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ImportanceLimited evidence is available on the comparative effectiveness of empagliflozin vs alternative second-line glucose-lowering agents in patients with type 2 diabetes (T2D) receiving routine care who have a broad spectrum of cardiorenal risk.ObjectiveTo evaluate the association of empagliflozin with cardiovascular outcomes relative to liraglutide and sitagliptin, stratified by age, sex, baseline atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and chronic kidney disease (CKD).Design, Setting, and ParticipantsThis retrospective comparative effectiveness cohort study used deidentified Medicare claims data from August 1, 2014, to September 30, 2018, with follow-up from drug initiation until treatment changes, death, or gap in Medicare enrollment (>30 days). Data analysis was performed from October 1, 2021, to April 30, 2022. Medicare fee-for-service beneficiaries older than 65 years with T2D were included. A total of 45 788 patients (22 894 propensity score–matched pairs initiating treatment with either empagliflozin or liraglutide) were included in cohort 1, and 45 624 patients (22 812 propensity score–matched pairs initiating treatment with either empagliflozin or sitagliptin) were included in cohort 2.ExposuresEmpagliflozin vs liraglutide (cohort 1) or empagliflozin vs sitagliptin (cohort 2).Main Outcomes and MeasuresPrimary outcomes were (1) modified major adverse cardiovascular events (MACEs), including a composite of myocardial infarction, stroke, and all-cause mortality, and (2) hospitalization for heart failure (HHF). Hazard ratios (HRs) and rate differences (RDs) per 1000 person-years were estimated, adjusting for 143 baseline covariates using 1:1 propensity score matching.ResultsAmong 45 788 patients in cohort 1, the mean (SD) age was 71.9 (5.1) years; 23 396 patients (51.1%) were female, 22 392 (48.9%) were male, and 38 049 (83.1%) were White. Among 45 624 patients in cohort 2, the mean (SD) age was 72.1 (5.1) years; 21 418 patients (46.9%) were female, 24 206 (53.1%) were male, and 37 814 (82.9%) were White. Relative to patients initiating liraglutide, those initiating empagliflozin had a similar risk of the modified MACE outcome (HR, 0.90; 95% CI, 0.79-1.03) and a reduced risk of HHF (HR, 0.66; 95% CI, 0.52-0.82). Across subgroups, empagliflozin was associated with a lower risk of the modified MACE outcome in patients with a history of ASCVD (HR, 0.83; 95% CI, 0.71-0.98) and HF (HR, 0.77; 95% CI, 0.60-1.00) compared with liraglutide, and potential heterogeneity in estimates was observed by sex (male: HR, 0.85 [95% CI, 0.71-1.01]; female: HR, 1.16 [95% CI, 0.94-1.42]; P = .02 for homogeneity). However, reductions in the risk of HHF were observed across most subgroups (eg, ASCVD: HR, 0.66 [95% CI, 0.51-0.85]; HF: HR, 0.66 [95% CI, 0.49-0.88]). Compared with sitagliptin, empagliflozin was associated with reduced risks of the modified MACE outcome (HR, 0.68; 95% CI, 0.60-0.77) and HHF (HR, 0.45; 95% CI, 0.36-0.56), which were consistent across all subgroups. Absolute benefits of empagliflozin vs sitagliptin were larger in patients with a history of ASCVD (modified MACE: RD, −17.6 [95% CI, −24.9 to −10.4]; HHF: RD, −16.7 [95% CI, −21.7 to −11.9]), HF (modified MACE: RD, −41.1 [95% CI, −59.9 to −22.6]; HHF: RD, −50.4 [95% CI, −67.5 to −33.9]), or CKD (modified MACE: RD, −26.7 [95% CI, −41.3 to −12.3]; HHF: RD, −31.9 [95% CI, −43.5 to −20.8]).Conclusions and RelevanceIn this comparative effectiveness study of older adults, empagliflozin was associated with a lower risk of HHF (relative to both liraglutide and sitagliptin) and the modified MACE outcome (relative to sitagliptin), with larger absolute benefits in patients with established cardiorenal diseases. These findings suggest that older adults with T2D might benefit more from empagliflozin vs liraglutide or sitagliptin with respect to the risk of HHF; with respect to the risk of MACEs, empagliflozin might be preferable to liraglutide only in patients with cardiovascular disease history and to sitagliptin across all patient subgroups.

Launched in 2002, originator adalimumab (Humira) is the top revenue-generating drug in the United States. Between 2016 and 2019, the US Food and Drug Administration approved 5 adalimumab biosimilars, yet none have been marketed owing to patent dispute settlements. We sought to calculate the cost of this delayed entry to Medicare over this period by estimating the difference between reported spending on originator adalimumab and estimated spending on originator and biosimilar adalimumab products assuming timely biosimilar market entry. Estimates of potential biosimilar spending were calculated based on the following evidence-based projections: (i) market capture of 15% for the first biosimilar and 5.5% for successive biosimilars in their first year on the market, and 5% annually thereafter; (ii) price reductions of 3.5% per year and 2.4% per additional biosimilar entry for originator adalimumab; and (iii) price discounts of 25% at launch, 3.4% per year, and 1.7% per additional biosimilar entry for biosimilar adalimumab. Based on these assumptions, had adalimumab biosimilars launched upon approval, estimated non-rebate spending on them would have been $18.3 million in 2016, $225.7 million in 2017, $436.2 million in 2018, and $727.7 million in 2019, whereas estimated non-rebate spending on originator adalimumab would have been $2.33 billion, $2.04 billion, $1.78 billion, and $1.42 billion. Cumulative spending on adalimumab would have thus been $8.98 billion instead of an observed $12.11 billion. Accounting for estimated rebates, total predicted savings would have been $2.19 billion. Reforms for timely biosimilar availability will be critical in ensuring optimal savings for Medicare after biosimilar approval.

Within the EMPRISE® monitoring program, we evaluated the cardiovascular effectiveness of empagliflozin (EMPA) vs. glucagon-like peptide-1 receptor agonists (GLP1RA) or liraglutide using data from Medicare and 2 U.S. commercial claims databases [2014- (2018 for Medicare) ]. We identified patients ≥18 years with type 2 diabetes initiating (i) EMPA vs. GLP1-RA or (ii) EMPA vs. liraglutide. Primary outcomes were hospitalization for heart failure (HHF) , myocardial infarction (MI) , stroke, and all-cause mortality (Medicare only) . After 1:1 propensity score matching, we estimated pooled HR (95% CI) overall and in subgroups of patients with and without baseline cardiovascular disease (CVD) . We identified 105,955 pairs of EMPA vs. GLP1RA initiators and 72,498 pairs of EMPA vs. liraglutide initiators (Table) . Relative to GLP1RA, EMPA had a lower risk of HHF [HR:0.62 (95% CI, 0.53, 0.71) ] and a similar risk of MI [0.95 (0.85, 1.07) ], stroke [1. (0.94, 1.27) ], and mortality [0.91 (0.77, 1.08) ]. Results were consistent for patients with and without CVD. When we compared EMPA vs. liraglutide, estimates were similar to those from GLP1 RA, both overall and across subgroups. Among real-world patients, EMPA was associated with a reduced risk of HHF, but with similar risk of MI, stroke, and mortality, across the broad spectrum of CVD, compared with GLP-1RA overall or liraglutide. Disclosure P.T.Htoo: Employee; Johnson & Johnson. S.Schneeweiss: None. E.Patorno: Research Support; Boehringer Ingelheim International GmbH, National Institutes of Health, Patient-Centered Outcomes Research Institute. H.Tesfaye: None. J.M.Paik: None. D.J.Wexler: Other Relationship; Elsevier, Novo Nordisk, UpToDate. M.Najafzadeh: None. R.Glynn: Research Support; Amarin Corporation, AstraZeneca, Kowa Pharmaceuticals America, Inc., Novartis AG, Pfizer Inc. A.Deruaz-luyet: Employee; Boehringer Ingelheim International GmbH, Other Relationship; IQVIA Inc., Sanofi. S.F.Fazeli farsani: Employee; Boehringer Ingelheim International GmbH. L.Koeneman: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company.

EMPRISE is a 5-year monitoring program that evaluates the effectiveness and safety of empagliflozin (EMPA) using Medicare and 2 U.S. commercial claims [2014-20 (2018 for Medicare) ]. We identified 190,226 patients ≥18 years with type 2 diabetes initiating EMPA or a dipeptidyl peptidase-4 inhibitors (DPP-4i) , and followed them up for heart failure hospitalization in primary (HHF-Specific) or any discharge positions (HHF-Broad) , a composite of myocardial infarction (MI) and stroke, and all-cause mortality (ACM) (Medicare only) . Safety outcomes were lower-limb amputations (LLA) , non-vertebral fractures, diabetic ketoacidosis (DKA) , acute kidney injury (AKI) , renal and bladder cancers (CA) . We estimated pooled HR (95% CI) after propensity score matching, adjusting for 143 baseline covariates. Compared to DPP4i, EMPA was associated with a reduced risk of HHF [HHF-Specific: 0.47 (0.41, 0.55) ; HHF-Broad: 0.67 (0.62, 0.72) ], a similar risk of the composite of MI or stroke [0.92 (0.84, 1.02) ], and a reduced risk of ACM [0.56 (0.46, 0.68) ]. EMPA was associated with a reduced risk of AKI [0.73 (0.68, 0.78) ], an increased risk of DKA [1.88 (1.51, 2.34) ], and a similar risk of LLA, fractures, and renal and bladder CA. Our findings support the cardiovascular effectiveness of EMPA in routine care with a safety profile in line with documented information. Disclosure P.T.Htoo: Employee; Johnson & Johnson. S.Schneeweiss: Consultant; Aetion, Inc., Research Support; Boehringer Ingelheim International GmbH. E.Patorno: Research Support; Boehringer Ingelheim International GmbH, National Institutes of Health, Patient-Centered Outcomes Research Institute. H.Tesfaye: None. J.M.Paik: None. D.J.Wexler: Other Relationship; Elsevier, Novo Nordisk, UpToDate. M.Najafzadeh: None. R.Glynn: Research Support; Amarin Corporation, AstraZeneca, Kowa Pharmaceuticals America, Inc., Novartis AG, Pfizer Inc. A.Deruaz-luyet: Employee; Boehringer Ingelheim International GmbH, Other Relationship; IQVIA Inc., Sanofi. S.F.Fazeli farsani: Employee; Boehringer Ingelheim International GmbH. L.Koeneman: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company.

List prices for brand-name drugs have risen steeply, often despite the introduction of competition from other brand-name drugs in the same therapeutic class. List prices, however, do not reflect an...

BACKGROUND/OBJECTIVES Restricted mean survival time (RMST) summarizes treatment effect in terms of a gain or loss in the event-free days. It remains uncertain whether communicating treatment benefit and harm using RMST-based summary is more effective than conventional summary based on absolute and relative risk reduction. We compared the effect of RMST-based approach and conventional approach on decisional conflict using an example of intensive versus standard blood pressure-lowering strategies. DESIGN On-line survey. SETTING A convenience sample of patients in the United States. PARTICIPANTS Two hundred adults aged 65 and older with hypertension requiring anti-hypertensive treatment (response rate 85.5%). INTERVENTIONS Participants were randomly assigned to either RMST-based summary or conventional summary about the benefit and harm of blood pressure-lowering strategies. MEASUREMENTS Decisional Conflict Scale (DCS), ranging from 0 (no conflict) to 100 (high conflict), and preference for intensive blood pressure-lowering strategy. RESULTS Participants assigned to RMST-based approach (n = 100) and conventional approach (n = 100) had similar age (mean [standard deviation, SD]: 72.3 [5.6] vs 72.8 [5.5] years) and proportions of female (50 [50.0%] vs 61 [61.0%]) and white race (92 [92.0%] vs 92 [92.0%]). The mean (SD) DCS score was 25.2 (15.0) for RMST-based approach and 25.6 (14.1) for conventional approach (p = 0.84). The number (%) of participants who preferred intensive strategy was 10 (10.0%) for RMST-based approach and 14 (14.0%) for conventional approach (p = 0.52). The results were consistent in subgroups defined by age, sex, education level, cardiovascular disease status, and predicted mortality risk categories. CONCLUSION In a sample of relatively healthy older adults with hypertension, RMST-based approach was as effective as conventional approach on decisional conflict about choosing a blood pressure-lowering strategy. This study provides proof-of-concept evidence that RMST-based approach can be used in conjunction with absolute and relative risk reduction for communicating treatment benefit and harm in a decision aid.

Non-cardiovascular multimorbidity often coexists in older adults with cardiovascular disease (CVD), but their clinical significance is uncertain. Using Medicare data, we examined common non-cardiovascular comorbidity patterns and their association with clinical outcomes in beneficiaries with congestive heart failure (CHF), acute myocardial infarction (AMI), or atrial fibrillation (AF). We created 3 CVD cohorts of beneficiaries diagnosed with CHF (n=57,285), AMI (n=24,808), and AF (n=36,277) before January 1, 2016. Within each cohort, we applied latent class analysis to classify beneficiaries based on 7 non-cardiovascular comorbidities, including dementia, cancer, chronic kidney disease (CKD), chronic lung disease, depression, diabetes, and musculoskeletal disease. Mortality, cardiovascular and non-cardiovascular hospitalization, and home time lost until December 31, 2016 were compared across non-cardiovascular multimorbidity classes. Similar non-cardiovascular multimorbidity classes emerged from 3 CVD cohorts: 1) minimal, 2) depression (or lung-depression in AMI cohort), 3) diabetes-CKD, and 4) multi-system class. Compared to minimal class, multi-system class had the highest risk of mortality (hazard ratio [HR], 3.0 to 3.7), cardiovascular hospitalization (HR, 1.6 to 3.4) and non-cardiovascular hospitalization (HR, 2.8 to 6.0), and home time lost (rate ratio, 2.8 to 4.8), followed by lung-depression/depression or diabetes-CKD classes. In CHF and AF cohorts, multimorbidity classes were associated with greater increase in non-cardiovascular hospitalizations than cardiovascular hospitalizations. Our findings emphasize that improving health of older adults with CVD requires attention to non-cardiovascular multimorbidity.

This article presented a solution for torsion vibration a nanotube made of pores material. Based on the porosity distribution, the material properties are assumed to vary according to a function al...

Introduction: Under-treatment with oral anticoagulants (OAC) in atrial fibrilliation (AF) is a persistent management gap, particularly in older adults. Understanding patterns of OAC adoption may enable design of implementation strategies to improve evidence-based care. Objectives: Determine changes in OAC use and overall uptake of direct oral anticoagulants (DOACs) in older adults. Methods: We analyzed administrative claims data (years 2010 to 2018) from Optum Clinformatics Data Mart to identify Medicare Advance Plan beneficiaries (aged ≥65) with AF and CHA 2 DS 2 -VASc score ≥2. We excluded patients with history of intracranial hemorrhage and end-stage renal disease. We calculated the proportion of patients prescribed a DOAC, warfarin, or no OAC each year. We examined uptake by patient subgroups, including those with dementia diagnoses and those with frailty, defined by a claims-based frailty index. Results: Our sample size ranged from 123,700 in 2010 to 398,385 in 2018. The mean age ranged 76-79 years and the proportion of women ranged 50-53%. The proportion of eligible patients receiving OAC increased from 50.9% to 53.8% for the total sample (+2.9%) (Figure A). This increase was greater for younger patients (65-79 years: 53.7% to 58.1% vs ≥80 years: 48.9 to 49.5%) (Figures B & C), those with dementia (dementia: 39.6% to 44.8% vs no dementia: 52.5% to 55.3%) (Figures D & E), and those with frailty (frailty: 48.1% to 52.1% vs no frailty: 53.4% to 55.3%) (Figures F & G). There was a consistent decreasing trend in warfarin use in all subgroups from 2010 to 2018 (51 to 19 % in the total population, Figures A-G). Conclusion: Following the advent of DOACs, overall OAC use modestly increased in older adults, including for those with dementia and frailty. A large proportion of patients with guidelines-based eligibility for OAC remain untreated. Implementation strategies for improving OAC use are needed, particularly for high-risk older patients who stand to benefit the most.

The EMPA-REG OUTCOME trial showed cardioprotective effects of empagliflozin (EMPA) in patients with established cardiovascular diseases (CVD). Within the Empagliflozin Comparative Effectiveness and Safety (EMPRISE) multi-database study of patients in routine care, we evaluated the relative cardiovascular benefits of EMPA versus therapeutic alternatives in older patients with type 2 diabetes (T2D) across the broad spectrum of cardiovascular risk. Using Medicare data (08/2014-09/2018), we identified 31,719 pairs of 1:1 propensity score-matched (PSM) T2D patients ≥65 years initiating EMPA or a GLP-1RA [Cohort 1], and 23,307 pairs initiating EMPA or a DPP-4i [Cohort 2]. We assessed (i) a modified major adverse cardiovascular event (MACE) outcome (MI, stroke, all-cause mortality) and (ii) hospitalization for heart failure (HHF) in primary discharge position. In each cohort, we estimated hazard ratios (HR) and rate differences (RD) per 1,000 person years of follow-up, adjusting for >140 baseline covariates and accounting for death as a competing risk, overall and in subgroups (i) with and (ii) without baseline CVD (that includes atherosclerotic CVD and HF). After PSM, exposure groups had similar characteristics (Table 1). Compared to GLP-1RA, EMPA had a similar risk of the modified MACE outcome [HR (95% CI): 1.05 (0.93,1.18)] and a reduced risk of HHF [HR 0.70 (0.57,0.86)]. Absolute benefit for HHF was larger in patients with CVD [RD -6.24 (-9.92, -2.56)] than in patients without CVD [RD -0.81 (-2.15, 0.54)]. Compared to DPP-4i, EMPA reduced the risk of both modified MACE outcome [HR: 0.67(0.59,0.77)] and HHF [HR: 0.46 (0.37,0.57)]. For both outcomes, the absolute benefit with EMPA was larger among patients with CVD compared to those without CVD. EMPA reduced the risk of HHF vs. GLP-1RA and DPP-4i and the risk of a modified MACE outcome vs. DPP-4i. The absolute benefit associated with EMPA was larger among patients with CVD compared to those without CVD.

Objective Over 99% of the EMPA-REG OUTCOME trial participants had established cardiovascular disease (CVD). We aimed to investigate effectiveness and safety outcomes among patients with type 2 diabetes (T2D) initiating empagliflozin vs dipeptidyl peptidase-4 inhibitor (DPP-4i) across the broad spectrum of cardiovascular risk. Methods In a population-based cohort study we identified 39,072 pairs of 1:1 propensity score-matched adult patients with T2D initiating empagliflozin or DPP-4i, using data from 2 U.S. commercial insurance databases and Medicare between 08/2014-09/2017. Primary outcomes were a composite of myocardial infarction (MI)/stroke, and hospitalization for heart failure (HHF). Safety outcomes were bone fractures, lower-limb amputations (LLA), diabetic ketoacidosis (DKA), and acute kidney injury (AKI). We estimated pooled hazard ratios (HR) and 95% CI adjusting for >140 baseline covariates. Results Study participants had mean age of 60 years and only 28% had established CVD. Compared to DPP-4i, empagliflozin was associated with similar risk of MI/stroke [HR (95% CI), 0.99 (0.81-1.21)], and lower risk of HHF [0.48 (0.35-0.67) and 0.63 (0.54-0.74), based on a primary and any HF discharge diagnosis, respectively]. The HR was 0.52 (0.38-0.72) for all-cause mortality (ACM) and 0.83 (0.70-0.98) for a composite of MI/stroke/ACM. Empagliflozin was associated with a similar risk of LLA and fractures, an increased risk of DKA [1.71 (1.08-2.71)], and a decreased risk of AKI [0.60 (0.43-0.85)]. Conclusions In clinical practice, the initiation of empagliflozin vs DPP-4i was associated with a lower risk of HHF, ACM, and MI/stroke/ACM, a similar risk of MI/stroke, and a safety profile consistent with documented information. This article is protected by copyright. All rights reserved.

BackgroundRestricted mean survival time analysis offers an intuitive and robust summary of treatment effect compared with HRs.ObjectiveTo examine the effect of intensive versus standard blood pressure (BP) control on death or cardiovascular events in type 2 diabetes.DesignSecondary analysis of the Action to Control Cardiovascular Risk in Diabetes Blood Pressure trial.Setting77 sites in the USA and Canada.Participants4733 adults with type 2 diabetes at high risk for cardiovascular events.InterventionsSystolic BP target MeasurementsComposite endpoint of death, non-fatal myocardial infarction or non-fatal stroke.ResultsThe mean event-free survival time over 5 years (1825 days) was similar between intensive and standard BP control (1716 vs 1714 days; mean difference, 1.3 (95% CI −18.1 to 20.7) days). However, intensive BP treatment was more beneficial for those assigned to standard glycaemic control (1725 vs 1697 days; mean difference, 28.1 (95% CI 0.4 to 55.9) days), but not for those assigned to intensive glycaemic control (1706 vs 1731 days; mean difference, −25.2 (95% CI −52.3 to 1.9) days) (p=0.008 for interaction). In subgroup analysis, the mean event-free survival time difference between intensive and standard BP treatment was −76.0 (95% CI –131.8 to –20.3) days for those with cognitive impairment and 21.8 (95% CI −24.0 to 67.5) days for those with normal cognitive function (p=0.008 for interaction). The effect was not different by age, sex and baseline cardiovascular disease status.ConclusionsIntensive BP treatment may reduce death and cardiovascular events among patients with type 2 diabetes receiving standard glycaemic treatment and without cognitive impairment.Trial registration numberNCT00000620; Post-results.

In the EMPA REG OUTCOME trial, empagliflozin (EMPA) reduced the risk of cardiovascular (CV) death, all-cause mortality, and hospitalization for heart failure (HHF) in patients with type 2 diabetes (T2D) and established CV disease (CVD). We assessed the CV effectiveness of EMPA in real-world T2D patients with and without CVD within EMPRISE, a study on the effectiveness, safety and healthcare utilization of EMPA, based on Medicare and 2 U.S. commercial claims datasets (2014-2019). Using data from 2014-2018 (2014-2017 in Medicare), we identified 1:1 propensity score-matched patients ≥18 years with T2D initiating EMPA or a DPP4 inhibitor (DPP4i) with and without CVD (14,920 and 40,443 matched pairs). We assessed HHF, a composite of MI or stroke, an expanded atherosclerotic CV (ASCV) event (MI, stroke, unstable angina, or coronary revascularization), and death. We estimated pooled HR and RD with 95% CI adjusting for >140 covariates. Over a mean follow-up of 6.3 months, EMPA vs. DPP4i initiators with and without CVD had reductions in the risk of HHF [HR, 0.71 (0.60-0.84) and 0.55 (0.42-0.73)] and mortality [HR, 0.53 (0.37-0.76) and 0.46 (0.29-0.74)], with larger benefits in patients with CVD on an absolute risk scale as shown by RD, but similar risk of ASCV events, including MI or stroke (Table). EMPA was associated with risk reductions in HHF and mortality, but similar risk of ASCV events in patients with and without CVD. Disclosure E. Patorno: Research Support; Self; Boehringer Ingelheim International GmbH, National Institutes of Health. S. Schneeweiss: Other Relationship; Self; Aetion. H. Tesfaye: None. D. J. Wexler: Board Member; Self; Novo Nordisk. R. Glynn: Research Support; Self; AstraZeneca, Kowa Research Institute, Inc., Novartis AG, Pfizer Inc. M. Najafzadeh: None. L. G. Bessette: Consultant; Self; Aetion, Inc. L. Zabotka: None. L. Koeneman: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. A. Deruaz-luyet: Employee; Self; Boehringer Ingelheim (Canada) Ltd., Employee; Spouse/Partner; Sanofi-Aventis Deutschland GmbH.

In the EMPA-REG OUTCOME trial empagliflozin (EMPA) reduced the risk of cardiovascular death, all-cause mortality, and hospitalization for heart failure in patients with type 2 diabetes (T2D) and established cardiovascular disease. The comparative safety of EMPA in routine care is yet to be established. EMPRISE studies the effectiveness, safety and healthcare utilization of EMPA, based on data from Medicare and 2 U.S. commercial claims datasets (2014-2019). In an interim analysis using data from 2014-2018 (2014-2017 in Medicare), we identified 55,580 pairs of 1:1 propensity score-matched patients ≥18 years with T2D initiating EMPA or a DPP4 inhibitor (DPP4i). Safety outcomes of interest included lower-limb amputations (LLA), bone fractures, diabetic ketoacidosis hospitalization (DKA), and acute kidney injury hospitalization (AKI). We estimated pooled HR and RD/1000 PY with their 95% CI adjusting for >140 baseline covariates. Over a mean follow up of 6.3 months, EMPA initiators had similar risk of LLA and fractures, an increased risk of DKA [HR, 2.01 (1.37-2.95); RD, 1.44 (0.72,2.17) per 1000 PY], and a decreased risk of AKI [HR, 0.66 (0.59-0.74); RD, -8.59 (-10.93,-6.25) per 1000 PY], compared with DPP4i (Table). In routine care, the initiation of EMPA was associated with a safety profile in line with documented information. Disclosure E. Patorno: Research Support; Self; Boehringer Ingelheim International GmbH, National Institutes of Health. S. Schneeweiss: Other Relationship; Self; Aetion. H. Tesfaye: None. D. J. Wexler: Board Member; Self; Novo Nordisk. R. Glynn: Research Support; Self; AstraZeneca, Kowa Research Institute, Inc., Novartis AG, Pfizer Inc. M. Najafzadeh: None. L. G. Bessette: Consultant; Self; Aetion, Inc. H. Zakoul: None. L. Koeneman: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. A. Deruaz-luyet: Employee; Self; Boehringer Ingelheim (Canada) Ltd., Employee; Spouse/Partner; Sanofi-Aventis Deutschland GmbH.

Sequential analysis is used in clinical trials and postmarket drug safety surveillance to prospectively monitor efficacy and safety to quickly detect benefits and problems, while taking the multiple testing of repeated analyses into account. When there are multiple outcomes, each one may be given a weight corresponding to its severity. This paper introduces an exact sequential analysis procedure for multiple weighted binomial end points; the analysis incorporates a drug’s combined benefit and safety profile. It works with a variety of alpha spending functions for continuous, group, or mixed group-continuous sequential analysis. The binomial probabilities may vary over time and do not need to be known a priori. The new method was implemented in the free R Sequential package for both one- and two-tailed sequential analysis. An example is given examining myocardial infarction and major bleeding events in patients who initiated non-steroidal antiinflammatory drugs.

Background: The EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 diabetes Mellitus Patients) showed that empagliflozin, a sodium-glucose cotransporter-2 inhibitor, reduces the risk of hospitalization for heart failure (HHF) by 35%, on top of standard of care in patients with type 2 diabetes mellitus (T2D) and established cardiovascular disease. The EMPRISE (Empagliflozin Comparative Effectiveness and Safety) study aims to assess empagliflozin’s effectiveness, safety, and healthcare utilization in routine care from August 2014 through September 2019. In this first interim analysis, we investigated the risk of HHF among T2D patients initiating empagliflozin versus sitagliptin, a dipeptidyl peptidase-4 inhibitor. Methods: Within 2 commercial and 1 federal (Medicare) claims data sources in the United States, we identified a 1:1 propensity score–matched cohort of T2D patients ≥18 years old initiating empagliflozin or sitagliptin from August 2014 through September 2016. The HHF outcome was defined as a HF discharge diagnosis in the primary position (HHF-specific); a broader definition was based on a HF discharge diagnosis in any position (HHF-broad). Hazard ratios (HRs) and 95% CIs were estimated controlling for over 140 baseline characteristics in each data source and pooled by fixed-effects meta-analysis. Results: After propensity-score matching, we identified 16,443 patient pairs who initiated empagliflozin or sitagliptin. Average age was approximately 59 years, almost 54% of the participants were males, and approximately 25% had records of existing cardiovascular disease. Compared with sitagliptin, the initiation of empagliflozin decreased the risk of HHF-specific by 50% (HR, 0.50; 95% CI, 0.28–0.91), and the risk of HHF-broad by 49% (HR, 0.51;95% CI, 0.39–0.68), over a mean follow-up of 5.3 months. The results were consistent in patients with and without baseline cardiovascular disease, and for empagliflozin at both the 10- and 25-mg daily doses; analyses comparing empagliflozin versus the dipeptidyl peptidase-4 inhibitor class, and comparing sodium-glucose cotransporter-2 inhibitor versus dipeptidyl peptidase-4 inhibitor classes also produced consistent findings. Conclusions: The first interim analysis from EMPRISE showed that compared with sitagliptin, the initiation of empagliflozin was associated with a decreased risk of HHF among patients with T2D as treated in routine care, with and without a history of cardiovascular disease. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03363464.

Bronchoscopy is the safest procedure for lung cancer diagnosis when an invasive evaluation is required after imaging procedures. However, its sensitivity is relatively low, especially for small and peripheral lesions. We assessed benefits and costs of introducing a bronchial gene-expression classifier (BGC) to improve the performance of bronchoscopy and the overall diagnostic process for early detection of lung cancer. We used discrete-event simulation to compare clinical and economic outcomes of two different strategies with the standard practice in former and current smokers with indeterminate nodules: (i) location-based strategy-integrated the BGC to the bronchoscopy indication; (ii) simplified strategy-extended use of bronchoscopy plus BGC also on small and peripheral lesions. Outcomes modeled were rate of invasive procedures, quality-adjusted-life-years (QALYs), costs and incremental cost-effectiveness ratios. Compared to the standard practice, the location-based strategy (i) reduced absolute rate of invasive procedures by 3.3% without increasing costs at the current BGC market price. It resulted in savings when the BGC price was less than $3,000. The simplified strategy (ii) reduced absolute rate of invasive procedures by 10% and improved quality-adjusted life expectancy, producing an incremental cost-effectiveness ratio of $10,109 per QALY. In patients with indeterminate nodules, both BGC strategies reduced unnecessary invasive procedures at high risk of adverse events. Moreover, compared to the standard practice, the simplified use of BGC for central and peripheral lesions resulted in larger QALYs gains at acceptable cost. The location-based is cost-saving if the price of classifier declines.

Dans EMPA-REG-OUTCOME, l’empagliflozine a reduit le risque de deces CV, deces toutes causes et hospitalisations pour insuffisance cardiaque (hIC) chez les patients DT2 avec maladie CV (MCV) etablie. Nous avons evalue l’efficacite CV d’empagliflozine en vie reelle chez des DT2 avec et sans MCV dans EMPRISE, etude sur l’efficacite, la tolerance, l’utilisation de soins avec l’empagliflozine, basee sur Medicare et deux bases commerciales americaines (2014–2019). En utilisant les donnees de 2014–2018 (Medicare:2014–2017), nous avons identifie les DT2 ≥ 18 an s apparies sur score de propension 1:1 initiant empagliflozine ou i-DPP4, avec et sans MCV (14920 et 40443 paires de patients apparies). Nous avons evalue les hIC, un composite d’IDM ou AVC, les Evenements CV atherosclerotiques (ECVAS) elargis (IDM, AVC, angor instable ou revascularisation coronaire) et les deces. Nous avons estime le HR combine et la difference des taux (DT) (IC95 %) apres ajustement sur > 140 covariables. Sur un suivi moyen 6,3 mois, les patients initiant empagliflozine versus iDPP4 avec et sans MCV ont presente des reductions du risque d’hIC [HR, 0,71 (0,60–0,84) et 0,55 (0,42–0,73)] et de deces [HR, 0,53 (0,37–0,76) et 0,46 (0,29–0,74)], les benefices observes etaient plus importants chez les patients avec une MCV sur une echelle de risque absolu, comme indique par les DT [DT pour l’hIC: −13,09 (−19,63,−6,55) avec MCV et −2,79 (−4,10, −1,48) sans MCV], mais avec un risque similaire d’ECVAS. L’empagliflozine etait associee a des reductions du risque d’hIC et de deces, mais a un risque similaire d’ECVAS chez les patients avec et sans MCV.

Objectives The Women's Health Initiative (WHI) randomized trial identified age differences in the benefit-risk profile of estrogen-alone (ET) use. The impact of WHI trial on disease-associated medical expenditures attributable to subsequent decreased ET utilization has, however, not been measured. Therefore, the objective of this analysis was to quantify the age-specific disease-associated medical expenditures attributable to reduced ET utilization after the WHI Hormone Therapy (HT) trials. Methods Population-level disease counts and associated expenditures between 2003 and 2015 were compared between an observed ET-user population versus a hypothetical ET-user population assuming absence of the WHI HT trials, constructed by extrapolating ET utilization rates from 1996 to 2002 assuming pre-WHI HT rates would have continued without publication of the WHI HT trial data (2002-2004). Analyses were stratified by age (50-59, 60-69, and 70-79 years). Input data were extracted from Medical Expenditure Panel Survey and the literature. The primary outcomes were: ET utilization, chronic diseases (breast cancer, stroke, coronary heart disease, colorectal cancer, pulmonary embolism, and hip fracture) and disease-associated direct medical expenditures. Results Over 13 years, the decline in ET utilization was associated with $4.1 billion expenditure for excess chronic diseases (37,549 excess events) among women in their 50s, compared to savings of $1.5 billion and $4.4 billion for diseases averted by lower ET utilization among women in their 60s (13,495 fewer events) and 70s (40,792 fewer events), respectively. Conclusion The decline in ET utilization had differential disease and expenditure consequences by age groups in the United States. These results are limited by the lack of inclusion of vasomotor symptom benefit and costs of alternative medications for these symptoms in the analysis.

EMPRISE aims to study the effectiveness, safety and healthcare utilization of empagliflozin (EMPA) in routine care patients. In an interim analysis, we assessed the comparative cardiovascular (CV) effectiveness of EMPA in older adults. Using data from Medicare (2014-2017), we identified 11,579 pairs of 1:1 propensity score-matched patients ≥66 years with type 2 diabetes initiating EMPA or a DPP-4 inhibitor (DPP-4i), and 17,500 pairs initiating EMPA or a GLP-1 receptor agonist (GLP-1RA). We assessed hospitalization for heart failure (HHF), defined as a HF discharge diagnosis in the primary (HHF-Specific) or in any position (HHF-Broad) and a modified MACE outcome (MI, stroke, or all-cause mortality). We estimated HR and 95% CI adjusting for >140 baseline covariates. Compared to DPP-4i, EMPA was associated with a decreased risk of HHF [HHF-Specific: 0.43 (0.30-0.63); HHF-Broad: 0.57 (0.47-0.69)] and MACE [HR (95% CI) = 0.63 (0.50-0.79)]. Compared to GLP-1RA, EMPA had a reduced risk of HHF [HHF-Specific: 0.67 (0.50-0.91); HHF-Broad: 0.83 (0.71-0.96)] and a similar risk of MACE [1.02 (0.85-1.23)](Table 1). Results for the individual components of MACE were consistent and robust to competing risks. These findings, addressing the comparative effectiveness of EMPA in routine care patients with mean age of 72 years, complement available information from RCTs. Disclosure E. Patorno: Other Relationship; Self; Boehringer Ingelheim International GmbH. A. Pawar: None. L.G. Bessette: None. M. Najafzadeh: None. D.J. Wexler: Other Relationship; Self; Novo Nordisk A/S. J. Franklin: None. A. Deruaz-Luyet: Employee; Self; Boehringer Ingelheim International GmbH. Employee; Spouse/Partner; Sanofi-Aventis Deutschland GmbH. K. Brodovicz: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. L. Koeneman: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. S. Schneeweiss: None. Funding Boehringer Ingelheim

[Figure: see text] BACKGROUND: More than 80% of children with cancer become long-term survivors, yet most survivors experience late effects of treatment. Little is known about how parents and physicians consider late-effects risks against a potential survival benefit when making treatment decisions. METHODS: We used a discrete choice experiment to assess the importance of late effects on treatment decision-making and acceptable trade-offs between late-effects risks and survival benefit. We surveyed 95 parents of children with cancer and 41 physicians at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center to assess preferences for 5 late effects of treatment: neurocognitive impairment, infertility, cardiac toxicity, second malignancies, and impaired growth and development. RESULTS: Each late effect had a statistically significant association with treatment choice, as did survival benefit (P < .001). Avoidance of severe cognitive impairment was the most important treatment consideration to parents and physicians. Parents also valued cure and decreased risk of second malignancies; physician decision-making was driven by avoidance of second malignancies and infertility. Both parents and physicians accepted a high risk of infertility (parents, a 137% increased risk; physicians, an 80% increased risk) in exchange for a 10% greater chance of cure. CONCLUSIONS: Avoidance of severe neurocognitive impairment was the predominant driver of parent and physician treatment preferences, even over an increased chance of cure. This highlights the importance of exploring parental late-effects priorities when discussing treatment options.

Aim: We examined characteristics of early sacubitril/valsartan users in a large US electronic health records database. Patients & methods: We identified three cohorts of patients with heart failure (HF): sacubitril/valsartan patients with a prior HF diagnosis; patients with HF with reduced ejection fraction; and patients with HF treated with an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker and a β-blocker. Results: Sacubitril/valsartan patients were younger than patients in the other cohorts; the mean age of sacubitril/valsartan patients increased by 2 years in the first 15 months of marketing. Most sacubitril/valsartan patients had prior use of HF treatment. Conclusion: Overall, sacubitril/valsartan patients resembled those in the HF with reduced ejection fraction cohort, and commonly used other drugs for HF.

In the presence of heterogeneity of treatment effect (HTE), the average treatment effect from a randomized controlled trial (RCT) may not be applicable to different patients, such as those in observational settings. Our objective was to develop a novel approach that uses individual-level simulation to expand RCT results to target patient populations in the presence of HTE. For this purpose, we compared the results of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, and two observational studies that compared benefits and risks of dabigatran to warfarin in patients with atrial fibrillation. We developed a simulation model that replicates the rates of ischemic stroke and major bleeding observed in RE-LY using published outcome risk models and participants' baseline characteristics. We used our validated simulation model to predict what the results of the RCT would have been had it been conducted in populations similar to those in the observational studies.

Background The response to therapeutics varies widely in patients with depression and anxiety, making selection of an optimal treatment choice challenging. IDgenetix®, a novel pharmacogenomic test, has been shown to improve outcomes by predicting the likelihood of response to different psychotherapeutic medications. Objective The objective of this study was to estimate the cost effectiveness of implementing a novel pharmacogenomic test (IDgenetix®) to guide treatment choices in patients with depression and/or anxiety compared with treatment as usual from the US societal perspective. Methods We developed a discrete event simulation to compare clinical events, quality-adjusted life-years, and costs of the two treatment strategies. Target patients had a Hamilton Rating Scale for Depression Score ≥ 20 and/or a Hamilton Rating Scale for Anxiety score ≥ 18 at baseline. Remission, response, and no response were simulated based on the observed rates in the IDgenetix® randomized controlled trial. Quality-adjusted life-years and direct and indirect costs attributable to depression and anxiety were estimated and compared over a 3-year time horizon. We conducted extensive deterministic and probabilistic sensitivity analyses to assess the robustness of the results. Results The model predicted cumulative remission rates of 78 and 66% in IDgenetix® and treatment as usual groups, respectively. Estimated discounted quality-adjusted life-years were 2.09 and 1.94 per patient for IDgenetix® and treatment as usual, respectively, which resulted in 0.15 incremental quality-adjusted life-years (95% credible interval 0.04–0.28). The total costs after accounting for a US$2000 test cost were US$14,124 for IDgenetix® compared with US$14,659 for treatment as usual, suggesting a US$535 (95% credible interval − 2902 to 1692) cost saving per patient in the IDgenetix® group. Incremental quality-adjusted life-year gain (0.49) and cost savings (US$6800) were substantially larger in patients with severe depression (Hamilton Rating Scale for Depression score ≥ 25). Conclusion Using the IDgenetix® test to guide the treatment of patients with depression and anxiety may be a dominant strategy, as it improves quality-adjusted life-years and decreases overall costs over a 3-year time horizon. Electronic supplementary material The online version of this article (10.1007/s40273-017-0587-0) contains supplementary material, which is available to authorized users.

Antimicrobial resistance is of growing concern. To encourage development of new treatments, some commentators have suggested regulators exercise increased flexibility on the clinical evidence required for approval. We examined all 1065 new drugs and biologics approved by the US Food and Drug Administration between 1984 and 2018 and recorded each drug's use of the Orphan Drug Act, fast-track, priority review, accelerated approval, and breakthrough therapy programmes, as well as dates of investigational new drug application, new drug application, and new drug approval, which were used to calculate clinical development and review times. There were 178 (17%) antimicrobial products, which were more likely than non-antimicrobial products to benefit from priority review (103 [58%] of 178 vs 402 [45%] of 887, p=0·0023), fast-track designation (58 [37%] of 157 vs 151 [19%] of 814], p

Background The EMPA‐REG OUTCOME trial showed that empagliflozin reduced the risk of cardiovascular death and hospitalization for heart failure (HHF) in diabetic patients with cardiovascular disease. EMPRISE is a study programme on the effectiveness, safety and healthcare utilization of empagliflozin in routine care, leveraging real‐world data from two commercial and one federal US data sources from 2014 to 2019. Objectives To describe rationale and design of EMPRISE, assess ability to minimize confounding and evaluate the time to reach sufficient statistical power for a key study outcome, HHF, using baseline information from the first year of EMPRISE. Methods In 3 claims data sets, we identified a 1:1 propensity score (PS)‐matched cohort of diabetic patients ≥18 years initiating empagliflozin or a dipeptidyl peptidase‐4 inhibitor (DPP4i), resulting in 6643 total pairs. The PS model included >140 baseline covariates. We measured covariate balance via standardized differences (SD) and postmatching c‐statistic. We computed the incidence rate (IR) of HHF, predicted exposure accrual over time and calculated expected power. Results After PS matching, patient characteristics were balanced with SD, The EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) programme of studies aims to assess the comparative effectiveness, safety and impact on healthcare utilization of empagliflozin, based on real‐world data from two commercial and Medicare databases from 2014 to 2019 in the United States. In three claims data sets, we identified a 1:1 propensity score‐matched cohort of diabetic patients ≥18 years initiating empagliflozin or a dipeptidyl peptidase‐4 inhibitor from August 2014 to September 2015 (the first year of EMPRISE), resulting in 6643 total pairs. We demonstrated solid confounding control, as measured by the superior balance across treatment groups in a wide range of potential confounding factors and their proxies after propensity score matching and confirmed that we will reach adequate patient accrual rates for the achievement of powered interim analyses for all primary outcomes.

Background Current recommendations of The US Preventive Services Task Force (USPSTF) on colorectal cancer (CRC) screening strategies are based on models that assume 100% adherence to screening. Since adherence can largely affect the outcomes of a screening modality, we aimed to assess the comparative effectiveness of CRC screening strategies under published rates of actual adherence. Methods We developed an individual-level simulation model and validated it against landmark trials and USPSTF models. Then we assessed the effectiveness of colonoscopy (COL), flexible sigmoidoscopy (FS), high-sensitivity guaiac fecal occult blood test (HS-gFOBT), fecal immunochemical test (FIT), multitarget stool DNA test (FIT-DNA), computed tomography colonography (CTC), and methylated SEPT9 DNA test (SEPT9) in reducing CRC incidence and mortality. For each strategy, we also estimated the incremental life-years gained, number of colonoscopies, and adverse events. Results Assuming 100% adherence, FIT-DNA, FIT, HS-gFOBT, and SEPT9 averted 58 to 59 CRC cases and 28 CRC deaths; COL and CTC strategies 56 cases and 27 deaths, while FS averted 39 cases and 19 deaths per 1,000 individuals. Life-years gained were similar across FIT-DNA, FIT, HS-gFOBT, SEPT9, CTC, and COL strategies. The total number of colonoscopies was highest with COL (3,567), followed by SEPT9 (3,231), HS-gFOBT (2,584), FIT-DNA (2,079), FIT (2,067), CTC (1,691) and FS (1,538) strategies. Assuming actual adherence, SEPT9 averted 54 CRC cases and 26 CRC deaths, followed by COL with 49 cases and 24 deaths, and FIT-DNA, FIT, CTC and HS-gFOBT with approximately 36 to 41 cases and 18 to 21 deaths averted per 1000 individuals screened. Life-years gained reflected the effectiveness of each strategy in reducing CRC cases and deaths. Conclusions Adherence is a key factor in determining the effectiveness of CRC screening and strategies with higher expected adherence rates have the potential to reduce cancer incidence and mortality. Key messages Adherence has a substantial impact on screening outcomes, such as cancer incidence and mortality, and may influence selection of optimal screening strategies. Strategies with higher expected adherence rates can lead to clinically meaningful benefits compared to strategies that may have better one-time sensitivity and/or specificity.

Current recommendations of The US Preventive Services Task Force (USPSTF) on colorectal cancer (CRC) screening strategies are based on models that assume 100% adherence. Since adherence can have a large effect on screening outcomes, we aimed to compare the effectiveness of CRC screening strategies under reported adherence rates at the population level. We developed and validated a microsimulation model to assess the effectiveness of colonoscopy (COL), flexible sigmoidoscopy (FS), high‐sensitivity guaiac fecal occult blood‐test (HS‐gFOBT), fecal immunochemical test (FIT), multitarget stool DNA test (FIT‐DNA), computed tomography colonography (CTC), and methylated SEPT9 DNA test (SEPT9) in terms of CRC incidence and mortality, incremental life years gained (LYG), number of colonoscopies, and adverse events for men and women 50 years or older over their lifetime. We assessed outcomes under 100% adherence rates and reported adherence rates. We also performed sensitivity analyses to evaluate the impact of varying adherence levels on CRC outcomes. Assuming 100% adherence, FIT‐DNA, FIT, HS‐gFOBT, and SEPT9 averted 42‐45 CRC cases and 25‐26 CRC deaths, COL 46 cases and 26 deaths, CTC 39 cases and 23 deaths, FS 32 cases and 19 deaths per 1000 individuals. Assuming reported adherence, SEPT9 averted 37 CRC cases and 23 CRC deaths, COL 34 cases and 20 deaths, FIT‐DNA, FIT, CTC and HS‐gFOBT 16‐25 cases and 10‐16 deaths per 1000 individuals. LYG reflected the effectiveness of each strategy in reducing CRC cases and deaths. Adverse events were more common for COL (3.7 per 1000 screened) and annual SEPT9 (3.4 per 1000 screened), and proportional to the number of colonoscopies. Among the screening strategies recommended by USPSTF, colonoscopy results in the largest benefit when we account for adherence. Adherence rates higher than 65%‐70% would be required for any stool or blood‐based screening modality to match the benefits of colonoscopy., Although adherence to colorectal cancer screening has a substantial impact on clinical outcomes, estimating the magnitude of this impact has been challenging. This study provides a quantitative analysis of the extent to which differences in adherence rates affect clinical outcomes of different screening strategies. We found that higher adherence can lead to meaningful benefits when compared to strategies with better one‐time sensitivity and/or specificity, but lower adherence rates. This is relevant for optimizing screening strategies when considering other factors in addition to test performance, such as access to screening and patient behavior.

Background Empagliflozin (EMPA) reduced the risk of hospitalization for heart failure (HHF) (HR 0.65; 95% CI 0.50- 0.85) as demonstrated in the EMPA-REG OUTCOME trial in adults with type 2 diabetes (T2D) and established CV disease. However, the impact of EMPA treatment initiation on healthcare resource utilization (HCRU) in routine care in patients with history of heart failure (HF) or without history of HF remains unexplored. Purpose To compare HCRU among EMPA and dipeptidyl peptidase-4 inhibitor (DPP4i) initiators with and without HF history at time of treatment initiation. Methods We analyzed HCRU in the first two years after marketing of EMPA as part of EMPRISE, a non-interventional study on the comparative effectiveness, safety and HCRU of EMPA for T2D patients in routine care in two US commercial and Medicare claims datasets (08/2014–09/2016). We identified a 1:1 propensity-score-matched cohort of T2D patients ≥18 years initiating either EMPA or a DPP4i with and without baseline HF, and assessed the balance at baseline (period of 365 days) on ≥140 covariates including clinical, HCRU, and cost-related covariates using absolute standardized differences. We compared the risk of first all-cause hospitalization, risk of first HHF, risk of first emergency department (ED) visit, hospital length of stay (LOS), HF-related LOS, number of hospital admissions, HF-related hospital admissions, office visits, and ED visits in EMPA and DDP4i initiators. Results After propensity score matching, we identified 2,050 pairs with HF and 15,428 pairs without HF in the three datasets with mean follow-up of 5.2 and 5.4 months, respectively. All baseline characteristics were well balanced (with aSD Compared to DPP4i, the hazard ratio (HR) for first hospitalization was 0.68 (95% CI: 0.56, 0.83) for EMPA initiators with HF, and 0.89 (95% CI: 0.80, 1.00) for initiators without HF. Risk of HF-related hospitalization and ED visit was lower in EMPA initiators with prior HF [HR=0.53 (0.38, 0.74) and HR=0.73 (0.58, 0.93), respectively] and without prior HF [HR=0.45 (0.27, 0.73) and HR=0.82 (0.70, 0.95), respectively]. Compared to DPP4i initiators, EMPA initiators with and without baseline HF had lower number of all hospital admissions [Incidence rate ratio (IRR)= 0.59 (0.50, 0.70) and IRR= 0.78 (0.71, 0.85), respectively] and HF-related hospital admissions [IRR=0.49 (0.37, 0.65) and IRR=0.34 (0.22, 0.53), respectively]. In-hospital days and HF-related in-hospital days per member per year (PMPY) in patients with and without HF history initiating EMPA were lower than DDP4i (Table 1). Conclusions Results observed in this interim analysis of EMPRISE showed reduction in overall HCRU as well as HF-related HCRU in both patients with and without heart failure (HF) initiating EMPA compared to DDP4i initiators. Acknowledgement/Funding This study was supported by a research grant to the Brigham and Women's Hospital from Boehringer-Ingelheim.

ObjectivesTo characterize the trends, drivers, and potential modifiers of increased spending by US Medicare beneficiaries on medicines deemed essential by the World Health Organization.DesignRetrospective cost analysis of Medicare Part D Prescriber Public Use File, detailing annual generic and brand name drug prescribing and spending from 2011 through 2015 by Medicare Part D participants who filled prescriptions for WHO essential medicines.SettingUS Medicare System.Main outcome measuresTotal and per beneficiary Medicare spending, total and per beneficiary out-of-pocket patient spending, cumulative beneficiary count, claim count, and per unit drug cost. All spending measures were adjusted for inflation and reported in 2015 US dollars.ResultsMedicare Part D expenditures on 265 WHO essential medicines between 2011 and 2015 was $87.2bn (£68.4bn; €76.5bn), with annual spending increasing from $11.9bn in 2011 to $25.8bn in 2015 (116%). Patients’ out-of-pocket spending for essential medicines over the same period was $12.1bn. Total annual out-of-pocket spending increased from $2.0bn to $2.9bn (47%), and annual per beneficiary out-of-pocket spending on these drugs increased from $20.42 to $21.17 (4%). Total prescription count increased from 376.1m to 498.9m (33%), and cumulative beneficiary count grew from 95.9m to 135.8m (42%). Of the essential medicines included in the study, the per unit cost of 133 (50%) agents increased faster than the average inflation rate during this period. Overall, approximately 58% of the increase in total spending during this period can be attributed to the introduction of novel agents.ConclusionsSpending associated with essential medicines grew substantially from 2011 to 2015, driven largely by the increased use of two expensive novel drugs used in treating hepatitis C. Approximately 22% of increased total spending during this period can be attributed to increases in per unit cost of existing drugs. These trends may limit patients’ access to essential drugs while also increasing healthcare system costs.

EMPRISE studies the effectiveness, safety and healthcare utilization of empagliflozin (EMPA), a SGLT2 inhibitor, using data from Medicare and 2 U.S. commercial claims datasets (2014-2019). In an analysis on data from 2014-2016, we identified 17,551 pairs of 1:1 propensity score-matched patients ≥18 years with type 2 diabetes initiating EMPA or a DPP-4 inhibitor (DPP-4i). We assessed a composite CV outcome (MI, stroke, or all-cause mortality) and an extended CV outcome (plus heart failure hospitalization or coronary revascularization). Safety outcomes of interest were lower-limb amputations, bone fractures, diabetic ketoacidosis (DKA), and acute kidney injury. We estimated pooled HR and 95% CI adjusting for >140 baseline covariates. Compared to DPP-4i, EMPA was associated with a trend to lower risk of the CV outcome [HR (95% CI) = 0.82 (0.62-1.10)], and a lower risk of the extended CV outcome [0.73 (0.60-0.88)], heart failure hospitalization [0.56 (0.43-0.73)]. Risk of safety outcomes were in line with current evidence despite small numbers, Table 1. We observed a numerical increase in DKA risk [1.74 (0.84-3.58)]. Early findings from EMPRISE showed that compared with DPP-4i, EMPA was associated with a lower risk of CV outcomes with varying levels of precision, and a safety profile consistent with currently documented information. Disclosure E. Patorno: Research Support; Self; National Institute on Aging. Other Relationship; Self; Boehringer Ingelheim International GmbH. A. Pawar: None. J. Franklin: Research Support; Self; U.S. Food and Drug Administration. M. Najafzadeh: Consultant; Self; Epigenomics. A. Deruaz-Luyet: Employee; Self; Boehringer Ingelheim International GmbH. Employee; Spouse/Partner; Medtronic, Sanofi. K. Brodovicz: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. S. Sambevski: Employee; Self; Boehringer Ingelheim International GmbH. L.G. Bessette: None. M. Kulldorff: None. S. Schneeweiss: Consultant; Self; Aetion, WHISCON, LLC. Funding Boehringer Ingelheim

EMPRISE studies the comparative effectiveness, safety and health care resource utilization of empagliflozin (EMPA) in Medicare and 2 U.S. commercial claims datasets (2014-2019). In this first analysis, we evaluated healthcare costs and medications burden associated with EMPA vs. dipeptidyl peptidase 4 inhibitors (DPP-4i) use in routine care patients with type 2 diabetes (T2D). We identified a 1:1 propensity-score-matched cohort of T2D patients ≥18 years initiating either EMPA or DPP-4i between 08/2014-09/2016. Total (inpatient, outpatient, pharmacy) cost and medication burden were compared for EMPA vs. DPP-4i. We identified 17,549 matched pairs with balanced baseline characteristics (Table 1) with mean follow-up of 5.4 months. Per member per year (PMPY) total cost was similar among EMPA vs. DDP4i initiators ($17,771 vs. $17,814; Diff= -$43, 95% CI: -1,380─1,295). Medical costs tended to be lower and pharmacy costs were higher in EMPA initiators. Distinct medication prescriptions were slightly lower among EMPA initiators [Incidence rate ratio 0.97, 95% CI: 0.96─0.98]. Results stratified by history of CV disease were consistent. Within the first two years of EMPRISE, we observed similar total cost, driven by trend towards lower medical and higher pharmacy costs, and lower medication burden in EMPA vs. DDP4i initiators. Disclosure A. Pawar: None. E. Patorno: Research Support; Self; National Institute on Aging. Other Relationship; Self; Boehringer Ingelheim International GmbH. A. Deruaz-Luyet: Employee; Self; Boehringer Ingelheim International GmbH. Employee; Spouse/Partner; Medtronic, Sanofi. K. Brodovicz: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. A.V. Ustyugova: Employee; Self; Boehringer Ingelheim International GmbH. N. Gautam: None. L.G. Bessette: None. S. Schneeweiss: Consultant; Self; Aetion, WHISCON, LLC. M. Najafzadeh: Consultant; Self; Epigenomics. Funding Boehringer Ingelheim

Background Benefit-risk assessment (BRA) methods can combine measures of benefits and risks into a single value. Objectives To examine BRA metrics for prospective monitoring of new drugs in electronic health care data. Methods Using two electronic health care databases, we emulated prospective monitoring of three drugs (rofecoxib vs. nonselective nonsteroidal anti-inflammatory drugs, prasugrel vs. clopidogrel, and denosumab vs. bisphosphonates) using a sequential propensity score–matched cohort design. We applied four BRA metrics: number needed to treat and number needed to harm; incremental net benefit (INB) with maximum acceptable risk; INB with relative-value–adjusted life-years; and INB with quality-adjusted life-years (QALYs). We determined whether and when the bootstrapped 99% confidence interval (CI) for each metric excluded zero, indicating net favorability of one drug over the other. Results For rofecoxib, all four metrics yielded a negative value, suggesting net favorability of nonselective nonsteroidal anti-inflammatory drugs over rofecoxib, and the 99% CI for all but the number needed to treat and number needed to harm excluded the null during follow-up. For prasugrel, only the 99% CI for INB-QALY excluded the null, but trends in values over time were similar across the four metrics, suggesting overall net favorability of prasugrel versus clopidogrel. The 99% CI for INB-relative-value–adjusted life-years and INB-QALY excluded the null in the denosumab example, suggesting net favorability of denosumab over bisphosphonates. Conclusions Prospective benefit-risk monitoring can be used to determine net favorability of a new drug in electronic health care data. In three examples, existing BRA metrics produced qualitatively similar results but differed with respect to alert generation.

Analyses using administrative claims databases or national registries provide estimates of benefits and harms of medications in real-world settings for large and diverse patient populations. Whereas claims-based nonrandomized studies and randomized-controlled trials (RCTs) have distinct limitations, their strengths are complementary. Integrating RCT and claims data offers substantial synergies. We propose obtaining routinely collected longitudinal claims data from RCT participants and discuss the added value of the novel evidence that can be derived from this "information overlap."

Randomized controlled trials (RCTs) provide evidence for regulatory agencies, shape clinical practice, influence formulary decisions, and have important implications for patients. However, many patient groups that are major consumers of drugs are under-represented in randomized trials. We review three methods to extrapolate evidence from trial participants to different target populations following market approval and discuss how these could be implemented in practice to support regulatory and health technology assessment decisions. Although these methods are not a substitute for less restrictive pre-approval RCTs or rigorous observational studies when sufficient data are available in the post-approval setting, they can help to fill the evidence gap that exists in the early marketing period. Early evidence using real-world data and methods for extrapolating evidence should be reported with clear explanation of assumptions and limitations especially when used to support regulatory and health technology assessment decisions.

New regimens for hepatitis C virus (HCV) have shorter treatment durations and increased rates of sustained virologic response compared with existing therapies but are extremely expensive.To evaluate the cost-effectiveness of these treatments under different assumptions about their price and efficacy.Discrete-event simulation.Published literature.Treatment-naive patients infected with chronic HCV genotype 1, 2, or 3.Lifetime.Societal.Usual care (boceprevir-ribavirin-pegylated interferon [PEG]) was compared with sofosbuvir-ribavirin-PEG and 3 PEG-free regimens: sofosbuvir-simeprevir, sofosbuvir-daclatasvir, and sofosbuvir-ledipasvir. For genotypes 2 and 3, usual care (ribavirin-PEG) was compared with sofosbuvir-ribavirin, sofosbuvir-daclatasvir, and sofosbuvir-ledipasvir-ribavirin (genotype 3 only).Discounted costs (in 2014 U.S. dollars), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios.Assuming sofosbuvir, simeprevir, daclatasvir, and ledipasvir cost $7000, $5500, $5500, and $875 per week, respectively, sofosbuvir-ledipasvir was cost-effective for genotype 1 and cost $12 825 more per QALY than usual care. For genotype 2, sofosbuvir-ribavirin and sofosbuvir-daclatasvir cost $110 000 and $691 000 per QALY, respectively. For genotype 3, sofosbuvir-ledipasvir-ribavirin cost $73 000 per QALY, sofosbuvir-ribavirin was more costly and less effective than usual care, and sofosbuvir-daclatasvir cost more than $396 000 per QALY at assumed prices.Sofosbuvir-ledipasvir was the optimal strategy in most simulations for genotype 1 and would be cost-saving if sofosbuvir cost less than $5500. For genotype 2, sofosbuvir-ribavirin-PEG would be cost-saving if sofosbuvir cost less than $2250 per week. For genotype 3, sofosbuvir-ledipasvir-ribavirin would be cost-saving if sofosbuvir cost less than $1500 per week.Data are lacking on real-world effectiveness of new treatments and some prices.From a societal perspective, novel treatments for HCV are cost-effective compared with usual care for genotype 1 and probably genotype 3 but not for genotype 2.CVS Health.