Small vessel cerebrovascular disease is associated with cognition in prospective Alzheimer's clinical trial participants.

BACKGROUND: Secondary prevention clinical trials for Alzheimer's disease (AD) target amyloid accumulation in asymptomatic, amyloid-positive individuals, but it is unclear to what extent other pathophysiological processes, such as small vessel cerebrovascular disease, account for participant performance on the primary cognitive outcomes in those trials. White matter hyperintensities are areas of increased signal on T2-weighted magnetic resonance imaging (MRI) that reflect small vessel cerebrovascular disease. They are associated with cognitive functioning in older adults and with clinical presentation and course of AD, particularly when distributed in posterior brain regions. The purpose of this study was to examine to what degree regional WMH volume is associated with performance on the primary cognitive outcome measure in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study, a secondary prevention trial. METHODS: Data from 1791 participants (59.5% women, mean age (SD) 71.6 (4.74)) in the A4 study and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) companion study at the screening visit were used to quantify WMH volumes on T2-weighted fluid-attenuated inversion recovery (FLAIR) MR images. Cognition was assessed with the preclinical Alzheimer cognitive composite (PACC). We tested the association of total and regional WMH volumes with PACC performance, adjusting for age, education, and amyloid positivity status, with general linear models. We also considered interactions between WMH and amyloid positivity status. RESULTS: Increased frontal and parietal lobe WMH volume was associated with poorer performance on the PACC. While amyloid positivity was also associated with lower cognitive test scores, WMH volumes did not interact with amyloid positivity status. CONCLUSION: These results highlight the potential of small vessel cerebrovascular disease to drive AD-related cognitive profiles. Measures of small vessel cerebrovascular disease should be considered when evaluating outcome in trials, both as potential effect modifiers and as a possible target for intervention or prevention.

Contribution of extracerebral tracer retention and partial volume effects to sex differences in Flortaucipir-PET signal.

Clinically normal females exhibit higher 18F-flortaucipir (FTP)-PET signal than males across the cortex. However, these sex differences may be explained by neuroimaging idiosyncrasies such as off-target extracerebral tracer retention or partial volume effects (PVEs). 343 clinically normal participants (female = 58%; mean[SD]=73.8[8.5] years) and 55 patients with mild cognitive impairment (female = 38%; mean[SD] = 76.9[7.3] years) underwent cross-sectional FTP-PET. We parcellated extracerebral FreeSurfer areas based on proximity to cortical ROIs. Sex differences in cortical tau were then estimated after accounting for local extracerebral retention. We simulated PVE by convolving group-level standardized uptake value ratio means in each ROI with 6 mm Gaussian kernels and compared the sexes across ROIs post-smoothing. Widespread sex differences in extracerebral retention were observed. Although attenuating sex differences in cortical tau-PET signal, covarying for extracerebral retention did not impact the largest sex differences in tau-PET signal. Differences in PVE were observed in both female and male directions with no clear sex-specific bias. Our findings suggest that sex differences in FTP are not solely attributed to off-target extracerebral retention or PVE, consistent with the notion that sex differences in medial temporal and neocortical tau are biologically driven. Future work should investigate sex differences in regional cerebral blood flow kinetics and longitudinal tau-PET.

Cerebrovascular disease drives Alzheimer plasma biomarker concentrations in adults with Down syndrome.

Importance: By age 40 years over 90% of adults with Down syndrome (DS) have Alzheimer's disease (AD) pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with DS have elevated cerebrovascular disease (CVD) markers that track with the clinical progression of AD, suggesting a role for CVD that is hypothesized to be mediated by inflammatory factors. Objective: To examine the pathways through which small vessel CVD contributes to AD-related pathophysiology and neurodegeneration in adults with DS. Design: Cross sectional analysis of neuroimaging, plasma, and clinical data. Setting: Participants were enrolled in Alzheimer's Biomarker Consortium - Down Syndrome (ABC-DS), a multisite study of AD in adults with DS. Participants: One hundred eighty-five participants (mean [SD] age=45.2 [9.3] years) with available MRI and plasma biomarker data were included. White matter hyperintensity (WMH) volumes were derived from T2-weighted FLAIR MRI scans and plasma biomarker concentrations of amyloid beta (Aß42/Aß40), phosphorylated tau (p-tau217), astrocytosis (glial fibrillary acidic protein, GFAP), and neurodegeneration (neurofilament light chain, NfL) were measured with ultrasensitive immunoassays. Main Outcomes and Measures: We examined the bivariate relationships of WMH, Aß42/Aß40, p-tau217, and GFAP with age-residualized NfL across AD diagnostic groups. A series of mediation and path analyses examined causal pathways linking WMH and AD pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. Results: There was a direct and indirect bidirectional effect through GFAP of WMH on p-tau217 concentration, which was associated with NfL concentration in the entire sample. Among cognitively stable participants, WMH was directly and indirectly, through GFAP, associated with p-tau217 concentration, and in those with MCI, there was a direct effect of WMH on p-tau217 and NfL concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. Conclusions and Relevance: The findings suggest that among individuals with DS, CVD promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of AD. This work joins an emerging literature that implicates CVD and its interface with neuroinflammation as a core pathological feature of AD in adults with DS.

Factors Associated With Disease-Modifying Therapy Adherence and Persistence in Multiple Sclerosis: A Scoping Literature Review.

BACKGROUND: Patients with multiple sclerosis (MS) receiving disease-modifying therapies (DMT) show published adherence rates of 27.0% to 93.8% and published persistence rates of 49.7% to 96.5%. Improvements in DMT adherence and persistence are key to optimizing MS care, and enhanced understanding could improve MS disease management and identify research gaps. This scoping literature review aims to examine the nature and findings of the literature evaluating factors associated with DMT adherence and persistence in patients with MS. METHODS: Eligible articles included in the literature review were quantitative clinical studies written in English, included adherence or persistence as primary outcomes, and accounted for covariates/confounders. The articles were assessed to identify factors associated with adherence/persistence and analyzed according to DMT type (self-injectable, oral, infusion). RESULTS: Fifty-eight studies (103,450 patients) were included. Study distribution by DMT type was self-injectable only (n = 41), oral only (n = 2), infusion only (n = 1), and more than 1 type (n = 14). Older age and previous DMT use were associated with increased adherence and/or persistence. Increased alcohol consumption, DMT adverse events, higher education, and higher body mass index were negatively associated with adherence and/or persistence. Greater number and severity of relapses was associated with increased adherence but decreased persistence. CONCLUSIONS: Most studies examined factors associated with adherence and persistence to self-injectable DMTs. These factors should be evaluated further for oral and infusion DMTs. Insights into the modifiable factors associated with adherence and persistence could guide treatment decisions and help improve adherence and clinical outcomes.

Implantable Penile Prosthesis for Erectile Dysfunction: Insurance Coverage in the United States.

INTRODUCTION: A manufacturer's benefit verification database was evaluated to ascertain United States health plan insurance coverage for implantable penile prostheses for erectile dysfunction. METHODS: All-payer and employer-sponsored health plan benefit verification databases were queried to determine implantable penile prosthesis approval status. For the all-payer analysis, data by payer were available and presented for 2019-2021 to assess approval status varied by payer and over time. For the employer-sponsored health plan analysis, data by payer were available from 2018-2021. RESULTS: Benefit verification records for the all-payer database were available for 3,167 patients in 2019, 3,016 in 2020, and 2,837 in 2021. Insurance type was preferred provider organization (27.5%), Medicare Advantage (26.9%), Medicare (15.9%), or point-of-service (10.5%). Most patients were approved or verified for implantable penile prosthesis coverage (79.4% in 2019, 79.6% in 2020, and 78.4% in 2021). Coverage was most extensive for government-based insurance (Medicare 98.7%, Medicare Advantage 97.1%, Tricare 100%, and Veterans Affairs 80.0%) but was also favorable for commercial insurance (75.0%). The most common reason for lack of coverage was employer exclusion; the proportion of patients with no coverage due to exclusion increased from 13.5% in 2019 to 17.5% in 2021. Analyses of the employer-sponsored health plan database (n=3,083 patients) showed that 63.1% of patients were approved or verified for coverage and 34.2% did not have coverage due to health plan exclusions. CONCLUSIONS: Approximately 80% of patients had implantable penile prosthesis coverage. Employer exclusion was the most common reason for lagging coverage; rates of employer exclusion increased 29.3% from 2019-2021.

Static and group-based trajectory analyses of factors associated with non-adherence in patients with multiple sclerosis newly-initiating once- or twice-daily oral disease-modifying therapy.

Background: Increased understanding of adherence may facilitate optimal targeting of interventions. Objective: To utilize group-based trajectory modeling (GBTM) to understand longitudinal patterns of adherence and factors associated with non-adherence in patients with multiple sclerosis (MS) newly-initiating once-/twice-daily oral disease-modifying therapy (DMT) (fingolimod, dimethyl fumarate, or teriflunomide). Methods: Commercial plan data were analyzed using proportion of days covered (PDC) to evaluate factors associated with non-adherence. GBTM clustered patient subgroups with similar longitudinal patterns of adherence measured by monthly PDC (≥80%) and multinomial logistic regression identified factors associated with adherence trajectory subgroups. Results: Among 7689 patients, 39.5% were non-adherent to once-/twice-daily oral DMTs. Characteristics associated with non-adherence (PDC<80%) included younger age, female, depression or migraine, switching during follow-up, more frequent dosing, relapse, and absence of magnetic resonance imaging. GBTM elucidated three adherence subgroups: Immediately Non-Adherent (14.9%); Gradually Non-Adherent (19.5%), and Adherent (65.6%). Additional factors associated with adherence (i.e. region, chronic lung disease) were identified and factors differed among trajectory subgroups. Conclusion: These analyses confirmed that a significant proportion of patients with MS are non-adherent to once-/twice-daily oral DMTs. Unique patterns of non-adherence and factors associated with patterns of adherence emerged. The approach demonstrated how quantitative trajectories can help clinicians develop tailored interventions.

The Epidemic of COVID-19-Related Erectile Dysfunction: A Scoping Review and Health Care Perspective.

INTRODUCTION: COVID-19 infection is expected to be associated with an increased likelihood of erectile dysfunction (ED). Considering the high transmissibility of COVID-19, ED may be a concerning consequence for a large segment of the population. AIMS: To (1) summarize existing published evidence for the impact of COVID-19 on the prevalence, severity, treatment, and management of ED; and (2) identify health-related trends in the emerging literature and identify gaps in the existing research literature and make recommendations for future research needs in the area. METHODS: A scoping literature search was conducted on April 27, 2021. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (Preferred Reporting Items for Systematic Reviews and Meta-Analyses-ScR) checklist was followed. The literature search was performed in PubMed using the terms: COVID-19, erectile, sexual, and dysfunction. A total of 693 publications were screened for relevance. Studies were appraised for their level of evidence based on study design and the rigor of methodology. RESULTS: The evidence that COVID-19 infection causes or impacts ED is compelling. Four topics emerged regarding the nature of the association between COVID-19 and ED: (1) the biological impact of COVID-19 infection on ED; (2) the mental health impact of COVID-19 on ED; (3) the impact of COVID-19 on the management of ED and access to ED treatment; and (4) health disparities and the impact of COVID-19 on ED. Long-term and well-designed studies are needed to clarify the extent of the impact of COVID-19 on ED. The pandemic exposed several vulnerabilities within worldwide healthcare and social systems. CONCLUSION: COVID-19 has a uniquely harmful impact on men's health and erectile function through biological, mental health, and healthcare access mechanisms. As the pandemic wanes, strategies to identify long-term effects and additional health care support may be needed to adequately mitigate the impact of COVID-19 on men's health. Hsieh T-C, Edwards NC, Bhattacharyya SK, et al.The Epidemic of COVID-19-Related Erectile Dysfunction: A Scoping Review and Health Care Perspective. Sex Med Rev 2022;10:286-310.

Live birth rates, infertility diagnosis, and infertility treatment in women with and without multiple sclerosis: Data from an administrative claims database.

BACKGROUND: Real-world data regarding live birth rates (LBRs) and infertility in women with multiple sclerosis (MS) are lacking. This study compared LBRs, infertility diagnoses, and infertility treatments in women with and without MS. METHODS: Using a retrospective US administrative claims database, patients 18-55 years with MS were matched 1:1 to patients without MS to compare LBRs, infertility diagnoses, and infertility treatments used between cohorts. RESULTS: Overall LBRs were lower in women with MS (n=96,937) versus women without (n=96,937; 5.0% vs 7.0%; p<0.0001). A greater proportion of women with MS than without had a diagnosis of infertility (8.5% vs 8.1%; p=0.0006). Fewer women with MS than without used any infertility treatment (1.0% vs 1.2%; p=0.0002). Among women with or without MS who received infertility treatments, no significant difference was observed in LBRs with oral (32.2% vs 31.5%; p=0.8536) or injectable (44.0% vs 49.3%; p=0.2603) treatment. CONCLUSION: Women with MS had a lower LBR, received more infertility diagnoses, and were less likely to receive infertility treatment than women without MS. There was no difference in LBRs following infertility treatment. Claims-data studies provide valuable exploratory analyses that reflect interactions between patients and the healthcare system.

Addressing Health-Care System Inequities in the Management of Erectile Dysfunction: A Call to Action.

Erectile dysfunction (ED) is a common, burdensome, and costly urologic condition strongly related to all aspects of general health, from physical to mental. ED has profound consequences as it may interfere physical well-being, quality of life (QoL), self-esteem, relationships, self-worth, and productivity. It is therefore important to ensure that all types of effective ED treatments are consistently accessible to patients. While federal and state mandates ensure access to treatment for women's breast health, female-factor infertility, and gender affirmation to ensure that these individuals do not experience a diminished QoL, there are no comparable mandates for men's sexual and reproductive health. The burden of ED necessitates a call to action to improve the accessibility of ED treatments. The call to action steps include: (a) coverage for pharmacological, surgical, and other ED treatments should be viewed in the same way as coverage for other health issues, whether male or female and regardless of the stages of treatment, physical dysfunction, or physical changes; (b) American Urological Association (AUA) guidelines for the management of ED should be followed, including implementation of templates in electronic medical records (EMRs) to support adherence to the guidelines; and (c) coverage criteria should explicitly state that the criteria are intended to support gender equity for sexual and reproductive health care and should not be used to prevent men from receiving medically necessary ED treatments. This call to action offers a pathway to support every man who seeks treatment for ED as a medically necessary intervention by removing systemic health-care barriers.

Real-world adherence to, and persistence with, once- and twice-daily oral disease-modifying drugs in patients with multiple sclerosis: a systematic review and meta-analysis.

BACKGROUND: Nonadherence to disease-modifying drugs (DMDs) for multiple sclerosis (MS) is associated with poorer clinical outcomes, including higher rates of relapse and disease progression, and higher medical resource use. A systematic review and quantification of adherence and persistence with oral DMDs would help clarify the extent of nonadherence and nonpersistence in patients with MS to help prescribers make informed treatment plans and optimize patient care. The objectives were to: 1) conduct a systematic literature review to assess the availability and variability of oral DMD adherence and/or persistence rates across 'real-world' data sources; and 2) conduct meta-analyses of the rates of adherence and persistence for once- and twice-daily oral DMDs in patients with MS using real-world data. METHODS: A systematic review of studies published between January 2010 and April 2018 in the PubMed database was performed. Only studies assessing once- and twice-daily oral DMDs were available for inclusion in the analysis. Study quality was evaluated using a modified version of the Newcastle-Ottawa Scale, a tool for assessing quality of observational studies. The random effects model evaluated pooled summary estimates of nonadherence. RESULTS: From 510 abstracts, 31 studies comprising 16,398 patients with MS treated with daily oral DMDs were included. Overall 1-year mean medication possession ratio (MPR; n = 4 studies) was 83.3% (95% confidence interval [CI] 74.5-92.1%) and proportion of days covered (PDC; n = 4 studies) was 76.5% (95% CI 72.0-81.1%). Pooled 1-year MPR ≥80% adherence (n = 6) was 78.5% (95% CI 63.5-88.5%) and PDC ≥80% (n = 5 studies) was 71.8% (95% CI 59.1-81.9%). Pooled 1-year discontinuation (n = 20) was 25.4% (95% CI 21.6-29.7%). CONCLUSIONS: Approximately one in five patients with MS do not adhere to, and one in four discontinue, daily oral DMDs before 1 year. Opportunities to improve adherence and ultimately patient outcomes, such as patient education, medication support/reminders, simplified dosing regimens, and reducing administration or monitoring requirements, remain. Implementation of efforts to improve adherence are essential to improving care of patients with MS.

Relapses and disease-modifying drug treatment in pregnancy and live birth in US women with MS.

OBJECTIVE: To evaluate relapse rates and disease-modifying drug (DMD) treatment in US women with multiple sclerosis (MS) and a live birth. METHODS: This retrospective administrative claims database study used US commercial health plan data from women with MS and a live birth from January 1, 2006, to June 30, 2015. Relapses and DMD treatment were evaluated 1-year prepregnancy, during pregnancy, during puerperium (6 weeks postpregnancy), and 1-year postpregnancy. Relapse was defined as MS-related hospitalization, emergency room visit, or outpatient visit with corticosteroid prescription within 7 days. Generalized estimating equation models for longitudinal data tested for differences between prepregnancy vs the other time periods. RESULTS: A total of 2,158 patients were eligible. The odds of relapse declined during pregnancy (odds ratio [OR] 0.623, 95% confidence interval [CI] 0.521-0.744; p < 0.0001), increased during puerperium (OR 1.710, 95% CI 1.358-2.152; p < 0.0001), and ended at a higher level during the last 3 postpartum quarters (OR 1.216, 95% CI 1.052-1.406; p = 0.0081). The proportion of women with DMD treatment was rather low overall: approximately 20% prepregnancy, bottoming to 1.9% during the second trimester, and peaking at 25.5% 9 to 12 months postpartum. DMD treatment declined significantly during pregnancy (OR 0.171, 95% CI 0.144-0.203; p < 0.0001), remained lower during puerperium (OR 0.361, 95% CI 0.312-0.418; p < 0.0001), and ended at a higher level during the last 3 postpartum quarters (OR 1.259, 95% CI 1.156-1.371; p < 0.0001). CONCLUSIONS: The rate of MS relapse decreased during pregnancy, increased 6 months postpartum, and decreased 6 to 12 months postpartum. DMD treatment was uncommon in the year before pregnancy, further decreased immediately prepregnancy and during pregnancy, and increased postpartum.

Pregnancy rates and outcomes in women with and without MS in the United States.

OBJECTIVE: To compare pregnancy prevalence and complications in women with and without multiple sclerosis (MS). METHODS: This retrospective US administrative claims study used data from January 1, 2006, to June 30, 2015. All data for women with MS were included. A nationally representative 5% random sample from approximately 58 million women without MS was used to compute the dataset. Annual pregnancy rates, identified via diagnosis/procedure codes and adjusted for covariates, were estimated via logistic regression. Claims for pregnancy and labor/delivery complications were compared using propensity score matching. RESULTS: From 2006 to 2014, the adjusted proportion of women with MS and pregnancy increased from 7.91% to 9.47%; the adjusted proportion without MS and with pregnancy decreased from 8.83% to 7.75%. The difference in linear trend (0.17% increase and 0.15% decrease in per-annum pregnancy rates) was significant (t statistic = 7.8; p < 0.0001). After matching (n = 2,115 per group), a higher proportion of women with MS than without had claims for premature labor (31.4% vs 27.4%; p = 0.005), infection (13.3% vs 10.9%; p = 0.016), cardiovascular disease (3.0% vs 1.9%; p = 0.028), anemia/acquired coagulation disorders (2.5% vs 1.3%; p = 0.007), neurologic complications (1.6% vs 0.6%; p = 0.005), sexually transmitted diseases (0.4% vs 0.1%; p = 0.045), acquired fetal damage (27.8% vs 23.5%; p = 0.002), and congenital fetal malformations (13.2% vs 10.3%; p = 0.004). CONCLUSIONS: Pregnancy rates in this population of women with MS have been increasing. High rates of claims for several peripartum complications were observed in women with and those without MS. Claims data provide knowledge of interactions patients have with the health care system and are valuable initial exploratory analyses.

Comorbidity in US patients with multiple sclerosis.

OBJECTIVE: To assess the trends in the prevalence of comorbidities in US patients with multiple sclerosis (MS), and the association of demographic characteristics with the presence of comorbidities. STUDY DESIGN: A retrospective analysis was conducted from a sample of 5 million patients from the IMS Health Real World Data Adjudicated Claims - US database. METHODS: Comorbidity in patients with MS was assessed by year (2006-2014), and logistic regression models evaluated the association of age, sex, and region with select comorbidities. RESULTS: The most common comorbidities from 2006 to 2014 were hyperlipidemia and hypertension (25.9%-29.7% of patients within an individual year), followed by gastrointestinal disease (18.4%-21.2% of patients) and thyroid disease (12.9%-17.1% of patients). The proportion with a claim for hyperlipidemia increased from 2006 to 2009, was stable from 2009 to 2011, and then declined from 2011 to 2014. The proportion with a claim for hypertension generally increased from 2006 to 2013, then declined from 2013 to 2014. The proportion with a claim for gastrointestinal disease, thyroid disease, and anxiety generally increased from 2006 to 2014. Claims for comorbidities were statistically significantly more likely among older age groups (p<0.05), with the exception of anxiety and alcohol abuse, which were statistically significantly less likely among older age groups. Claims for gastrointestinal disease (OR=0.75), thyroid disease (OR=0.36), chronic lung disease (OR=0.76), arthritis (OR=0.71), anxiety (OR=0.63), and depression (OR=0.69) were statistically significantly less likely among males versus females (all p<0.05). Claims for hyperlipidemia (OR=1.39), hypertension (OR=1.25), diabetes (OR=1.31), and alcohol abuse (OR=2.41) were significantly more likely among males (p<0.05). Many comorbidity claims were statistically significantly more likely in the Northeast and South compared with the Midwest and West. CONCLUSION: This study provides select comorbidity claims estimates in US patients with MS, and thus highlights the importance of comprehensive patient care approaches.

Factors associated with early initiation of disease-modifying drug treatment in newly-diagnosed patients with multiple sclerosis.

OBJECTIVE: To examine the time to first disease-modifying drug (DMD) treatment and to identify factors associated with early DMD initiation in newly-diagnosed patients with MS. METHODS: This retrospective cohort study included newly-diagnosed patients with MS from a US administrative claims database, aged 18-65 years, with a first MS diagnosis (ICD-9-CM code: 340.xx) between January 1, 2007 and June 30, 2013 (index date), continuous eligibility for 12 months pre- and 24 months post-index, and initiated DMD treatment within 2 years. Time to first DMD within 24 months post-index was evaluated. A logistic regression model predicted earlier initiation of DMD treatment (within 60 days of MS diagnosis). RESULTS: In total, 37.4% of patients initiated DMD treatment within 2 years of MS diagnosis and were included in the primary analysis (n = 7,124). Mean (standard deviation [SD]) time from MS diagnosis to first DMD was 112.6 (148.3) days (median = 51); 30.7% received first DMD in <30 days, 55.1% in <60 days, and 18.5% not until ≥180 days after diagnosis. Logistic regression found that younger age; not living in the Northeast; diagnoses of balance disorders, numbness, and optical neuritis; the absence of musculoskeletal diagnoses; and a neurologist visit or MRI within 90 days before diagnosis were associated with DMD initiation within 60 days. CONCLUSIONS: In this population of patients initiating DMD treatment within 2 years of MS diagnosis, mean time to first DMD was 112.6 days. Identifying factors associated with delayed treatment may provide better understanding of the reasons for delay, leading to improved disease management.

Cost-consequence analysis of antibiotic-impregnated shunts and external ventricular drains in hydrocephalus.

OBJECT: Despite multiple preventive strategies for reducing infection, up to 15% of patients with shunt catheters and 27% of patients with external ventricular drains (EVDs) may develop an infection. There are few data on the cost-effectiveness of measures to prevent hydrocephalus catheter infection from the hospital perspective. The objective of this study was to perform a cost-consequence analysis to assess the potential clinical and economic value of antibiotic-impregnated catheter (AIC) shunts and EVDs compared with non-AIC shunts and EVDs in the treatment of hydrocephalus from a hospital perspective. METHODS: The authors used decision analytical techniques to assess the clinical and economic consequences of using antibiotic-impregnated shunts and EVDs from a hospital perspective. Model inputs were derived from the published, peer-reviewed literature. Clinical studies comparing infection rates and the clinical and economic impact of infections associated with the use of AICs and standard catheters (non-AICs) were evaluated. Outcomes assessed included infections, deaths due to infection, surgeries due to infection, and cost associated with shunt- and EVD-related infection. A subanalysis using only AIC shunt and EVD Level I evidence (randomized controlled trial results) was conducted as an alternate to the cumulative analysis of all of the AIC versus non-AIC studies (13 of the 14 shunt studies and 4 of the 6 EVD studies identified were observational). Sensitivity analyses were conducted to determine how changes in the values of uncertain parameters affected the results of the model. RESULTS: In 100 patients requiring shunts, AICs may be associated with 0.5 fewer deaths, 71 fewer hospital days, 11 fewer surgeries, and $128,228 of net savings in hospital costs due to decreased infection. Results of the subanalysis showed that AICs may be associated with 1.9 fewer deaths, 1611 fewer hospital days, 25 fewer surgeries, and $346,616 of net savings in hospital costs due to decreased infection. The rate of decrease in infection with AIC shunts was shown to have the greatest impact on the cost savings realized with use of AIC shunts. In 100 patients requiring EVDs, AICs may be associated with 2.7 fewer deaths and 82 fewer hospital days due to infection. The relative risk of more severe neurological impairment was estimated to be 5.33 times greater with EVD infection. Decreases in infection with AIC EVDs resulted in an estimated $264,069 of net savings per 100 patients treated with AICs. Results of the subanalysis showed that AIC EVDs may be associated with 1.0 fewer deaths, 31 infection-related hospital days averted, and $74,631 saved per 100 patients treated with AIC EVDs. As was seen with AIC shunts, the rate of decrease in infection with AIC EVDs was shown to have the greatest impact on the cost savings realized with use of AIC EVDs. CONCLUSIONS: The current value analysis demonstrates that evidence supports the use of AICs as effective and potentially cost-saving treatment.

The role of decision analytic modeling in the health economic assessment of spinal intervention.

STUDY DESIGN: Narrative review. OBJECTIVE: To review the common tenets, strengths, and weaknesses of decision modeling for health economic assessment and to review the use of decision modeling in the spine literature to date. SUMMARY OF BACKGROUND DATA: For the majority of spinal interventions, well-designed prospective, randomized, pragmatic cost-effectiveness studies that address the specific decision-in-need are lacking. Decision analytic modeling allows for the estimation of cost-effectiveness based on data available to date. Given the rising demands for proven value in spine care, the use of decision analytic modeling is rapidly increasing by clinicians and policy makers. METHODS: This narrative review discusses the general components of decision analytic models, how decision analytic models are populated and the trade-offs entailed, makes recommendations for how users of spine intervention decision models might go about appraising the models, and presents an overview of published spine economic models. RESULTS: A proper, integrated, clinical, and economic critical appraisal is necessary in the evaluation of the strength of evidence provided by a modeling evaluation. As is the case with clinical research, all options for collecting health economic or value data are not without their limitations and flaws. There is substantial heterogeneity across the 20 spine intervention health economic modeling studies summarized with respect to study design, models used, reporting, and general quality. There is sparse evidence for populating spine intervention models. Results mostly showed that interventions were cost-effective based on $100,000/quality-adjusted life-year threshold. Spine care providers, as partners with their health economic colleagues, have unique clinical expertise and perspectives that are critical to interpret the strengths and weaknesses of health economic models. CONCLUSION: Health economic models must be critically appraised for both clinical validity and economic quality before altering health care policy, payment strategies, or patient care decisions. LEVEL OF EVIDENCE: 4.

The threshold rate of oral atypical anti-psychotic adherence at which paliperidone palmitate is cost saving.

OBJECTIVE: To identify, estimate, and compare 'real world' costs and outcomes associated with paliperidone palmitate compared with branded oral atypical anti-psychotics, and to estimate the threshold rate of oral atypical adherence at which paliperidone palmitate is cost saving. METHODS: Decision analytic modeling techniques developed by Glazer and Ereshefsky have previously been used to estimate the cost-effectiveness of depot haloperidol, LAI risperidone, and, more recently, LAI olanzapine. This study used those same techniques, along with updated comparative published clinical data, to evaluate paliperidone palmitate. Adherence rates were based on strict Medication Event Monitoring System (MEMS) criteria. The evaluation was conducted from the perspective of US healthcare payers. RESULTS: Paliperidone palmitate patients had fewer mean annual days of relapse (8.7 days; 6.0 requiring hospitalization, 2.7 not requiring hospitalization vs 17.8 days; 12.4 requiring hospitalization, 5.4 not requiring hospitalization), and lower annual total cost ($20,995) compared to oral atypicals (mean $22,481). Because paliperidone palmitate was both more effective and less costly, it is considered economically dominant. Paliperidone palmitate saved costs when the rate of adherence of oral atypical anti-psychotics was below 44.9% using strict MEMS criteria. Sensitivity analyses showed results were robust to changes in parameter values. For patients receiving 156 mg paliperidone palmitate, the annual incremental cost was $1216 per patient (ICER = $191 per day of relapse averted). Inclusion of generic risperidone (market share 18.6%) also resulted in net incremental cost for paliperidone palmitate ($120; ICER = $13). Limitations of this evaluation include use of simplifying assumptions, data from multiple sources, and generalizability of results. CONCLUSIONS: Although uptake of LAIs in the US has not been as rapid as elsewhere, many thought leaders emphasize their importance in optimizing outcomes in patients with adherence problems. The findings of this analysis support the cost-effectiveness of paliperidone palmitate in these patients.

Comparing the cost-effectiveness of disease-modifying drugs for the first-line treatment of relapsing-remitting multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is an inflammatory autoimmune disorder of the central nervous system that primarily afflicts young adults. Approximately 400,000 people in the United States are affected by MS. Although several forms of MS exist, the most common course is known as relapsing-remitting MS (RRMS), which affects about 85% of MS patients. This form of MS is characterized by relapses of neurologic symptoms followed by periods of recovery. Progression of disease can lead to increasingly severe disability. Since the introduction of immunomodulatory biologic agents, such as interferon betas and glatiramer acetate, treatment has helped to change the course of the disease. Under budgetary constraints, health services payers are challenged to differentiate the economic value of these agents for formulary selection and/or placement. OBJECTIVE: The primary objective of this analysis was to evaluate the 2-year cost-effectiveness of 4 disease modifying drugs (DMDs) used as first-line treatment of RRMS: glatiramer acetate, interferon (IFN) Beta-1a IM injection, IFN Beta-1a SC injection, and IFN Beta-1b SC injection. METHODS: An Excel-based model was developed to compare the relative effectiveness and cost components of relapses, disability progression, and DMDs in the treatment of RRMS over a 2-year time horizon. The relative risk reduction (RRR) method was used to compare reduction in relapse rates and disease progression data from pivotal randomized double-blind placebo-controlled clinical trials of the DMDs. RRRs for relapses and disability progression, respectively, were calculated as the relative difference (treatment vs. placebo) in relapse rates and disease progression rates from placebo-controlled clinical trials. These RRRs were applied to the weighted average rates of relapse and number of disability progression steps seen in the placebo arms of the pivotal studies. The evaluation was conducted from the perspective of a U.S. health care payer (only direct medical costs considered). Medical savings were calculated as costs saved due to relapses avoided and prevention in disability progression steps. In the base case analysis, we assumed 89.4% persistence, a cost per relapse of $4,682, and a cost per disability progression step of $1,788. Monthly cost of therapy was defined as wholesale acquisition cost ($0 contractual discounts and $25 patient copayment assumed in the base case analysis) plus routine monitoring costs as assessed by an expert panel. The primary economic endpoint was cost per relapse avoided. Costs and outcomes occurring in the second year were discounted 3% to bring to 2008 present values. Oneway and multiway probabilistic (Monte Carlo) sensitivity analyses were conducted on key input variables to assess their impact on cost per relapse avoided. RESULTS: Without DMD treatment, patients were predicted to experience 2.55 relapses and 0.44 disability progression steps over a 2-year period (discounted values). The 2-year reductions in clinical relapses for treatment with glatiramer acetate, IFN Beta-1a IM injection, IFN Beta-1a SC injection, and IFN Beta-1b were 0.66, 0.42, 0.74, and 0.70, respectively. The 2-year reductions in disability progression steps for treatment with glatiramer acetate, IFN Beta-1a IM injection, IFN Beta-1a SC injection, and IFN Beta-1b were 0.05, 0.15, 0.12, and 0.11, respectively. In the base case analysis, IFN Beta-1a SC injection, IFN Beta-1b SC injection, and glatiramer acetate had the most favorable costs per relapse avoided ($80,589; $87,061; and $88,310; respectively) and IFN Beta-1a IM injection had the least favorable cost-effectiveness ratio ($141,721 per relapse avoided). Sensitivity analyses showed that these results were robust to changes in key input parameters, such as the number of relapses and disease progression steps in untreated patients, the RRR in clinical relapse and progression rates, the rate of persistence, the average cost of relapse, and the average cost of a disease progression step. CONCLUSION: This evaluation suggests that IFN Beta-1a SC injection, IFN Beta-1b SC injection, and glatiramer acetate represent the most cost-effective DMDs for the treatment of RRMS, where cost-effectiveness is defined as cost per relapse avoided, assuming that (a) the RRR in relapses and disease progression steps calculated from multiple DMD placebo-controlled clinical trials reflect real differences among DMDs over 2 years; and (b) resource unit costs derived from published sources reflect economic consequences of relapses and disease progression.

One-year clinical and economic consequences of oral atypical antipsychotics in the treatment of schizophrenia.

OBJECTIVE: To assess the clinical and economic consequences of oral atypical antipsychotic treatment (aripiprazole, olanzapine, paliperidone ER, quetiapine, risperidone, and ziprasidone) in schizophrenia over one-year from a US healthcare system perspective. METHODS: The decision model captured rates of discontinuation, symptom response, frequency and duration of relapse, adverse events (extrapyramidal symptoms and weight gain), resource utilization, and unit costs. Published randomized, double-blind, placebo-controlled clinical trial data were used to obtain response rates for comparators. Published clinical trial data from long-term effectiveness trials reflective of typical clinical settings were used for time on therapy, rates of discontinuation, likelihood of switching, relapse rates, and adverse event rates. Drug costs were based on Wholesale Acquisition Cost weighted by Wolters Kluwer Retail and First Databank Pricing drug utilization data. PharMetrics Patient-Centric database was utilized for length of stay, frequency of relapse, and unit cost of healthcare resource data. A clinical expert panel provided resource-use information not available in published literature or healthcare databases. To test the robustness of the findings, sensitivity analyses were performed using plausible ranges of key model input parameters. RESULTS: The model estimated that, over 1 year, clinical outcomes of patients administered oral atypical antipsychotics would not vary considerably. This is partly due to differences 'washing out' because of frequent switching and discontinuation of medication. Economic outcomes did vary among pharmacotherapies: paliperidone ER was associated with cost savings in direct medical costs per patient per year compared to risperidone (cost savings using paliperidone ER vs. risperidone: $793), quetiapine ($1191), olanzapine ($1259), ziprasidone ($2159), and aripiprazole ($2204)). Limitations of this analysis include the absence of direct head-to-head long-term comparative data for antipsychotics. However, the results of the decision analysis held true when tested through a multitude of sensitivity analyses. CONCLUSION: This modeling study showed that paliperidone ER had the most favorable clinical and economic outcomes compared to other oral atypical antipsychotics for patients with schizophrenia. The analysis supports the notion that frequent discontinuation of medication is a problem with all oral antipsychotic treatments for schizophrenia.