Citations

BACKGROUND: Cisplatin-based neoadjuvant chemotherapy is the standard of care for muscle invasive bladder cancer (MIBC). OBJECTIVE: To compare the efficacy and safety of the two most commonly used cisplatin-based regimens; gemcitabine, and cisplatin (GC) vs. accelerated (dose-dense: dd) or conventional methotrexate, vinblastine, adriamycin, and cisplatin (MVAC). METHODS: We searched MEDLINE, Embase, Scopus and other sources. Outcomes of interest included overall survival, downstaging to pT≤1, pathologic complete response (pCR), recurrence, and toxicity. Meta-analysis was conducted using the random-effects model. RESULTS: We identified 24 studies. Efficacy outcomes were comparable between MVAC and GC for MIBC. dd-MVAC was associated with favorable efficacy compared to GC in terms of downstaging (OR 1.45; 95%CI 1.15–1.82) and all-cause mortality at longest follow-up (OR 0.63; 95%CI 0.44–0.81). However, GC was associated with a better safety profile in terms of febrile neutropenia (OR 0.32; 95%CI 0.13–0.80), anemia (OR 0.32; 95%CI 0.18–0.54), nausea and vomiting (OR 0.27; 95%CI 0.12–0.65) compared to dd-MVAC. Compared to MVAC, patients receiving GC had an increased risk of developing grade 3–4 thrombocytopenia (OR 4.70; 95%CI 1.59–13.89) and a lower risk of nausea and vomiting (OR 0.05; 95%CI 0.01–0.31). Certainty in the estimates was very low for most outcomes. CONCLUSIONS: Efficacy and safety outcomes were comparable between MVAC and GC for MIBC. Including non-peer-reviewed studies showed higher efficacy with dd-MVAC. A phase III randomized trial comparing the two regimens is needed to guide clinical practice.

Abstract Purpose The aim of the study was to appraise the current evidence on the optimal serum level for lamotrigine (LAM) in the treatment of mood disorders (major depressive disorder, bipolar disorder). Methods Major databases were searched for randomized controlled trials, open-label trials, and observational studies reporting serum LAM levels in adult patients treated with LAM for mood disorders. Results A total of 814 abstracts were screened and 24 articles were selected for full-text review. Seven studies (226 bipolar disorder and 17 major depressive disorder patients) including 1 randomized controlled trial (n = 43), 3 prospective (n = 53), and 3 retrospective (n = 147) studies met the study criteria with a study duration range from 6 to 96 weeks. Lamotrigine daily dosage varied from 25 to 425 mg/d among the studies. Studies reported inconsistent findings between LAM concentration and efficacy. Three studies did not identify a relationship between LAM levels and a significant improvement in mood symptoms. Two studies (n = 99) reported higher response rates with LAM serum levels of greater than 3.25 μg/mL and 1 study (n = 25) reported a wide therapeutic window of 5 to 11 μg/mL. Overall, LAM was well tolerated with no major significant adverse effects. Conclusions Most studies showed a minimum LAM threshold level of 3 μg/mL in patients with mood disorders; however, the data are inconsistent regarding the therapeutic range for LAM. Based on the pooled data, there is inconsistent evidence to make conclusive recommendations on therapeutic LAM serum levels for mood improvement. Further studies including larger sample sizes are required to address this relevant clinical question.

Purpose Nearly all health care professionals engage in continuous professional development (CPD), yet little is known about the cost and cost-effectiveness of physician CPD. Clarification of key concepts, comprehensive identification of published work, and determination of research gaps would facilitate application of existing evidence and planning for future investigations. The authors sought to systematically map study themes, methods, and outcomes in peer-reviewed literature on the cost and value of physician CPD. Method The authors conducted a scoping review, systematically searching MEDLINE, Embase, PsycInfo, and Cochrane Library databases for comparative economic evaluations of CPD for practicing physicians through April 2020. Two reviewers, working independently, screened all articles for inclusion. Three reviewers iteratively reviewed all included articles to inductively identify key features including participants, educational interventions, study designs, cost ingredients, and cost analyses. Two reviewers then independently reexamined all included articles to code these features. Results Of 3,338 potentially eligible studies, 111 were included. Physician specialties included internal, family, or general medicine (80 studies [72%]), surgery (14 studies [13%]), and medicine subspecialties (7 studies [6%]). Topics most often addressed general medicine (45 studies [41%]) or appropriate drug use (37 studies [33%]). Eighty-seven studies (78%) compared CPD with no intervention. Sixty-three studies (57%) reported the cost of training, and 79 (71%) evaluated the economic impact (money saved/lost following CPD). Training cost ingredients (median 3 itemized per study) and economic impact ingredients (median 1 per study) were infrequently and incompletely identified, quantified, or priced. Twenty-seven studies (24%) reported cost–impact expressions such as cost-effectiveness ratio or net value. Nineteen studies (17%) reported sensitivity analyses. Conclusions Studies evaluating the costs and economic impact of physician CPD are few. Gaps exist in identification, quantification, pricing, and analysis of cost outcomes. The authors propose a comprehensive framework for appraising ingredients and a preliminary reference case for economic evaluations.

Background: This is the first systematic review and meta-analysis to investigate the effect of resistance training (RT) on survival and other cardiovascular outcomes including ischemic heart disease events and stroke. Methods: An experienced librarian searched databases up to September 25 th , 2017, for randomized trials and cohort studies that evaluated the effect of RT on survival and cardiovascular events in the general population. The databases included Ovid MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus. Two investigators conducted the screening process independently and in duplicate. Cochrane tools were used to assess the risk of bias in clinical trials and observational studies. We calculated hazard ratios and 95% confidence intervals using RevMan and fixed and random effect models and had a subgroup analysis based on doses of RT and for the combination of RT and aerobic exercise (AE) vs no exercise. Results: The search identified 1429 studies from which 10 (one randomized trial) met the inclusion criteria, including 338,254 participants with a mean follow up of 8.14 years. The meta-analysis showed that RT, in comparison with no exercises, is associated with 24% lower all-cause mortality and 48% lower mortality when combined with AE. Based on subgroup analysis, performing 1-2 sessions of RT/week is associated with lower all-cause mortality by 28% (HR 0.72, 95% CI 0.66-0.78) whereas > 5 sessions of RT/week has no association with all-cause mortality (HR 0.99, 95% CI 0.76-1.31). Further, RT alone or combined with AE is associated with lower CV mortality compared to no exercise (Figures). Finally, RT alone also showed a borderline association with lower all-cancer mortality. Heterogeneity was present for several comparisons, and subsequent analysis will explore sources of this variability. Using study design-specific Cochrane risk of bias tools, no major sources of bias were identified in the included studies. One cohort study looked at the effect of RT on coronary heart disease events and found 23% risk reduction in men, while no study specifically assessed the effect of RT on cerebrovascular outcomes. Conclusion: RT is associated with lower all-cause, CV and all-cancer mortality. RT appears to have an additive effect when combined with AE.

Importance: Up to 10% of patients with acute myocardial infarction (AMI) have right bundle branch block (RBBB), and RBBB has been associated with a higher risk of mortality. We performed a systematic review and meta-analysis to determine the prognostic significance of RBBB for patients with AMI. Acute coronary syndrome (ACS) Data Sources: We have systematically searched Ovid, Scopus and Web of Science through January 2014. Study Selection: Reviewers working independently and in duplicate screened all eligible abstracts, selecting studies that described all-cause mortality or cardiovascular death in patients with RBBB and suspected ACS. We excluded studies that reported unadjusted outcomes. Knowledge synthesis: We pooled risk ratio with hazard ratio in studies reporting those outcomes. When reported, odds ratio was converted into risk ratio using reported event rate in each study’s unexposed -read: non RBBB- group. Main Outcomes: All-cause mortality and cardiovascular mortality (death). Results: Eighteen studies were found that reported eligible data. All were observational studies, involving over 89,000 patients. In short-term follow up (up to 30 days), RBBB on presentation was associated with higher all-cause mortality rate, compared to patients without RBBB (RR 2.23, 95% CI 1.76-2.82). There was a trend for higher mortality at long-term follow up (range: 6 months-16 years) that did not reach statistical significance (RR 1.45, 95% CI 0.93-2.25). Figure-1 demonstrates the forest plot. Risk of bias was assessed with the Newcastle-Ottawa scale and majority of included studied were deemed moderate to high quality. Conclusion and Relevance: RBBB is associated with a more than 2-fold higher risk of all-cause mortality in patients with AMI at 30 days follow up. Patients with AMI and RBBB represent a high risk group for adverse outcomes. A sentence on the differential findings for new vs. old RBBB and association with outcomes could follow here.

Importance: Right bundle branch block (RBBB) is observed in approximately 5-14% of patients with heart failure (HF). Multiple observational studies have reported the association of RBBB with clinical outcomes in patients with HF. We performed a systematic review and meta-analysis to determine the prognostic significance of RBBB for patients with HF. Data Sources: We have systematically searched MEDLINE, EMBASE, Cochrane CENTRAL, Web of Science and Scopus through January 2014. Study Selection: Reviewers working independently and in duplicate screened all eligible abstracts that described all cause or cardiovascular mortality in patients with RBBB and HF. We excluded studies that reported unadjusted outcome, i.e.: unadjusted event rates. Knowledge synthesis: We pooled reported risk ratio and hazard ratio. Main Outcomes: All-cause mortality and cardiovascular mortality (death). Results: We found 12 relevant observational studies enrolling over 38,000 patients. Risk of bias was assessed using the Newcastle-Ottawa Scale. Included studies had at least a moderate quality. Seven of those evaluated prognosis of patients with RBBB and heart failure. After a mean follow up period of 2.5 years (range: 1-5 years), RBBB was associated with a statistically significant increased risk of all-cause mortality compared to patients with heart failure but no BBB, RR 1.27, 95% CI (1.08-1.50), Figure 1. The other 5 studies evaluated CHF patients receiving cardiac resynchronization therapy (CRT), comparing outcomes of patients with RBBB to those with LBBB. After a mean f/u period of 3 years, patients with RBBB were once again found to have an increased risk of all-cause mortality, RR 1.45, 95% CI 1.12-1.89. Conclusion and Relevance: RBBB in patients with HF is associated with higher all-cause mortality in comparison to patients without inter-ventricular conduction defects, as well as LBBB patients in patients undergoing CRT setting.

Objective: Multiple large population based observational studies have evaluated the association of various ECG changes with long term adverse outcomes demonstrating conflicting results regarding the significance of right bundle branch block (RBBB). Therefore, we conducted a systematic review and meta-analysis to determine the prognostic significance of RBBB in healthy population. Methods: This systematic review follows an a priori established protocol and is reported following the PRISMA statement (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). We systematically searched EMBASE, Web of Science and Scopus through January 2014. We also consulted with content experts to recommend studies for screening. Reviewers working independently and in duplicate screened all eligible abstracts, selecting randomized trials and prospective cohort studies that described all cause mortality or cardiovascular death in patients with RBBB. We excluded studies that reported unadjusted outcome or unadjusted event rates. For statistical analysis, hazard ratios were considered to approximate risk ratios. The main outcomes of the study are all-cause mortality and cardiovascular mortality. Results: Based on the eligibility, four large cohorts, with total patient count > 100,000 were included in the meta-analysis. Risk of bias was assessed using the Newcastle-Ottawa scale and included studies were deemed to be of high quality. As demonstrated in Figure 1, RBBB was not associated increase in all-cause mortality (RR 1.05; 95% CI 0.89-1.25) or cardiovascular mortality (RR 1.09; 95% CI 0.70-1.69). Conclusion: In asymptomatic healthy patients, RBBB is not associated with poor outcome.

OBJECTIVES: To evaluate the efficacy of the simultaneous hypertonic saline solution and IV furosemide (HSS+Fx) for patients with fluid overload compared with IV furosemide alone (Fx). DATA SOURCES: Electronic databases (MEDLINE, EMBASE, CENTRAL, Cochrane Database of Systematic Reviews, PsycINFO, Scopus, and WOS) were searched from inception to March 2020. STUDY SELECTION: Randomized controlled trials on the use of HSS+Fx in adult patients with fluid overload versus Fx were included. DATA EXTRACTION: Data were collected on all-cause mortality, hospital length of stay, heart failure–related readmission, along with inpatient weight loss, change of daily diuresis, serum creatinine, and 24-hour urine sodium excretion from prior to post intervention. Pooled analysis with random effects models yielded relative risk or mean difference with 95% CIs. DATA SYNTHESIS: Eleven randomized controlled trials comprising 2,987 acute decompensated heart failure patients were included. Meta-analysis demonstrated that HSS+Fx was associated with lower all-cause mortality (relative risk, 0.55; 95% CI, 0.46–0.67; p < 0.05; I2 = 12%) and heart failure–related readmissions (relative risk, 0.50; 95% CI, 0.33–0.76; p < 0.05; I2 = 61%), shorter hospital length of stay (mean difference, –3.28 d; 95% CI, –4.14 to –2.43; p < 0.05; I2 = 93%), increased daily diuresis (mean difference, 583.87 mL; 95% CI, 504.92–662.81; p < 0.05; I2 = 76%), weight loss (mean difference, –1.76 kg; 95% CI, –2.52 to –1.00; p < 0.05; I2 = 57%), serum sodium change (mean difference, 6.89 mEq/L; 95% CI, 4.98–8.79; p < 0.05; I2 = 95%), and higher 24-hour urine sodium excretion (mean difference, 61.10 mEq; 95% CI, 51.47–70.73; p < 0.05; I2 = 95%), along with decreased serum creatinine (mean difference, –0.46 mg/dL; 95% CI, –0.51 to –0.41; p < 0.05; I2 = 89%) when compared with Fx. The Grading of Recommendation, Assessment, Development, and Evaluation certainty of evidence ranged from low to moderate. CONCLUSIONS: Benefits of the HSS+Fx over Fx were observed across all examined outcomes in acute decompensated heart failure patients with fluid overload. There is at least moderate certainty that HSS+Fx is associated with a reduction in mortality in patients with acute decompensated heart failure. Factors associated with a successful HSS+Fx utilization are still unknown. Current evidence cannot be extrapolated to other than fluid overload states in acute decompensated heart failure.

e16522 Background: Cisplatin-based neoadjuvant chemotherapy is the standard of care for muscle invasive bladder cancer (MIBC) in cisplatin-eligible patients. This systematic review and meta-analysis provide an updated efficacy and safety comparison between the two most commonly used cisplatin-based regimens; dose-dense (dd) or conventional MVAC versus GC. Methods: We searched different databases for studies comparing MVAC versus GC in the neoadjuvant setting. Outcomes of interest included overall survival, downstaging to pT≤1, pathologic complete response (pCR), recurrence, and toxicity. Meta-analysis was conducted using the random-effects model. Results: We identified 24 studies from inception to March 2020; among them 17 were peer reviewed and 7 were only reported as abstracts in national or international meetings, including a phase 3, randomized-controlled clinical trial. Among peer-reviewed published studies, efficacy outcomes such as OS, downstaging and pCR were comparable between conventional MVAC and GC for MIBC. If including non-peer-reviewed studies, dd-MVAC was associated with favorable efficacy compared to GC in terms of downstaging (OR 1.45; 95% CI 1.15–1.82), and OS at longest follow-up (OR 0.63; 95% CI 0.44–0.81). However, GC was associated with a better safety profile in terms of febrile neutropenia (OR 0.32; 95% CI 0.13–0.80), anemia (OR 0.32; 95% CI 0.18–0.54), nausea and vomiting (OR 0.27; 95% CI 0.12–0.65) compared to dd-MVAC. Compared to MVAC, patients receiving GC had an increased risk of developing grade 3–4 thrombocytopenia (OR 4.70; 95% CI 1.59–13.89) and a lower risk of nausea and vomiting (OR 0.05; 95% CI 0.01-0.31). Certainty in the estimates was very low for most outcomes. Conclusions: Among peer-reviewed published studies, efficacy and safety outcomes were comparable between conventional MVAC and GC for MIBC. However, If including non-peer-reviewed studies, this analysis showed higher efficacy with dd-MVAC. A phase III randomized trial comparing the two regimens is needed to guide clinical practice