Real-life effectiveness of mepolizumab in severe asthma: a systematic literature review.

OBJECTIVE: The efficacy and safety of mepolizumab in patients with severe eosinophilic asthma in randomized controlled trials is well established. Following approval of mepolizumab as add-on therapy for severe eosinophilic asthma in multiple regions worldwide, it is now important to determine its impact in real-world settings in which patients are not subject to stringent eligibility criteria. This systematic literature review assessed published evidence of clinical outcomes, safety, and healthcare resource use among patients with severe asthma receiving mepolizumab in real-world settings. DATA SOURCES: Searches were conducted in Embase, MEDLINE, and MEDLINE In-Process via Ovid. STUDY SELECTIONS: Eligible studies were observational, and enrolled ≥10 patients with asthma who received mepolizumab 100 mg subcutaneously. Data extracted included annualized exacerbation rate, mean daily oral corticosteroid (OCS) dose, proportion of patients using OCS, several measures of lung function, patient-reported asthma control and health-related quality of life (HRQoL), safety, and economic burden. RESULTS: Twenty-three articles (22 unique studies; 2,040 patients with severe asthma on mepolizumab) were identified. Mepolizumab use was associated with a reduction in annualized exacerbation rates (requiring OCS) of 54-97% (p < 0.05 in all studies), reduced mean/median daily OCS doses, and OCS discontinuation during follow-up (27-84% of patients). Improvements in lung function, asthma control, and HRQoL were also observed. The most commonly reported adverse events included headache and arthralgia; discontinuation of mepolizumab due to adverse events occurred in 0-10.6% of patients. CONCLUSION: Findings show that patients with severe asthma consistently demonstrate clinically relevant benefits with mepolizumab treatment in a real-world setting.Supplemental data for this article is available online at at www.tandfonline.com/ijas .

Tisagenlecleucel versus historical standard therapies for pediatric relapsed/refractory acute lymphoblastic leukemia.

Aim: We compared outcomes from a single-arm study of tisagenlecleucel with standard of care (SOC) regimens in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL). Methods: The analysis included one tisagenlecleucel study, one blinatumomab study, one clofarabine monotherapy study, three studies of clofarabine combination regimens and two studies of other salvage chemotherapy. Matching-adjusted indirect comparison analyses were conducted. Results: After adjusting for baseline characteristics, tisagenlecleucel was associated with significantly prolonged overall survival compared with blinatumomab (hazard ratio [95% CI], 0.32 [0.16-0.64]); clofarabine monotherapy (0.24 [0.13-0.42]); clofarabine combination regimens (0.26 [0.15-0.45]); two salvage therapies (0.15 [0.09-0.25] and 0.27 [0.15-0.49]). Conclusion: The analysis demonstrated tisagenlecleucel was associated with substantially greater survival benefit versus all SOC regimens.

Systematic Literature Review of Systemic Corticosteroid Use for Asthma Management.

Systemic corticosteroid use to manage uncontrolled asthma and its associated healthcare burden may account for important health-related adverse effects. We conducted a systematic literature review to investigate the real-world extent and burden of systemic corticosteroid use in asthma. We searched MEDLINE and Embase databases to identify English-language articles published in 2010-2017, using search terms for asthma with keywords for oral corticosteroids and systemic corticosteroids. Observational studies, prescription database analyses, economic analyses, and surveys on oral/systemic corticosteroid use in children (>5 yr old), adolescents (12-17 yr old), and adults with asthma were included. We identified and reviewed 387 full-text articles, and our review included data from 139 studies. The included studies were conducted in Europe, North America, and Asia. Overall, oral/systemic corticosteroids were commonly used for asthma management and were more frequently used in patients with severe asthma than in those with milder disease. Long-term oral/systemic corticosteroid use was, in general, less frequent than short-term use. Compared with no use, long-term and repeated short-term oral/systemic corticosteroid use were associated with an increased risk of acute and chronic adverse events, even when doses were comparatively low. Greater oral/systemic corticosteroid exposure was also associated with increased costs and healthcare resource use. This review provides a comprehensive overview of oral/systemic corticosteroid use and associated adverse events for patients with all degrees of asthma severity and exposure duration. We report that oral/systemic corticosteroid use is prevalent in asthma management, and the risks of acute and chronic complications increase with the cumulative oral corticosteroid dosage.

Systematic review of societal costs associated with stroke, bleeding and monitoring in atrial fibrillation.

Aim: Economic consequences associated with the rise in nonvitamin K antagonist oral anticoagulant use on a societal level remain unclear. Materials & methods: Evidence from the past decade on the societal economic burden associated with stroke, bleeding and international normalized ratio monitoring in atrial fibrillation was collected and summarized through a systematic literature review. Results: There were 14 studies identified that reported indirect costs, which were highest among patients with hemorrhagic stroke and intracranial hemorrhage. The contribution of indirect costs to the total was marginal during acute treatment but substantially increased (30-50%) 2 years after stroke and bleeding events. Conclusion: Limited data were available on societal costs in atrial fibrillation and further research is warranted.

Real-world effectiveness of anti-TNF switching in psoriatic arthritis: a systematic review of the literature.

Anti-tumor necrosis factors (Anti-TNFs) are a class of biologic disease-modifying anti-rheumatic drugs indicated for the treatment of moderate-to-severe psoriatic arthritis (PsA). Refractory patients are commonly managed by switching from one anti-TNF to another. To assess the evidence on the effectiveness of anti-TNF cycling in PsA patients, a systematic review of the literature was conducted. MEDLINE- and Embase-indexed English-language publications were systematically searched from 1995 to 2015 for studies assessing real-world effectiveness outcomes of anti-TNF cycling in PsA patients. Of 1086 citations identified, 18 studies were included; most conducted in Europe. Six of seven studies testing between lines found significant differences in effectiveness between earlier and subsequent lines of anti-TNF therapy. First-line therapy yielded better results compared with second-line therapy, and significant differences were observed between second- and third-line anti-TNF treatments. In the only study with multivariate regression testing for predictors of response, Danish registry patients were less likely to respond (American College of Rheumatology 20 % or 50 % response) to a second anti-TNF course if safety, rather than lack of effect, caused them to switch (odds ratio [OR] 0.04; p = 0.003 and OR 0.05; p = 0.03, respectively). Effectiveness of anti-TNFs at second line and later is reported in a small number of real-world studies of PsA patients. Subsequent treatment lines may be associated with less response in some measures. More research is needed to quantify the effectiveness of sequential anti-TNF lines in this progressive population' and to compare these effects with responses to drugs with different mechanisms of action.

The association of lung function and St. George's respiratory questionnaire with exacerbations in COPD: a systematic literature review and regression analysis.

BACKGROUND: This study investigated the relationship between changes in lung function (as measured by forced expiratory volume in one second [FEV1]) and the St. George's Respiratory Questionnaire (SGRQ) and economically significant outcomes of exacerbations and health resource utilization, with an aim to provide insight into whether the effects of COPD treatment on lung function and health status relate to a reduced risk for exacerbations. METHODS: A systematic literature review was conducted in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials to identify randomized controlled trials of adult COPD patients published in English since 2002 in order to relate mean change in FEV1 and SGRQ total score to exacerbations and hospitalizations. These predictor/outcome pairs were analyzed using sample-size weighted regression analyses, which estimated a regression slope relating the two treatment effects, as well as a confidence interval and a test of statistical significance. RESULTS: Sixty-seven trials were included in the analysis. Significant relationships were seen between: FEV1 and any exacerbation (time to first exacerbation or patients with at least one exacerbation, p = 0.001); between FEV1 and moderate-to-severe exacerbations (time to first exacerbation, patients with at least one exacerbation, or annualized rate, p = 0.045); between SGRQ score and any exacerbation (time to first exacerbation or patients with at least one exacerbation, p = 0.0002) and between SGRQ score and moderate-to-severe exacerbations (time to first exacerbation or patients with at least one exacerbation, p = 0.0279; annualized rate, p = 0.0024). Relationships between FEV1 or SGRQ score and annualized exacerbation rate for any exacerbation or hospitalized exacerbations were not significant. CONCLUSIONS: The regression analysis demonstrated a significant association between improvements in FEV1 and SGRQ score and lower risk for COPD exacerbations. Even in cases of non-significant relationships, results were in the expected direction with few exceptions. The results of this analysis offer health care providers and payers a broader picture of the relationship between exacerbations and mean change in FEV1 as well as SGRQ score, and will help inform clinical and formulary-making decisions while stimulating new research questions for future prospective studies.

Effect of low doses of methamphetamine on rat limbic-related neurotensin systems.

Administration of methamphetamine (METH) alters limbic-related (LR) neurotensin (NT) systems. Thus, through a D1-receptor mechanism, noncontingent high doses (5-15 mg kg(-1)), and likely self-administration, of METH appears to reduce NT release causing its accumulation and an elevation of NT-like immunoreactivity (NTLI) in limbic-related NT pathways. For comparison, we tested the effect of low doses of METH, that are more like those used in therapy, on NTLI in the core and shell of the nucleus accumbens (NAc and NAs), prefrontal cortex (PFC), ventral tegmental area (VTA), the lateral habenula (Hb) and basolateral amygdala (Amyg). METH at the dose of 0.25 mg kg(-1) in particular, but not 1.00 mg kg(-1), decreased NTLI concentration in all of the LR structures studied, except for the prefrontal cortex; however, these effects were rapid and brief being observed at 5 h but not at 24 h after treatment. In all of the LR areas where NTLI levels were reduced after the low dose of METH, the effect was blocked by pretreatment with either a D1 or a D2 antagonist. Thus, opposite to high doses like those associated with abuse, the therapeutic-like low-dose METH treatment induced reduction in NT tissue levels likely reflected an increase in NT release and a short-term depletion of the levels of this neuropeptide in LR structures, manifesting features comparable to the response of basal ganglia NT systems to similar low doses of METH.

Plasma Fibrinogen as a Biomarker for Mortality and Hospitalized Exacerbations in People with COPD.

BACKGROUND: In 2010 the COPD Foundation established the COPD Biomarkers Qualification Consortium (CBQC) as a partnership between the Foundation, the Food and Drug Administration (FDA), and the pharmaceutical industry to pool publicly-funded and industry data to develop innovative tools to facilitate the development and approval of new therapies for COPD. We present data from the initial project seeking regulatory qualification of fibrinogen as a biomarker for the stratification of COPD patients into clinical trials. METHODS: This analysis pooled data from 4 publicly-funded studies and 1 industry study into a common database resulting in 6376 individuals with spirometric evidence of COPD. We used a threshold of 350 mg/dL to determine high vs. low fibrinogen, and determined the subsequent risk of hospitalizations from exacerbations and death using Cox proportional hazards models. RESULTS: High fibrinogen levels at baseline were present in 2853 (44.7%) of individuals with COPD. High fibrinogen was associated with an increased risk of hospitalized COPD exacerbations within 12 months (hazard ratio [HR]: 1.64; 95% confidence interval [CI]: 1.39-1.93) among participants in the Atherosclerosis Risk in Communities Study (ARIC), the Cardiovascular Health Study (CHS), and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. High fibrinogen was associated with an increased risk of death within 36 months (HR: 1.94; 95% CI: 1.62-2.31) among all participants. CONCLUSIONS: Fibrinogen levels ≥ 350 mg/dL identify COPD individuals at an increased risk of exacerbations and death and could be a useful biomarker for enriching clinical trials in the COPD population.

Responses of the rat basal ganglia neurotensin systems to low doses of methamphetamine.

RATIONALE: Administration of high doses of methamphetamine (METH) in a manner mimicking the binging patterns associated with abuse reduces NT release and causes its accumulation and elevated NT levels in extrapyramidal structures by a D1 mechanism. The relevance of these findings to the therapeutic use of METH needs to be studied. OBJECTIVES: The effect of low doses (comparable to that used for therapy) of METH on basal ganglia NT systems was examined and compared to high-dose and self-administration effects previously reported. METHODS: Rats were injected four times (2-h intervals) with either saline or low doses of METH (0.25, 0.50, or 1.00 mg/kg/subcutaneously (s.c.)). For the DA antagonist studies, animals were pretreated with a D1 (SCH23390) or D2 (eticlopride) antagonist 15 min prior to METH or saline treatments. Rats were sacrificed 5-48 h after the last injection. RESULTS: METH at doses of 0.25 and 0.50, but not 1.00 mg/kg, rapidly and briefly decreased NTLI concentration in all basal ganglia structures studied. In the posterior dorsal striatum, the reduction in NT level after low-dose METH appeared to be caused principally by D2 stimulation, but both D2 and D1 stimulation were required for the NT responses in the other basal ganglia regions. CONCLUSIONS: A novel finding from the present study was that opposite to abuse-mimicking high doses of METH, the therapeutically relevant low-dose METH treatment reduced NT tissue levels likely reflecting an increase in NT release and a short-term depletion of the levels of this neuropeptide in basal ganglia structures. The possible significance is discussed.

Relating relapse and T2 lesion changes to disability progression in multiple sclerosis: a systematic literature review and regression analysis.

BACKGROUND: In the treatment of multiple sclerosis (MS), the most important therapeutic aim of disease-modifying treatments (DMTs) is to prevent or postpone long-term disability. Given the typically slow progression observed in the majority of relapsing-remitting MS (RRMS) patients, the primary endpoint for most randomized clinical trials (RCTs) is a reduction in relapse rate. It is widely assumed that reducing relapse rate will slow disability progression. Similarly, MRI studies suggest that reducing T2 lesions will be associated with slowing long-term disability in MS. The objective of this study was to evaluate the relationship between treatment effects on relapse rates and active T2 lesions to differences in disease progression (as measured by the Expanded Disability Status Scale [EDSS]) in trials evaluating patients with clinically isolated syndrome (CIS), RRMS, and secondary progressive MS (SPMS). METHODS: A systematic literature review was conducted in Medline, Embase, CENTRAL, and PsycINFO to identify randomized trials published in English from January 1, 1993-June 3, 2013 evaluating DMTs in adult MS patients using keywords for CIS, RRMS, and SPMS combined with keywords for relapse and recurrence. Eligible studies were required to report outcomes of relapse and T2 lesion changes or disease progression in CIS, RRMS, or SPMS patients receiving DMTs and have a follow-up duration of at least 22 months. Ultimately, 40 studies satisfied these criteria for inclusion. Regression analyses were conducted on RCTs to relate differences between the effect of treatments on relapse rates and on active T2 lesions to differences between the effects of treatments on disease progression (as measured by EDSS). RESULTS: Regression analysis determined there is a substantive clinically and statistically significant association between concurrent treatment effects in relapse rate and EDSS; p < 0.01. Lower treatment effects were associated with higher relative rates of disease progression. Significant associations between T2 lesion measures and EDSS measures also were found (p < 0.05), with some suggestion that the strength of the association may differ for older versus newer DMTs. CONCLUSIONS: Treatment differences in relapse reduction and T2 lesions are positively related to differences in disease progression over the first two years of treatment.

A systematic review assessing the economic impact of sildenafil citrate (Viagra) in the treatment of erectile dysfunction.

INTRODUCTION: Sildenafil was the first oral phosphodiesterase type 5 (PDE5) inhibitor introduced as primary therapy for erectile dysfunction (ED). In the 7 years following its market launch, sildenafil was prescribed by more than 750,000 physicians to more than 23 million men worldwide. To date, few studies have evaluated the economic impact of sildenafil in treating ED. AIM: To evaluate the cost-effectiveness and impact of sildenafil on health care costs for patients with ED in multiple countries. MAIN OUTCOMES MEASURES: Economic outcomes including cost, cost-effectiveness, cost of illness, cost consequence, resource use, productivity, work loss, and willingness to pay (WTP) were investigated. METHODS: Using keywords related to economic outcomes and sildenafil, we systematically searched literature published between July 2001 and July 2011 using MEDLINE and EMBASE. Included articles pertained to costs, WTP, and economic evaluations. RESULTS: In the last 10 years, 12 studies assessed economic outcomes associated with sildenafil for ED. Most studies were conducted in the United States and the United Kingdom, with one study identified in Canada and one from Mexico. Six studies evaluated cost of illness, cost consequence, or cost of care, and four studies evaluated WTP or drug pricing by country in the United States and the United Kingdom. In the United States and the United Kingdom, costs to health care systems have increased with demand for treatment. Cost analyses suggested that sildenafil would lower direct costs compared with other PDE5 inhibitors. U.S. and U.K. studies found that patients exhibited WTP for sildenafil. The two cost-effectiveness models we identified examined ED sub-groups, those with spinal cord injury and those with diabetes or hypertension. These models indicated favorable cost-effectiveness profiles for sildenafil compared with other active-treatment options in both Mexico and Canada. CONCLUSIONS: The relative value of sildenafil vs. surgically implanted prosthetic devices and other PDE5 inhibitors, is underscored by patients' WTP, and cost-effectiveness in ED patients with comorbidities.

Comparison of hand-assisted laparoscopy versus open and laparoscopic techniques in urology procedures: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Hand-assisted laparoscopic surgery (HALS) is an integral part of the urologist's armamentarium. We aimed to perform a comprehensive meta-analysis comparing HALS renal surgery with open and laparoscopic techniques. METHODS: A systematic review and meta-analysis of HALS renal procedures (donor nephrectomy, nephrectomy, or nephroureterectomy) from 1996 to 2007 was performed. RESULTS: Sixty-two studies of 30 donor nephrectomy, 21 radical nephrectomy, and 14 nephroureterectomy procedures in 5446 patients were included in the analysis. In donor nephrectomy, estimated blood loss (EBL) was statistically significant for HALS vs the open and laparoscopic cohorts, -69.0 mL (95% confidence interval [CI], -129.7, -8.2) and -40.1 mL (95% CI, -68.2, -12.0), respectively. Length of stay (LOS) was shorter compared with the open group, -1.7 days (95% CI, -2.3, -1.1). For nephroureterectomy, EBL (-29.9 mL (95% CI, -242.3, 182.5)), and LOS (-1.5 d [95% CI, -2.8, -0.3]) again favored HALS vs open procedures. Operating room (OR) time and warm ischemia time (WIT) were statistically significant in favor of HALS donor nephrectomy vs the laparoscopic cohort; -36.8 minutes (95% CI, -61.3, -12.3) and -1.3 minutes (95% CI, -1.8, -0.7), respectively. For radical nephrectomy, both EBL -232.9 mL (95% CI, -383.6, -82.2) and LOS -2.4 days (95% CI, -3.5, -1.3) were statistically significant, favoring HALS vs the open group. CONCLUSION: We report the largest meta-analysis of HALS renal surgery to date. When compared with open surgery, HALS allows for a significant decrease in EBL and LOS. Compared with laparoscopic donor nephrectomy, HALS resulted in a significant decrease in blood loss, OR time, and WIT.

Use of topical tretinoin and the development of noncutaneous adverse events: evidence from a systematic review of the literature.

BACKGROUND: Topical retinoids have been in clinical use for the treatment of chronic skin conditions, including acne, photodamage, and psoriasis, for 30 years. OBJECTIVE: A systematic literature review was conducted to assess the incidence of noncutaneous adverse events (AE) among patients treated with topical retinoids with a focus on topical tretinoin studies reported before the Veterans Affairs Topical Tretinoin Chemoprevention trial. METHODS: Electronic literature searches were conducted in Embase and MEDLINE for literature reporting development of nonteratogenic, noncutaneous AE among patients treated with topical retinoids published through September 2008. RESULTS: The search yielded 2778 citations, of which 20 studies met inclusion criteria. Tretinoin was used in 14 of the studies. Other retinoids assessed included isotretinoin, adapalene, alitretinoin, and tazarotene. Within patients receiving topical tretinoin, 27.9% reported the occurrence of at least one noncutaneous AE. The majority of noncutaneous AE were transient and judged not to be related to tretinoin treatment. LIMITATIONS: The conclusions of this study apply largely to tretinoin compared with other topical retinoids. Many of the included trials were designed to evaluate the efficacy of topical treatment and reporting of safety events concentrated on incidence of localized AE, rather than systemic or noncutaneous events. CONCLUSION: We found no clear evidence of a relationship between the use of topical tretinoin and the development of noncutaneous AE before a recent report of excess mortality in a clinical trial. The majority of noncutaneous AE reported by patients receiving topical retinoids consisted of nonsevere, nonspecific symptoms that were judged not to be related to treatment.