The Cost-Effectiveness of Rivaroxaban Plus Aspirin Compared with Aspirin Alone in the COMPASS Trial: A US Perspective.

BACKGROUND: Rivaroxaban 2.5 mg twice daily with aspirin 100 mg daily was shown to be better than aspirin 100 mg daily for preventing cardiovascular (CV) death, stroke or myocardial infarction in patients with either stable coronary artery disease (CAD) or peripheral artery disease (PAD). The cost-effectiveness of this regimen in this population is essential for decision-makers to know. METHODS: US direct healthcare system costs (in USD) were applied to hospitalized events, procedures and study drugs utilized by all patients. We determined the mean cost per participant for the full duration of the trial (mean follow-up of 23 months) plus quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER) over a lifetime using a two-state Markov model with 1-year cycle length. Sensitivity analyses were performed on the price of rivaroxaban and the annual discontinuation rate. RESULTS: The costs of events and procedures were reduced for Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) patients who received rivaroxaban 2.5 mg orally (BID) plus acetylsalicylic acid (ASA) compared with ASA alone. Total costs were higher for the combination group ($7426 versus $4173) after considering acquisition costs of the study drug. Over a lifetime, patients receiving rivaroxaban plus ASA incurred $27,255 more and gained 1.17 QALYs compared with those receiving ASA alone resulting in an ICER of $23,295/QALY. ICERs for PAD only and polyvascular disease subgroups were lower. CONCLUSION: Rivaroxaban 2.5 mg BID plus ASA compared with ASA alone was cost-effective (high value) in the USA. COMPASS ClinicalTrials.gov identifier: NCT01776424.

Terlipressin vs Midodrine Plus Octreotide for Hepatorenal Syndrome-Acute Kidney Injury: A Propensity Score-Matched Comparison.

INTRODUCTION: Evidence on the comparison of treatments for hepatorenal syndrome-acute kidney injury (HRS-AKI) in a US population is limited. An indirect comparison of terlipressin plus albumin vs midodrine and octreotide plus albumin (MO) may provide further insight into treatment efficacy. METHODS: Cohorts of patients treated for HRS-AKI characterized by inclusion of patients with serum creatinine (SCr) <5 mg/dL and baseline acute-on-chronic liver failure grades 0-2 and exclusion of patients listed for transplant if model for end-stage liver disease scores ≥35 were pooled from (i) the CONFIRM and REVERSE randomized controlled trials (N = 159 meeting eligibility criteria from N = 216 overall, treated with terlipressin) and (ii) a retrospective review of medical records from 10 US tertiary hospitals (2016-2019; N = 55 treated with MO meeting eligibility criteria from N = 200 overall). The primary end point comparing the 2 cohorts was HRS reversal defined as achieving SCr ≤1.5 mg/dL at least once during the treatment. Covariate balancing propensity scoring was used to adjust for differences in baseline characteristics. RESULTS: HRS-AKI reversal was achieved in 52.35% of terlipressin-treated patients compared with 20% of MO-treated patients (adjusted mean difference 32.35%, 95% confidence interval [CI] 17.40-47.30, P < 0.0001). Terlipressin-treated patients had increased overall survival (adjusted hazard ratio 0.57, 95% CI 0.35-0.93, P = 0.02) but similar transplant-free survival (adjusted hazard ratio 0.79, 95% CI 0.53-1.17, P = 0.24). Achievement of HRS-AKI reversal was associated with increased OS and TFS regardless of treatment ( P < 0.001). DISCUSSION: Consistent with prior reports, terlipressin plus albumin is more effective in improving kidney function and achieving HRS-AKI reversal than MO plus albumin based on indirect comparison in a US population.

Matching-Adjusted Indirect Comparison of the Long-Term Efficacy of Deucravacitinib Versus Adalimumab for Moderate to Severe Plaque Psoriasis.

INTRODUCTION: Deucravacitinib, an oral tyrosine kinase 2 (TYK2) inhibitor, is approved in the United States to treat adults with moderate-to-severe plaque psoriasis (PsO). This study compared the long-term efficacy of deucravacitinib and adalimumab using results from long-term extension (LTE) trials. METHODS: Open-label LTE trials were identified for an indirect treatment comparison (deucravacitinib: POETYK PSO-LTE [NCT04036435]; adalimumab: REVEAL extension [NCT00195676]). To ensure study design comparability, patients initially randomized to placebo and switched to deucravacitinib or adalimumab after week 16 were compared. The primary outcome was an ≥ 75% reduction in Psoriasis Area and Severity Index score (PASI 75) at week 112 postrandomization. Secondary outcomes were PASI 75 at week 52 and an ≥ 90% reduction in PASI score (PASI 90) at weeks 52 and 112. Missing PASI data were imputed. A matching-adjusted indirect comparison was conducted; individual patient-level data from POETYK PSO-LTE were reweighted to balance baseline characteristics with those from the REVEAL extension. RESULTS: Before reweighting, on average, patients in the POETYK PSO-LTE (N = 329) versus the REVEAL (N = 345) extension were older, had a lower body weight, received more prior systemic treatments, and had higher baseline PASI scores and week 16 placebo PASI 75 and PASI 90 response rates. Following reweighting, adjusted week 112 PASI 75 response rates were significantly higher for deucravacitinib versus adalimumab (67.2% vs. 54.0%; mean difference [95% CI], 13.2 [4.0-22.5] percentage points). Deucravacitinib had a numerically higher adjusted week 112 PASI 90 response rate (41.3% vs. 34.0%; mean difference [95% CI], 7.3 [-2.0 to 16.7] percentage points). The treatments had similar week 52 adjusted PASI 75 and PASI 90 response rates. CONCLUSION: In this interim analysis, adults with moderate to severe PsO had higher long-term response rates at 2 years when treated with deucravacitinib versus adalimumab. Deucravacitinib response rates remained stable whereas adalimumab response rates declined in year 2.

Plaque psoriasis is an inflammatory disease that causes red, itchy, dry patches (called plaques) on the skin. The disease cannot be cured, but the symptoms can be treated. Deucravacitinib and adalimumab are two treatments approved for use in adults with moderate to severe plaque psoriasis; deucravacitinib is an oral medication and adalimumab is injected with a needle under the skin. Each treatment has proven its efficacy compared with placebo (a pill or injection with no active effect) in separate clinical trials, but because no two clinical trials are exactly alike, the results cannot be accurately compared. Matching-adjusted indirect comparison is a method used to compare the results of one clinical trial with those of another when a direct comparison is not possible; characteristics from the patients in one trial are made to match the patient population in the other trial, and the adjusted results are compared. We performed a matching-adjusted indirect comparison of an open-label extension trial of deucravacitinib with an open-label extension trial of adalimumab to study the long-term efficacy of each treatment. At 1 year of treatment, we observed that similar proportions of patients receiving each treatment achieved a 75% or 90% improvement from their baseline Psoriasis Area and Severity Index score, called PASI 75 or PASI 90, respectively. At 2 years of treatment, similar proportions achieved PASI 90, but the proportion of patients receiving deucravacitinib who achieved PASI 75 was greater than that of patients receiving adalimumab.

The burden of ovarian cancer in the USA from 2007 to 2018: evidence from the Medical Expenditure Panel Survey.

Aim: To evaluate the economic and humanistic burden of ovarian cancer in the USA. Methods: Medical Expenditure Panel Survey data (2007-2018) were used to estimate all-cause healthcare resource use and costs for economic burden and examine the activities of daily living and quality-of-life (QoL) measures for humanistic burden between ovarian cancer patients and a non-cancer population. Results: Compared with controls, patients with ovarian cancer had more comorbidities and worse QoL. Their predicted number of annual hospitalizations and office-based visits was significantly higher, as were their estimated annual all-cause total healthcare costs. Total costs were driven by hospitalization costs. Conclusion: The study identified the burden of ovarian cancer and demonstrated that patients with ovarian cancer have greater healthcare resource use, higher costs and worse QoL than the non-cancer population. Future research is needed to develop strategies for managing ovarian cancers and inform decision-making to reduce disease burden.

What is this article about? The article discusses the impact that ovarian cancer has, both in terms of economics and quality of life. We used data from 2007 to 2018 to identify women with ovarian cancer as well as women without cancer for the sake of comparison. What were the results? We found that individuals with ovarian cancer face considerable burdens, and their treatment costs have a notable impact on healthcare systems. Compared with women without cancer, women with ovarian cancer are older and have a greater number of additional illnesses, and their quality of life is lower. Their use of healthcare resources is greater and hence the costs associated with their treatment are higher. What do the results of the study mean? This study adds to the existing data about the burden imposed by ovarian cancer, on individuals as well as on healthcare systems. Interventions are needed to reduce the impacts of the disease.

Mimicking Clinical Trials Using Real-World Data: A Novel Method and Applications.

INTRODUCTION: Simulating individual-level trial data when only summary data are available is often useful for meta-analysis, forming external control arms and calibrating trial results to real-world data (RWD). The joint distribution of baseline characteristics in a trial is usually simulated by combining its summary data with RWD's correlations. However, RWD correlations may not be a perfect proxy for the trial. A misspecified correlation structure could bias any analysis in which the outcomes generating models are nonlinear or include effect modifiers. METHODS: We developed an iterative algorithm using copula and resampling, which was based on the estimated propensity score for the likelihood of enrollment in a trial given participants' characteristics. Validation was performed using Monte Carlo simulations under different scenarios in which the marginal and joint distributions of covariates differ between trial samples and RWD. Two applications were illustrated using an actual trial and the Surveillance, Epidemiology, and End Results-Medicare data. We calculated the standardized mean difference (SMD) to assess the generalizability of the trial and explored the feasibility of generating an external control by applying a parametric Weibull model trained in RWD to predict survival in the simulated trial cohort. RESULTS: Across all scenarios, approximated correlations derived from the algorithm were closer to the true correlations than the RWD's correlations. The algorithm also successfully reproduced the joint distribution of characteristics for the actual trial. A similar SMD was observed using simulated data and individual-level trial data. The 95% confidence intervals were overlapped between adjusted survival estimates from the simulated trial and actual trial Kaplan-Meier estimates. CONCLUSIONS: The algorithm could be a feasible way to simulate individual-level data when only summary data are available. Further research is needed to validate our approach with larger sample sizes. HIGHLIGHTS: The correlation structure is crucial to building the joint distribution of patient characteristics, and a misspecified correlation structure could potentially influence predicted outcomes.An iterative algorithm was developed to approximate a trial's correlation structure using published summary trial data and real-world data.The algorithm could be a feasible way to simulate individual-level trial data when only trial summary data are available.

The cost-effectiveness of rivaroxaban with or without aspirin in the COMPASS trial.

AIMS: The Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial demonstrated that rivaroxaban 2.5 mg BID with aspirin 100 mg was more effective than aspirin 100 mg daily alone for the prevention of cardiovascular (CV) death, stroke, or myocardial infarction in patients with stable coronary artery disease (CAD) or peripheral artery disease (PAD). We aimed to examine the cost-effectiveness of rivaroxaban using patient-level data from the COMPASS trial. METHODS AND RESULTS: We performed an in-trial analysis and extrapolated our results for 33 years using a two-state Markov model with a 1-year cycle length. Hospitalization events, procedures, and study drugs were documented for patients. We applied country-specific (Canada, France, and Germany) direct healthcare system costs (in USD) to healthcare resources consumed by patients. Average cost per patient during the trial (mean follow-up of 23 months), quality-adjusted life years (QALYs), and lifetime cost-effectiveness were calculated. Costs of events and procedures were reduced with rivaroxaban 2.5 mg BID with aspirin. The addition of rivaroxaban 2.5 mg BID increased total costs for the combination group. Over a lifetime horizon (in trial +33 years), rivaroxaban plus aspirin was associated with 1.17 QALYs gained, yielding an incremental cost-effectiveness ratio (ICER) of $3946/QALY, $9962/QALY, and $10 264/QALY in Canada, France, and Germany, respectively. PAD and polyvascular disease subgroups had lower ICERs. CONCLUSION: Rivaroxaban 2.5 mg twice daily plus aspirin compared with aspirin alone reduces direct healthcare costs. After acquisition costs of rivaroxaban, the lifetime cost-effectiveness of 2.5 mg twice daily plus aspirin is highly cost-effective in Canada, France, and Germany.(COMPASS ClinicalTrials.gov identifier: NCT01776424).

Patient-reported outcomes in ZUMA-7, a phase 3 study of axicabtagene ciloleucel in second-line large B-cell lymphoma.

Here, we report the first comparative analysis of patient-reported outcomes (PROs) with chimeric antigen receptor T-cell therapy vs standard-of-care (SOC) therapy in second-line relapsed/refractory large B-cell lymphoma (R/R LBCL) from the pivotal randomized phase 3 ZUMA-7 study of axicabtagene ciloleucel (axi-cel) vs SOC. PRO instruments were administered at baseline, day 50, day 100, day 150, month 9, and every 3 months from randomization until 24 months or an event-free survival event. The quality of life (QoL) analysis set comprised patients with a baseline and ≥1 follow-up PRO completion. Prespecified hypotheses for Quality of Life Questionnaire-Core 30 (QLQ-C30) physical functioning, global health status/QoL, and EQ-5D-5L visual analog scale (VAS) were tested using mixed-effects models with repeated measures. Clinically meaningful changes were defined as 10 points for QLQ-C30 and 7 for EQ-5D-5L VAS. Among 359 patients, 296 (165 axi-cel, 131 SOC) met inclusion criteria for QoL analysis. At day 100, statistically significant and clinically meaningful differences in mean change of scores from baseline were observed favoring axi-cel over SOC for QLQ-C30 global health status/QoL (estimated difference 18.1 [95% confidence interval (CI), 12.3-23.9]), physical functioning (13.1 [95% CI, 8.0-18.2]), and EQ-5D-5L VAS (13.7 [95% CI, 8.5-18.8]; P < .0001 for all). At day 150, scores significantly favored axi-cel vs SOC for global health status/QoL (9.8 [95% CI, 2.6-17.0]; P = .0124) and EQ-5D-5L VAS (11.3 [95% CI, 5.4-17.1]; P = .0004). Axi-cel showed clinically meaningful improvements in QoL over SOC. Superior clinical outcomes and favorable patient experience with axi-cel should help inform treatment choices in second-line R/R LBCL. This trial was registered at www.clinicaltrials.gov as #NCT03391466.

Impact of Hypomethylating Agent Use on Hospital and Emergency Room Visits, and Predictors of Early Discontinuation in Patients With Higher-Risk Myelodysplastic Syndromes.

BACKGROUND: Previous analyses using the SEER-Medicare database have reported substantial underutilization of hypomethylating agents (HMAs) among patients with higher-risk myelodysplastic syndromes (MDS), and an association between poor HMA persistence and high economic burden. We aimed to compare rates of hospitalizations and emergency room (ER) visits among patients with higher-risk MDS according to use or non-use of HMA therapy, and to explore factors associated with early discontinuation of HMA therapy. PATIENTS AND METHODS: We used the 2010-2016 SEER-Medicare database to identify patients aged ≥66 years with a new diagnosis of refractory anemia with excess blasts (RAEB; a surrogate for higher-risk MDS) between 2011 and 2015. New hospitalizations and ER visits during the 12 months following MDS diagnosis were determined. Treatment discontinuation was defined as stopping HMA therapy before 4 cycles. RESULTS: Overall, 664 (55.8%) patients were HMA users and 526 (44.2%) non-users. Non-users had more hospitalizations (mean 0.47 vs. 0.30, P < .001) and ER visits (mean 0.69 vs. 0.41, P = .005) per month than HMA users. Among HMA users, 193 (29.1%) discontinued HMA therapy before 4 cycles, and 91 (47.2%) of these after 1 cycle. Older age and poor performance status were associated with higher risk of HMA discontinuation. CONCLUSION: An increased rate of hospitalizations and ER visits occurred in HMA non-users vs. HMA users. Approximately one-third of patients discontinued HMA therapy early. Predictors of discontinuation included older age and poor performance status. Novel approaches are needed to improve utilization and persistence with HMA therapy and associated outcomes, particularly among these higher-risk groups.

Racial Disparities in Access to Prostate Cancer Clinical Trials: A County-Level Analysis.

Background: African American men have a higher burden of prostate cancer compared with other populations. We sought to determine if they experience disparities in access to prostate cancer clinical trials. Methods: We created a database of all US counties by linking prostate cancer clinical trial data with county-level socioeconomic, demographic, and health-care facility data derived from several external data sources. Using this data linkage, we examined 2 potential access barriers. We investigated the relationship between the proportion of African Americans and access to cancer facilities, adjusting for county population size and other characteristics. Additionally, among counties with cancer facilities, we investigated the relationship between the proportion of African Americans and number of available prostate cancer trials per capita per year. We addressed these questions using logistic and negative binomial regression, respectively. Results: Between 2008 and 2015, 613 prostate cancer trial sites were found among 3145 US counties. Counties with a higher proportion of African Americans were less likely to have cancer facilities (adjusted odds ratio = 0.85, 95% confidence interval = 0.78 to 0.92). Among counties with cancer facilities, those with a higher proportion of African Americans had statistically significantly fewer prostate cancer trials per capita per year (rate ratio per 10% increase in African Americans = 0.90, 95% confidence interval = 0.83 to 0.96). Conclusions: Counties with higher proportions of African Americans seem less likely to have access to cancer facilities. Among counties with cancer facilities, those with higher proportions of African Americans appear to have fewer prostate cancer trials available per capita per year. Clinical trials in prostate cancer therapy should ensure adequate availability of enrollment sites in regions with high concentrations of African Americans.

Meta-analyzing count events over varying durations using the piecewise Poisson model: The case for poststroke seizures.

Meta-analyzing count data can be challenging when follow-up time varies across studies. Simply pooling aggregate data over time-periods would result in biased estimates, which may erroneously inform clinical decision-making. In this study, we exploit the convolution property of the Poisson distribution to develop a likelihood for observed cumulative counts over varying follow-up periods, where different Poisson distributions are used to represent the data generating processes for the latent counts in pre-defined successive intervals of follow-up. We illustrate this approach using an example of poststroke seizures, a case in which risk may change over time, and mimic its survival duration with time-varying hazard. Data were extracted from observational studies (1997-2016) reporting poststroke seizures over a maximum of 10 years of follow-up. Three clinically meaningful follow-up time intervals were considered: 0 to 7 days, 8 to 365 days, and 1 to 10 years poststroke. External validation was performed using claims data. Results suggest the incidence rate of seizures was 0.0452 (95% confidence interval: 0.0429, 0.0475), 0.0001 (0, 0.016), and 0.0647 (0.0441, 0.0941) for the three time intervals, respectively, indicating that the risk of seizures changes over time poststroke. We found that the model performed well against the incidence rate of seizures among actual retrospective cohort from claims data. The piecewise Poisson model presents a flexible way to meta-analyze count data over time and mimic survival curves. The results of the piecewise Poisson model are readily interpretable and may spur meaningful clinical action. The method may also be applied to other diseases. HIGHLIGHTS: It is challenging to perform a meta-analysis when follow-up time varies across studies. Ideally, outcomes over different time-periods should be pooled with individual patient-level data (IPD). A new model was developed to meta-analyze count data over time using aggregate-level data from previous published studies. The piecewise Poisson model could be a useful tool to estimate time-vary hazards given available data, and mimic survival curves over time which would be readily interpretable.

Burden of illness and research investments in translational sciences for pharmaceuticals in metastatic cancers.

AIM: To explore whether investments in translational sciences for six metastatic cancers follow idiosyncratic returns to those investments rather than levels of burden of illness (BI). METHODS: Associate the number of translational clinical trials in the USA involving oncolytic drugs approved during 2008-2013 and the level (in 2008) and changes (2002-2008 and 2008-2014) in cancer-specific years of life lost. RESULTS: Investments in trials were positively associated only with contemporary changes in BI (2008-2014). The relationship was stronger for government-sponsored comparative-effectiveness trials than for industry. CONCLUSION: Translational research investments follow anticipated changes to BI levels. Systematic quantification of these expected returns from specific investments can help guide investment decisions in translational health sciences and generate productive dialogue across stakeholders.

Healthcare Costs and Resource Utilization in Patients with Infantile Spasms Treated with H.P. Acthar Gel(®).

INTRODUCTION: The purpose of this study was to describe healthcare resource utilization and costs resulting from early (within 30 days of diagnosis) versus late (>30 days after diagnosis) treatment with prescriptions for H.P. Acthar(®) Gel (repository corticotropin injection; Acthar; Mallinckrodt) to manage infantile spasms (IS). METHODS: We included all patients in the Truven Health MarketScan(®) Commercial Claims and Encounters Database and the Truven Health MarketScan Multi-State Medicaid Database who were diagnosed with IS from 2007 to 2012. We performed unadjusted and adjusted regressions examining the relationship between healthcare resource utilization variables and their associated costs to compare outcomes in the early and late Acthar users. RESULTS: A total of 252 patients with IS who received Acthar fit our study criteria; 191 (76%) were early Acthar users. In adjusted analyses, we found that early Acthar use was associated with, on average, 3.8 fewer outpatient services (99% CI 0.7-6.7 fewer services). We did not find significant associations between early prescriptions for Acthar and number of hospitalizations, emergency room visits, prescription medications filled, or total costs of health services. CONCLUSION: Patients prescribed Acthar within 30 days of their IS diagnoses tended to have fewer outpatient services performed compared to patients prescribed Acthar later in the disease process. Although additional research is needed to confirm these exploratory findings, physicians may consider early treatment with Acthar to manage IS. FUNDING: This study was funded by a grant to the University of Washington from Mallinckrodt Pharmaceuticals.