit from broad-spectrum antibiotics as initial therapy for patients with high risk of community acquired pneumonia due to DRP (CAP-DRP). This study was initiated to validate its efficiency in the local setting. METHODS This is a single center cross-sectional study. Adult Filipino patients aged 18 years and above who were clinically diagnosed with CAP were included. DRIP score was performed within 48 hours of admission to patients admitted for CAP. A score of <4 was classified as low risk and a score of ≥ 4 was classified as high risk. Confirmation of the presence of DRP was done through review of microbiologic cultures. RESULTS A total of 195 patients were included. DRIP score identified patients at high or low risk of pneumonia due to DRP with a sensitivity of 62.1 (95% CI, 48.4 to 74.5), a specificity of 81% (95% CI, 73.4 to 87.2), a positive predictive value of 58.1% (95% CI, 44.8 to 70.5), and a negative predictive value of 83.5% (95% CI, 76, 89.4). The prevalence of pneumonia due to DRP was 29.7%. Pseudomonas aeruginosa was identified in 15 (7.14%) of patients and was the most common isolated DRP. Tube feeding (OR 5.24), prior infection with DRP (OR 4.47), and hospitalization within previous 60 days (OR 2.52) were identified to be the strongest risk factors associated with pneumonia due to DRP. A modified DRIP score (mDRIP) was derived by eliminating one of the major risk factors, which is residence in a long-term care facility. mDRIP has a sensitivity of 62.07%, specificity of 82.02%, positive likelihood ratio of 3.27 and negative likelihood ratio of 0.47. CONCLUSION This prospective study validated the performance of DRIP score in predicting pneumonia due to DRP. DRIP Score, as well as the modified DRIP score (mDRIP), are valuable prediction models that can be used in the local setting to possibly lessen unnecessary use and therefore preserve the utilization of broadspectrum antibiotics among low risk patients. Future studies are necessary to establish definitive benefit on patient outcome measures.

Background Evidence on the relative risk of death across all stages of Alzheimer’s disease (AD) is lacking but greatly needed for the evaluation of new interventions. We used data from the Uniform Data Set (UDS) of the National Alzheimer’s Coordinating Center (NACC) to assess the expected survival of a person progressing to a particular stage of AD and the relative risk of death for a person in a particular stage of AD compared with cognitively normal (CN) people. Methods This was a retrospective observational cohort study of mortality and its determinants in participants with incident mild cognitive impairment (MCI) due to AD or AD dementia compared with CN participants. Overall survival and hazard ratios of all-cause mortality in participants ≥ 50 years of age with clinically assessed or diagnosed MCI due to AD, or mild, moderate, or severe AD dementia, confirmed by Clinical Dementia Rating scores, versus CN participants were estimated, using NACC UDS data. Participants were followed until death, censoring, or until information to determine disease stage was missing. Results Aged between 50 and 104 years, 12,414 participants met the eligibility criteria for the study. Participants progressing to MCI due to AD or AD dementia survived a median of 3–12 years, with higher mortality observed in more severe stages. Risk of death increased with the severity of AD dementia, with the increase significantly higher at younger ages. Participants with MCI due to AD and CN participants had a similar risk of death after controlling for confounding factors. Conclusions Relative all-cause mortality risk increases with AD severity, more so at younger ages. Mortality does not seem to be higher for those remaining in MCI due to AD. Findings might imply potential benefit of lower mortality if preventing or delaying the progression of AD is successful, and importantly, this potential benefit might be greater in relatively younger people. Future research should replicate our study in other samples more representative of the general US population as well as other populations around the world.