High levels of interleukin-6 in patients with rheumatoid arthritis are associated with greater improvements in health-related quality of life for sarilumab compared with adalimumab.

BACKGROUND: Increased levels of cytokines, including interleukin-6 (IL-6), reflect inflammation and have been shown to be predictive of therapeutic responses, fatigue, pain, and depression in patients with rheumatoid arthritis (RA), but limited data exist on associations between IL-6 levels and health-related quality of life (HRQoL). This post hoc analysis of MONARCH phase III randomized controlled trial data evaluated the potential of baseline IL-6 levels to differentially predict HRQoL improvements with sarilumab, a fully human monoclonal antibody directed against both soluble and membrane-bound IL-6 receptor α (anti-IL-6Rα) versus adalimumab, a tumor necrosis factor α inhibitor, both approved for treatment of active RA. METHODS: Baseline serum IL-6 levels in 300/369 randomized patients were categorized into low (1.6-7.1 pg/mL), medium (7.2-39.5 pg/mL), and high (39.6-692.3 pg/mL) tertiles. HRQoL was measured at baseline and week (W)24 and W52 by Short Form 36 (SF-36) physical/mental component summary (PCS/MCS) and domain scores, Functional Assessment of Chronic Illness Therapy -fatigue, and duration of morning stiffness visual analog scale (AM-stiffness VAS). Linear regression of changes from baseline in HRQoL (IL-6 tertile, treatment, region as a stratification factor, and IL-6 tertile-by-treatment interaction as fixed effects) assessed predictivity of baseline IL-6 levels, with low tertile as reference. Pairwise comparisons of improvements between treatment groups were performed by tertile; least squares mean differences and 95% CIs were calculated. Similar analyses evaluated W24 patient-level response on minimum clinically important differences (MCID). RESULTS: At baseline, patients with high versus medium or low IL-6 levels (n = 100, respectively) reported worse (nominal p < 0.05) SF-36 MCS and role-physical, bodily pain, social functioning, role-emotional domain, and AM-stiffness VAS scores. There was a greater treatment effect with sarilumab versus adalimumab in high tertile versus low tertile groups in SF-36 PCS, physical functioning domain, and AM-stiffness VAS (nominal interaction p < 0.05). PCS improvements ≥MCID were higher in high (odds ratio [OR] 6.31 [2.37, 16.81]) versus low (OR 0.97 [0.43, 2.16]) tertiles with sarilumab versus adalimumab (nominal interaction p < 0.05). Adverse events between IL-6 tertiles were similar. CONCLUSIONS: Patients with high baseline IL-6 levels reported better improvements in PCS, physical functioning domain, and AM-stiffness scores with sarilumab versus adalimumab and safety consistent with IL-6R blockade. TRIAL REGISTRATION: NCT02332590 . Registered on 5 January 2015.

Biologic Disease-Modifying Antirheumatic Drug Prescription Patterns Among Rheumatologists in Europe and Japan.

INTRODUCTION: Tumor necrosis factor inhibitors (TNFi) are commonly used as first-line therapy (biologic disease-modifying antirheumatic drug [bDMARD] and targeted synthetic DMARD [tsDMARD]: defined as targeted therapy) for patients with moderate-to-severe rheumatoid arthritis (RA), usually combined with conventional synthetic DMARDs (csDMARDs) but sometimes as monotherapy. If treatment fails, patients cycle to another TNFi (cycling) or switch to a targeted therapy with a different mode of action (MOA; switching). The study aimed to examine prescribing patterns and reasons for current RA treatment practice in Europe (EU5: France, Germany, Italy, Spain, UK) and Japan. METHODS: Data were collected from the Adelphi Disease Specific Programme™ (DSP; Q1-Q2 2017). Rheumatologists seeing ≥ 10 (EU5) and ≥ 5 (Japan) patients with RA a month completed Patient Record Forms. Patients ≥ 18 years old, with RA diagnosis and complete RA-targeted therapy history were included. Patients were grouped based on first-line targeted therapy class, and on whether first-line targeted therapy was monotherapy (targeted therapy alone) or combination therapy (targeted therapy and csDMARD). Those patients receiving TNFi at first-line and with ≥ 1 targeted therapy were classified as TNFi cyclers or MOA switchers. Univariate analysis compared factors across groups. Patient demographics and characteristics compared across groups; physician reasoning for targeted therapy change; and time to discontinuation of targeted therapy. RESULTS: In EU5 and Japan, respectively, 1741 and 147 patients were included; at first-line, 80.8% and 64.6% received TNFi and 76.0% and 77.6% received combination therapy. Overall in EU5, more combination therapy than monotherapy patients reached maximum csDMARD dose before first-line targeted therapy (P < 0.05); disease severity was higher in patients initiating TNFi versus non-TNFi (P < 0.05). In Japan, trends were similar but not significant. The most common reason physicians gave for changing therapy following first-line targeted therapy was 'secondary lack of efficacy' (EU5: 46.2%; Japan: 53.8%). In EU5 and Japan, respectively, of 365 and 22 patients who received second-line targeted therapy, 52.1% and 54.5% were MOA switchers. In EU5, TNFi cyclers had longer time from diagnosis to second-line targeted therapy initiation than MOA switchers (P = 0.04). CONCLUSIONS: TNFis were the most commonly prescribed targeted therapy at first-line. Between 10 and 20% of patients prescribed a TNFi as first-line targeted therapy did so without concomitant csDMARD. Almost half of patients cycled to another TNFi at second-line.

Sarilumab and adalimumab differential effects on bone remodelling and cardiovascular risk biomarkers, and predictions of treatment outcomes.

BACKGROUND: Interleukin-6 (IL-6) is a pleiotropic cytokine that plays a key role in the pathogenesis of rheumatoid arthritis. Sarilumab is a human monoclonal antibody that binds membrane-bound and soluble IL-6 receptor-α to inhibit IL-6 signalling. The aim of this study was to compare the effects of sarilumab and adalimumab (a tumour necrosis factor alpha inhibitor) monotherapy on levels of circulating biomarkers associated with the acute-phase response, bone remodelling, atherothrombosis, anaemia of chronic disease and markers purported to reflect synovial lymphoid and myeloid cell infiltrates, as well as the potential of these biomarkers to differentially predict clinical and patient-reported outcomes with sarilumab vs. adalimumab. METHODS: In this post hoc analysis, serum samples were analysed at baseline and prespecified post-treatment timepoints up to week 24 in adults with moderate-to-severe active rheumatoid arthritis intolerant of or inadequate responders to methotrexate from the MONARCH trial (NCT02332590). RESULTS: Greater reductions in C-reactive protein (CRP; - 94.0% vs. -24.0%), serum amyloid A (SAA; - 83.2% vs. -17.4%), total receptor activator of nuclear factor-κB ligand (RANKL; - 18.3% vs. 10.5%) and lipoprotein (a) (- 41.0% vs. -2.8%) were observed at week 24 with sarilumab vs. adalimumab, respectively (adjusted p < 0.0001). Greater increases in procollagen type 1 N-terminal propeptide (P1NP) were observed with sarilumab vs. adalimumab at week 24 (22.8% vs. 6.2%, p = 0.027). Patients with high baseline SAA, CRP and matrix metalloproteinase-3 (MMP-3) were more likely to achieve clinical efficacy, including American College of Rheumatology 20% improvement criteria and Disease Activity Score (28 joints)-CRP < 3.2, and report improvements in patient-reported outcomes, including Health Assessment Questionnaire-Disability Index and pain visual analogue scale, with sarilumab than adalimumab. CONCLUSION: Sarilumab was associated with greater positive effects on bone remodelling and decreases in biomarkers of the acute-phase response, synovial inflammation and cardiovascular risk vs. adalimumab. High baseline concentrations of SAA, CRP and MMP-3 are predictive of clinical and patient-reported outcome responses to sarilumab treatment and prospective validation is warranted to confirm these results. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02332590. Registered on 5 January 2015.

Enhancing Statin Adherence Using a Motivational Interviewing Intervention and Past Adherence Trajectories in Patients with Suboptimal Adherence.

BACKGROUND: Statins have been shown to be effective in reducing the occurrence of cardiovascular (CV) events and are widely prescribed for the risk reduction of CV diseases and recurrent CV events. However, poor adherence prevents some patients from receiving the maximum benefit of the therapy. Motivational interviewing (MoI) is a patient-centered collaborative approach that can be used to improve medication adherence. Group-based trajectory modeling depicts patterns of adherence over time and may help tailor the MoI intervention to further enhance adherence. OBJECTIVE: To assess the effect of a phone-based MoI intervention tailored by patients' past adherence trajectory in improving adherence to statins among patients in a Medicare Advantage prescription drug plan (MAPD). METHODS: Patients continuously enrolled in an MAPD from 2013 to 2017 with a statin prescription between January and June 2015 to allow 2 years of pre-index period and 1 year of follow-up were included in the study. Adherence to statins was measured monthly during the 1-year follow-up as proportion of days covered (PDC) and incorporated into a group-based trajectory model to provide 4 distinct patterns of adherence: adherent, rapid decline, gradual decline, and gaps in adherence. Patients in the 3 nonadherent groups were randomized to either control or intervention. The intervention was an initial counseling call and up to 2 monthly follow-up calls by pharmacy students trained in MoI, providing education consistent with a previously identified pattern of use. Refill data at 6 months post-intervention were evaluated to examine the intervention's effect on PDC, as continuous and dichotomized as PDC ≥ 0.8, as well as discontinuation. Multivariable regression adjusted for baseline demographics, clinical characteristics, and past adherence trajectory. RESULTS: There were 152 patients included in the analysis who received MoI phone calls and 304 randomly selected controls. Mean PDC for the intervention group (0.67 ± 0.3) was significantly higher than the control (0.55 ± 0.4; P < 0.001). The intervention group was also less likely to discontinue (OR = 0.38; 95% CI = 0.19-0.76) and more likely to be adherent in the linear regression model (ß = 12.4; P < 0.001) as well as in the logistic regression model (OR = 1.87; 95% CI = 1.18-2.95). Previous adherence trajectories were significantly associated with adherence in the follow-up. CONCLUSIONS: Patients who received the MoI intervention were more likely to be adherent and less likely to discontinue the statin in the 6 months follow-up compared with controls. Future research can identify other approaches to tailor interventions and expand the intervention to other languages. This intervention may also prove valuable to improve adherence to other medications for chronic and asymptomatic diseases. DISCLOSURES: This study was funded by Regeneron Pharmaceuticals, which provided critical input during study design, implementation, and manuscript preparation. Abughosh reports grants from Sanofi, BMS/Pfizer, and Valeant Pharmaceuticals, unrelated to this study. Vadhariya reports a past internship at Regeneron Pharmaceuticals, unrelated to this study. Esse, Serna, and Gallardo are employees of CareAllies, a Cigna subsidiary. Boklage is an employee of Regeneron Pharmaceuticals. Choi was an employee of Sanofi during this study. Johnson, Essien, Fleming, and Holstad have nothing to disclose. A poster based on this study was presented at AMCP Nexus 2018; October 22-25, 2018; Orlando, FL.

Group-Based Trajectory Models to Identify Sociodemographic and Clinical Predictors of Adherence Patterns to Statin Therapy Among Older Adults.

BACKGROUND: The benefits of statins in the prevention of primary and secondary atherosclerotic cardiovascular (CV) disease events have been well documented. Suboptimal adherence is a persistent problem associated with increased CV events and increased healthcare utilization. Proportion of days covered (PDC) is widely used to measure medication adherence, and provides a single value that does not adequately depict different adherence behavior patterns. Group-based trajectory modeling has been used to identify adherence patterns (or trajectories) over time. The identification of characteristics unique to each pattern can help in the early identification of patients who are likely to be poor adherents and can inform the development of interventions. OBJECTIVES: To identify distinct trajectories of statin adherence in patients enrolled in a Medicare Advantage plan and the sociodemographic and clinical predictors associated with each trajectory. METHODS: Patients were included in the study if they were continuously enrolled in a Medicare Advantage plan between 2013 and 2016 and had a statin prescription between January 2015 and June 2015. We observed each patient for 360 days and computed the monthly PDC. The monthly PDC was incorporated into a group-based trajectory model to provide distinct patterns of adherence. Using group-based trajectory modeling, the patients were categorized into groups based on their adherence patterns. Multinomial logistic regression was performed to identify the sociodemographic and clinical factors associated with each group. RESULTS: A total of 7850 patients were included in the analysis and were categorized into 4 distinct groups based on statin adherence-rapid discontinuation (7.8%), gradual decline (16.8%), gaps in adherence (17.2%), and high or nearly perfect adherence (58.2%). Significant predictors of being placed into one or more of the low-adherence trajectories compared with the high-adherence trajectory included sex, age, low-income subsidy, language, Charlson Comorbidity Index score, statin intensity, and 90-day refills. CONCLUSIONS: The predictors identified in this study provide valuable insight into patient characteristics that increase the risk for statin nonadherence, which has the potential to inform targeted interventions. Identifying patient trajectories can inform the future development of protocols to individualize appropriate interventions for these patients.

Budget impact analysis of sarilumab for the treatment of rheumatoid arthritis in patients with an inadequate response to conventional synthetic DMARD or TNF inhibitor therapies.

OBJECTIVE: To estimate the 5-year budget impact (BI) on a US health plan of introducing sarilumab - a human immunoglobulin G1 anti-IL-6 receptor α monoclonal antibody - as combination treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or monotherapy in patients with moderate-to-severe rheumatoid arthritis (RA). METHODS: BI analysis was conducted from a commercial payer perspective. Treatment-eligible populations included adult patients with moderate-to-severe RA and inadequate response (IR) to csDMARDs or tumor necrosis factor (TNF)-α inhibitors-IR. All licensed biologic treatments recommended by the American College of Rheumatology guidelines were included. RESULTS: For a hypothetical plan of one million members, 409 csDMARD-IR and 345 TNF-IR patients were annually eligible for combination therapy and 226 csDMARD and TNF-IR patients for monotherapy with sarilumab. Based on 2018 US direct treatment costs, the introduction of sarilumab was estimated to save $526,424, $322,637 and $264,306 over 5 years for csDMARD-IR combination therapy patients, TNF-IR combination therapy patients, and csDMARD-IR/TNF-IR monotherapy patients, respectively. As sarilumab absorbed a greater market share over the horizon, annual savings increased from years 1 to 5, $28,610 (-0.14%) to $194,646 (-0.83%) in csDMARD-IR, $16,986 (-0.11%) to $120,893 (-0.67%) in TNF-IR, and $14,256 (-0.13%) to $98,040 (-0.79%) in monotherapy. One-way sensitivity analyses revealed that the model was most sensitive to variations in sarilumab adherence. CONCLUSION: Total cost savings of introducing sarilumab to a health-care plan accrued from years 1 to 5, attributable to the lower treatment cost, stable dosing paradigm, and price parity for the two available doses (150 and 200 mg every 2 weeks) compared with alternative biologic DMARDs that have substantial variability in dose titration/schedules.

Trends in Lipid Screening Among Adults in an Integrated Health Care Delivery System, 2009-2015.

BACKGROUND: Lipid screening determines eligibility for statins and other cardiovascular risk reduction interventions. OBJECTIVE: To examine trends in lipid screening among adults aged ≥20 years in a large, multiethnic, integrated health care delivery system in southern California. METHODS: Temporal trends in lipid screening were examined from 2009 to 2015 with an index date of September 30 of each year. Lipid screening was defined as the proportion of eligible members each year who (a) had ever been screened among those aged 20-39 years and (b) had been screened in the previous 6 years for those aged ≥ 40 years. Trends were analyzed by age, gender, and the presence of atherosclerotic cardiovascular disease (ASCVD) or diabetes without ASCVD status. RESULTS: More than 2 million individuals were included each year: 5%-6% had ASCVD (includes those with diabetes), 7%-8% had diabetes without ASCVD, and 87% had neither condition. Among the entire population, lipid screening increased from 79.8% in 2009 to 82.6% in 2015 (P < 0.0001). Among those with ASCVD or diabetes, lipid screening was 99% across all years. Among those without ASCVD or DM, screening increased from 76.9% in 2009 to 80.0% in 2015 (P < 0.0001), with higher screening among women compared with men and lower screening among individuals younger than 55 years. CONCLUSIONS: Consistently high rates of lipid screening were observed among individuals with ASCVD or diabetes. In individuals without these conditions, screening increased over time. However, there is room to further increase screening rates in adults younger than 55 years. DISCLOSURES: This manuscript and research work was supported by a contractual agreement between the Southern California Permanente Medical Group and Regeneron Pharmaceuticals and Sanofi U.S. Researchers from Regeneron and Sanofi collaborated on the study design, interpretation of data, and writing of the manuscript. Ling Grant, Harrison, Chang, Hsu, Cheetham, Wei, and Reynolds are employed by Kaiser Permanente Southern California. Scott is employed by Southern California Permanente Medical Group. Boklage is employed by Regeneron, and Romo-LeTourneau is employed by Sanofi. Preliminary results from this study were presented at the American Heart Association Scientific Sessions; November 12-16, 2016; New Orleans, LA.

Trends in Statin Use 2009-2015 in a Large Integrated Health System: Pre- and Post-2013 ACC/AHA Guideline on Treatment of Blood Cholesterol.

PURPOSE: Implementation of the 2013 ACC/AHA cholesterol treatment guideline is likely to vary by statin benefit group. The aim of this study was to document trends in statin use before and after introduction of the ACC/AHA guideline. METHODS: We conducted a retrospective study with annual cohorts from 2009 to 2015 among members of Kaiser Permanente Southern California aged ≥ 21 years. Members were categorized into four mutually exclusive statin benefit groups: atherosclerotic cardiovascular disease (ASCVD), LDL-C ≥ 190 mg/dL in the last year, diabetes (aged 40-75 years), and 10-year ASCVD risk ≥ 7.5% (aged 40-75 years). RESULTS: The cohorts ranged from 1,993,755 members in 2009 to 2,440,429 in 2015. Approximately 5% of patients had ASCVD, 1% had LDL-C ≥ 190 mg/dL, 6% had diabetes, and 10% had a 10-year ASCVD risk ≥ 7.5% each year. Trends in statin use were stable for adults with ASCVD (2009 78%; 2015 80%), recent LDL-C ≥ 190 mg/dL (2009 45%; 2015 44%), and diabetes (2009 74%; 2015 73%), but increased for patients with 10-year ASCVD risk ≥ 7.5% (2009 36%; 2015 47%). High-intensity statin use also increased 142% and 54% among patients with LDL-C ≥ 190 mg/dL and those with ASCVD ≤ 75 years of age, respectively. Moderate-to-high intensity statin utilization increased over 50% among those with a 10-year ASCVD risk ≥ 7.5%. CONCLUSIONS: Statin use increased substantially among patients with 10-year ASCVD risk ≥ 7.5% and use of appropriate statin dosage increased in each of the four statin benefit groups between 2009 and 2015; however, there is room for improvement.

Risk of Incident Atherosclerotic Cardiovascular DiseaseEvents by Achieved Atherogenic Lipid Levels Among62,428 Statin-Treated Individuals With Diabetes Mellitus.

The relevance of low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C) goals for primary prevention of atherosclerotic cardiovascular disease (ASCVD) among patients with diabetes was assessed. This retrospective cohort study included patients with type 2 diabetes, age 21 to 90years, taking statins, with no history of ASCVD as of January 1, 2006, in Kaiser Permanente Northern California, an integrated healthcare delivery system. Multivariate cox models were utilized to estimate hazard ratios (HRs) for incident ASCVD events by achieved LDL-C and non-HDL-C levels with adjustment for potential confounders. Incident ASCVD events were defined as a composite of myocardial infarction, ischemic stroke, or coronary heart disease death. A cohort of 62,428 patients, with mean age of 64.1years, 46.9% women, and mean follow-up of 6.0 years, was identified. After adjustment, the risk of incident ASCVD for these statin-treated patients was monotonically lower with decreasing achieved LDL-C levels (p<0.0001 for trend) and non-HDL-C levels (p <0.0001 for trend). Relative to achieved LDL-C ≥130 mg/dl, LDL-C <50 mg/dl had HR = 0.58 (95% confidence interval 0.49 to 0.69). Relative to achieved non-HDL-C ≥160mg/dl, non-HDL-C <80 mg/dl had HR = 0.59 (95% confidence interval 0.51 to 0.68). In a large cohort of statin-treated diabetic patients without ASCVD, a monotonically lower risk of incident ASCVD events was associated with lower achieved lipid levels. These findings support the use of LDL-C ornon-HDL-C treatment goals for ASCVD primary prevention in diabetic patients.

Statin Utilization Patterns and Outcomes for Patients with Acute Coronary Syndrome During and Following Inpatient Admissions.

PURPOSE: High-intensity statins (HIS) are recommended by current treatment guidelines for patients with clinical atherosclerotic cardiovascular disease and should be administered soon after an acute coronary syndrome (ACS) event and maintained thereafter. However, adherence to guidelines remains adequate. Statin utilization patterns during index hospitalization and the first year after ACS event, and the association between statin utilization and post-discharge clinical and economic outcomes, are described. METHODS: Retrospective, observational study of US adults from the MarketScan Research Databases (2002-2014) with ≥ 1 inpatient admission for ACS and no evidence of previous ACS event < 12 months prior to index. RESULTS: In total, 7802 patients met inclusion criteria. The most common index hospitalization primary diagnosis was myocardial infarction (94.6%). In the 3-month period before ACS admission, 3.4 and 14.9% of patients received HIS or low-to-moderate intensity statin, versus 13.2 and 30.7% during index hospitalization, and 16.4 and 45.1% in the year of follow-up. Of 1336 patients with a statin prescription filled on/after discharge, 53.2% filled prescriptions within 15 days of discharge and 14.9% delayed for > 91 days. The most common post-index hospital admissions for cardiovascular events were due to recurrent ACS (incidence rate = 115.2), heart failure (110.0), and revascularization (76.4). During follow-up, 2355 patients (30.2%) had all-cause inpatient admissions and 1136 (14.6%) had cardiovascular-specific admissions; mean all-cause medical and healthcare costs were $2456 and $2870, respectively, per patient per month. CONCLUSIONS: Statin dosing and utilization of HIS remains lower than recommended in current treatment guidelines, leaving patients at considerable risk of subsequent cardiovascular events.

Prescribing Patterns of Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors in Eligible Patients With Clinical Atherosclerotic Cardiovascular Disease or Heterozygous Familial Hypercholesterolemia.

Two proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors are approved for patients with atherosclerotic cardiovascular disease or heterozygous familial hypercholesterolemia who require additional low-density lipoprotein cholesterol (LDL-C) lowering. This retrospective study sought to determine differences between eligible patients who were prescribed and those who were not prescribed a PCSK9 inhibitor. Patients from an electronic medical record database were included in the analysis, and their demographic, clinical, and treatment characteristics were evaluated. Of 368,624 PCSK9 inhibitor-eligible patients, 1,752 (<0.5%) received a PCSK9 inhibitor prescription. Patients who received a PCSK9 inhibitor were more frequently associated with a higher cardiovascular disease risk category and a higher baseline LDL-C level (139.4 vs 103.5 mg/dl; p <0.0001) compared with those who did not. Patients with a PCSK9 inhibitor prescription were significantly more likely to be on ezetimibe, alone or in combination with a statin, at baseline compared with those without (29% vs 5%; p <0.0001). The use of a PCSK9 inhibitor was very low in the 2 groups of patients identified as PCSK9 inhibitor-eligible based on the American College of Cardiology Expert Consensus Decision Pathway. In conclusion, this study demonstrates that most PCSK9 inhibitor-eligible patients do not receive a PCSK9 inhibitor prescription, highlighting that many high-risk patients could benefit from additional LDL-C lowering with a PCSK9 inhibitor.

Budget Impact Analysis of PCSK9 Inhibitors for the Management of Adult Patients with Heterozygous Familial Hypercholesterolemia or Clinical Atherosclerotic Cardiovascular Disease.

OBJECTIVE: The aim of this study was to assess the budget impact of introducing the proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) alirocumab and evolocumab to market for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular (CV) disease requiring additional lowering of low-density lipoprotein cholesterol (LDL-C). METHODS: A 3-year model estimated the costs of lipid-modifying therapy (LMT) and CV events to a hypothetical US health plan of 1 million members, comparing two scenarios-with and without the availability of PCSK9i as add-on therapy to statins. Proportions of patients with uncontrolled LDL-C despite receiving statins, and at risk of CV events, were estimated from real-world data. Total undiscounted annual LMT costs (2017 prices, including PCSK9i costs of $14,563.50), dispensing and healthcare costs, including the costs of CV events, were estimated for all prevalent patients in the target population, based on baseline risk factors. Maximum PCSK9i utilization of 1-5% over 3 years according to risk group (following the same pattern as current ezetimibe use), and 5-10% as a secondary scenario, were assumed. RESULTS: Total healthcare budget impacts per target patient (and per member) per month for years 1, 2 and 3 were $3.62($0.10), $7.22($0.20) and $10.79($0.30), respectively, assuming 1-5% maximum PCSK9i utilization, and $15.81($0.44), $31.52($0.88) and $47.12($1.31), respectively, assuming 5-10% utilization. Results were sensitive to changes in model timeframe, years to maximum PCSK9i utilization and PCSK9i costs. CONCLUSIONS: The budget impact of PCSK9i as add-on therapy to statins for patients with hypercholesterolemia is relatively low compared with published estimates for other specialty biologics. Drug cost rebates and discounts are likely to further reduce budget impact.

Identification of Patients with Statin Intolerance in a Managed Care Plan: A Comparison of 2 Claims-Based Algorithms.

BACKGROUND: While statins are safe and efficacious, some patients may experience statin intolerance or treatment-limiting adverse events. Identifying patients with statin intolerance may allow optimal management of cardiovascular event risk through other strategies. Recently, an administrative claims data (ACD) algorithm was developed to identify patients with statin intolerance and validated against electronic medical records. However, how this algorithm compared with perceptions of statin intolerance by integrated delivery networks remains largely unknown. OBJECTIVE: To determine the concurrent validity of an algorithm developed by a regional integrated delivery network multidisciplinary panel (MP) and a published ACD algorithm in identifying patients with statin intolerance. METHODS: The MP consisted of 3 physicians and 2 pharmacists with expertise in cardiology, internal medicine, and formulary management. The MP algorithm used pharmacy and medical claims to identify patients with statin intolerance, classifying them as having statin intolerance if they met any of the following criteria: (a) medical claim for rhabdomyolysis, (b) medical claim for muscle weakness, (c) an outpatient medical claim for creatinine kinase assay, (d) fills for ≥ 2 different statins excluding dose increases, (e) decrease in statin dose, or (f) discontinuation of a statin with a subsequent fill for a nonstatin lipid-lowering therapy. The validated ACD algorithm identified statin intolerance as absolute intolerance with rhabdomyolysis; absolute intolerance without rhabdomyolysis (i.e., other adverse events); or as dose titration intolerance. Adult patients (aged ≥ 18 years) from the integrated delivery network with at least 1 prescription fill for a statin between January 1, 2011, and December 31, 2012 (first fill defined the index date) were identified. Patients with ≥ 1 year pre- and ≥ 2 years post-index continuous enrollment and no statin prescription fills in the pre-index period were included. The MP and ACD algorithms were applied to the population, and concordance was examined using individual (i.e., sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV]) and overall performance measures (i.e., accuracy, Cohen's kappa coefficient, balanced accuracy, F-1 score, and phi coefficient). RESULTS: After applying the inclusion criteria, 7,490 patients were evaluated for statin intolerance. The mean (SD) age of the population was 51.1 (8.5) years, and 55.7% were male. The MP and ACD algorithms classified 11.3% and 5.4% of patients as having statin intolerance, respectively. The concordance of the MP algorithm was mixed, with negative classification of statin intolerance measures having high concordance (specificity 0.91, NPV 0.97) and positive classification of statin intolerance measures having poor concordance (sensitivity 0.45, PPV 0.21). Overall performance measures showed mixed agreement between the algorithms. CONCLUSIONS: Both algorithms used a mix of pharmacy and medical claims and may be useful for organizations interested in identifying patients with statin intolerance. By identifying patients with statin intolerance, organizations may consider a variety of options, including using nonstatin lipid-lowering therapies, to manage cardiovascular event risk in these patients. DISCLOSURES: This study was funded by Regeneron Pharmaceuticals and Sanofi US. Boklage is employed by, and owns stock in, Regeneron, and Charland is employed by Sanofi. Bellows has received fees from Avenir for advisory board membership and grants from Myriad Genetics, Biogen, Janssen, and National Institutes of Health. Brixner reports advisory board and consultancy fees and grants from Sanofi. Mitchell reports consultancy fees from Sanofi. Study concept and design were contributed by Bellows, Boklage, Charland, and Brixner. Bellows, Sainski-Nguyen, and Olsen took the lead in data collection, along with Mitchell. Data interpretation was performed by Mitchell, along with the other authors. The manuscript was written by Bellows, Sainski-Nguyen, and Olsen and revised by all the authors.

The occurrence of hyponatremia and its importance as a prognostic factor in a cross-section of cancer patients.

BACKGROUND: Hyponatremia is prognostic of higher mortality in some cancers but has not been well studied in others. We used a longitudinal design to determine the incidence and prognostic importance of euvolemic and hypervolemic hyponatremia in patients following diagnosis with lymphoma, breast (BC), colorectal (CRC), small cell lung (SCLC), or non-small cell lung cancer (NSCLC). METHODS: Medical record and tumor registry data from two large integrated delivery networks were combined for patients diagnosed with lymphoma, BC, CRC, or lung cancers (2002-2010) who had ≥1 administration of radiation/chemotherapy within 6 months of diagnosis and no evidence of hypovolemic hyponatremia. Hyponatremia incidence was measured per 1000 person-years (PY). Cox proportional hazard models assessed the prognostic value of hyponatremia as a time-varying covariate on overall survival (OS) and progression-free survival (PFS). RESULTS: Hyponatremia incidence (%, rate) was 76 % each, 1193 and 2311 per 1000 PY, among NSCLC and SCLC patients, respectively; 37 %, 169 in BC; 64 %, 637 in CRC, and 60 %, 395 in lymphoma. Hyponatremia was negatively associated with OS in BC (HR 3.7; P = <.01), CRC (HR 2.4; P < .01), lung cancer (HR 2.4; P < .01), and lymphoma (HR 4.5; P < .01). Hyponatremia was marginally associated with shorter PFS (HR 1.3, P = .07) across cancer types. CONCLUSIONS: The incidence of hyponatremia is higher than previously reported in lung cancer, is high in lymphoma, BC, and CRC and is a negative prognostic indicator for survival. Hyponatremia incidence in malignancy may be underestimated. The effects of hyponatremia correction on survival in cancer patients require further study.

Cost-effectiveness analysis of universal noninvasive testing for post-treatment confirmation of Helicobacter pylori eradication and the impact of patient adherence.

BACKGROUND: The treatment failure rate for Helicobacter pylori eradication therapy is ~20% due to poor patient compliance and increased antibiotic resistance. This analysis assessed the cost-effectiveness of universal post-treatment testing to confirm eradication of H. pylori infection in adults. METHODS: Decision-analytic models evaluated the cost-effectiveness of universal post-treatment testing (urea breath test [UBT] or monoclonal fecal antigen test [mFAT]) vs no testing (Model 1), and UBT vs mFAT after adjusting for patient adherence to testing (Model 2) in adults who previously received first-line antimicrobial therapy. Patients testing positive received second-line quadruple therapy; no further action was taken for those testing negative or with no testing (Model 1) or for those nonadherent to testing (Model 2). In addition to testing costs, excess lifetime costs and reduced quality-adjusted life-years (QALYs) due to continuing H. pylori infection were considered in the model. RESULTS: Expected total costs per patient were higher for post-treatment testing (UBT: US$325.76; mFAT: US$242.12) vs no testing (US$182.41) in Model 1 and for UBT (US$336.75) vs mFAT (US$326.24) in Model 2. Expected QALYs gained per patient were 0.71 and 0.72 for UBT and mFAT, respectively, vs no testing (Model 1), and the same was 0.37 for UBT vs mFAT (Model 2). The estimated incremental costs per QALY gained for post-treatment testing vs no testing were US$82.90-US$202.45 and, after adjusting for adherence, US$28.13 for UBT vs mFAT. CONCLUSION: Universal post-treatment testing was found to be cost-effective for confirming eradication of H. pylori infection following first-line therapy. Better adherence to UBT relative to mFAT was the key to its cost-effectiveness.

Impact of patient adherence on the cost-effectiveness of noninvasive tests for the initial diagnosis of Helicobacter pylori infection in the United States.

OBJECTIVE: Previous US-based economic models of noninvasive tests for diagnosis of Helicobacter pylori infection did not consider patient adherence or downstream costs of continuing infection. This analysis evaluated the long-term cost-effectiveness of the urea breath test (UBT), fecal antigen test (FAT), and serology for diagnosis of H. pylori infection after incorporating information regarding test adherence. MATERIALS AND METHODS: A decision-analytic model incorporating adherence information evaluated the cost-effectiveness of the UBT, FAT, and serology for diagnosis of H. pylori infection. Positive test results led to first-line triple therapy; no further action was taken for nonadherence or negative results. Excess lifetime costs and reduced quality-adjusted life-years (QALYs) were estimated for patients with continuing H. pylori infection. RESULTS: In the base-case scenario with estimated adherence rates of 86%, 48%, and 86% for the UBT, monoclonal FAT, and serology, respectively, corresponding expected total costs were US$424.99, $466.41, and $404.98/patient. Test costs were higher for the UBT, but were fully or partially offset by higher excess lifetime costs for the monoclonal FAT and serology. The QALYs gained/patient with the UBT vs monoclonal FAT and serology were 0.86 and 0.27, respectively. The UBT was dominant vs the monoclonal FAT, leading to lower costs and higher QALYs; the UBT was cost-effective vs serology (incremental cost/QALY gained $74). CONCLUSION: Based on a comprehensive modeled analysis that included consideration of patient test adherence and long-term consequences resulting from continuing H. pylori infection, the UBT provided the greatest economic value among noninvasive tests for diagnosis of H. pylori infection, because of high patient adherence and excellent test performance.

Medical costs associated with use of systemic therapy in adults with colorectal cancer.

BACKGROUND: New cytotoxic agents and regimens, as well as immunotherapeutics, have recently been introduced for treatment of colorectal cancer (CRC).  OBJECTIVE: To identify the patient-related and clinical and treatment-related factors associated with higher total health care expenditures in newly diagnosed patients with CRC who are receiving systemic therapy (biologic or chemotherapy) from a commercially insured population.  METHODS: A longitudinal, retrospective analysis was employed to estimate costs and determinants of CRC treatment in a U.S. claims database for health care services used by commercial patients aged 18 to 64 years, who were diagnosed with CRC between January 1, 2005, and June 30, 2009. Generalized linear regression modeling was used to estimate the influence of demographic, clinical, and treatment factors on medical expenditures.  RESULTS: Among the 5,160 patients newly diagnosed with CRC, 99.6% of patients had chemotherapy; 32.6% had biologics; and 85.6% had other pharmaceuticals (excluding the chemotherapy and biologics of interest). The average annualized per patient cost of CRC treatment was $97,400 and consisted of chemotherapy ($17,500), biologics ($30,400), other pharmaceuticals ($2,300), inpatient treatment ($26,300), and outpatient treatment ($42,900). From first line only, first and second lines only, and third+ lines, the cost per patient was $70,500, $100,100, and $152,900, respectively. After adjusting for health care inflation, the average treatment cost of CRC patients increased by 73% from 2005 to 2009. Adjusted analyses showed that the higher medical cost for CRC patients was associated with use of new regimens, metastasis, comorbidities, surgery, radiation, insurance plan, age, sex, and region.   CONCLUSION: The health care cost of CRC treatment is increasing significantly over time, which is most likely caused by the use of new regimens, higher chances of surgery and radiation, and occurrence of various comorbidities and metastatic diseases due to increasing survival time.

Total costs and atrial fibrillation ablation success or failure in Medicare-aged patients in the United States.

INTRODUCTION: This retrospective cohort study compared the direct medical costs of successful versus unsuccessful catheter ablation in Medicare-aged patients with atrial fibrillation (AF), using medical claims data. METHODS: AF patients with > or = 12 months of continuous medical/pharmacy coverage pre- and postablation were identified from the MarketScan Medicare database (January 2003 to December 2006). For study inclusion, patients were required to have > or = 2 AF inpatient/outpatient visits within 6 months and to have received antiarrhythmic drug therapy within 12 months prior to the index ablation. Ablation success was defined as the absence of antiarrhythmic drug therapy 6-12 months postablation. RESULTS: Of 135 patients identified (67% men, mean age 73 years), ablation was successful in 69 (51.1%); most patients (96%) underwent a single procedure. Patients with successful ablation discontinued antiarrhythmic drug treatment after (mean) 54 days. Use of rate-control and anticoagulant drugs decreased after successful ablation, from 87% to 67% and from 86% to 64% of patients, respectively. Among failed ablation patients, 74% versus 70% received rate-control drugs, and 88% versus 82% received anticoagulants pre- versus postablation. Mean +/- SD per-patient procedural costs were $13,655+/-$12,761 for successful compared with $17,294+/-$26,502 (P=0.21) for failed ablation, while AF-related medical costs over 12 months postablation were $2394+/-$642 and $2703+/-$1706, respectively (P<0.001). Overall costs tended to be lower for successful ($16,049+/-$12,536) than for failed ($19,997+/-$13,958) AF ablation (P=0.07). These findings are subject to the limitations imposed by a retrospective database analysis and a small sample size. CONCLUSION: Outside the clinical-trial setting, catheter ablation for second-line treatment of AF proved unsuccessful in half of Medicare-aged patients. Direct medical costs did not differ significantly between patients with failed and successful ablations. The high rate and costs of AF ablation failure in the Medicare-aged population reinforce the need for better understanding of prognostic factors for ablation outcome.