Heart failure with mildly reduced and preserved ejection fraction: A review of disease burden and remaining unmet medical needs within a new treatment landscape.

This review provides a comprehensive overview of heart failure with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF), including its definition, diagnosis, and epidemiology; clinical, humanistic, and economic burdens; current pharmacologic landscape in key pharmaceutical markets; and unmet needs to identify key knowledge gaps. We conducted a targeted literature review in electronic databases and prioritized articles with valuable insights into HFmrEF/HFpEF. Overall, 27 randomized controlled trials (RCTs), 66 real-world evidence studies, 18 clinical practice guidelines, and 25 additional publications were included. Although recent heart failure (HF) guidelines set left ventricular ejection fraction thresholds to differentiate categories, characterization and diagnosis criteria vary because of the incomplete disease understanding. Recent epidemiological data are limited and diverse. Approximately 50% of symptomatic HF patients have HFpEF, more common than HFmrEF. Prevalence varies with country because of differing definitions and study characteristics, making prevalence interpretation challenging. HFmrEF/HFpEF has considerable mortality risk, and the mortality rate varies with study and patient characteristics and treatments. HFmrEF/HFpEF is associated with considerable morbidity, poor patient outcomes, and common comorbidities. Patients require frequent hospitalizations; therefore, early intervention is crucial to prevent disease burden. Recent RCTs show promising results like risk reduction of composite cardiovascular death or HF hospitalization. Costs data are scarce, but the economic burden is increasing. Despite new drugs, unmet medical needs requiring new treatments remain. Thus, HFmrEF/HFpEF is a growing global healthcare concern. With improving yet incomplete understanding of this disease and its promising treatments, further research is required for better patient outcomes.

Estimated health economic impact of conducting urine albumin-to-creatinine ratio testing alongside estimated glomerular filtration rate testing in the early stages of chronic kidney disease in patients with type 2 diabetes.

AIM: To estimate the health economic impact of undertaking urine albumin-to-creatinine ratio (UACR) testing versus no UACR testing in early stages of chronic kidney disease (CKD) progression in patients with type 2 diabetes (T2D). METHODS: An economic model, taking a UK healthcare system perspective, estimated the impact of UACR testing on additional costs, clinical benefits measured as prevented dialyses and cardiovascular-related deaths, life years gained (LYg), LYg before kidney failure, and incremental cost-effectiveness ratio (ICER). Sixteen of the 18 Kidney Disease: Improving Global Outcomes (KDIGO) heatmap categories were considered separately, and grouped in health states according to CKD risk. Results were derived for current standard-of-care and emerging CKD therapies. RESULTS: The cohort that adhered to both UACR and estimated glomerular filtration rate (eGFR) testing guidelines in early stages of CKD (n = 1000) was associated with approximately 500 LYg before kidney failure onset; costing approximately £2.5 M. ICERs across the KDIGO heatmap categories were approximately £5,000. LIMITATIONS: This model used data from a comprehensive meta-analysis that was initiated more than 10 years ago (2009). While this was the most comprehensive source identified, recent changes in the treatment landscape, patient population and social determinants of CKD will not be captured. Furthermore, a narrow approach was taken, aligning included costs with UK NHS reference materials. This means that some direct and indirect drivers of costs in late-stage disease have been excluded. CONCLUSIONS: UACR testing in the early stages of CKD is cost effective in T2D patients. Emerging therapies with the potential to slow CKD progression, mean that optimal monitoring through UACR/eGFR testing will become increasingly important for accurate identification and timely treatment initiation, particularly for the highest-risk A3 category.

Real-world evidence for steroidal mineralocorticoid receptor antagonists in patients with chronic kidney disease.

BACKGROUND: Mineralocorticoid receptor antagonists (MRAs) were shown to delay chronic kidney disease (CKD) progression in patients with hypertension and/or heart failure (HF) and proteinuria. OBJECTIVE: We conducted a systematic literature review on real-world evidence to identify the literature gaps related to the efficacy and safety outcomes of MRAs administered to CKD patients. RESULTS: A total of 751 records were identified of which, 23 studies (26 publications) were analyzed. Studies included heterogeneous populations, including the overall CKD, CKD and diabetes, CKD and HF, and CKD and a history of cardiovascular disease. Most of the studies were small and non-rigorous, resulting in a notable lack of evidence in these populations. In the overall CKD population, steroidal MRAs resulted in a significant or sustained eGFR reduction but no efficacy in delaying progression to end-stage kidney disease. No cardiovascular protection was found. Results for all-cause mortality and hospitalization for HF were inconsistent; however, the longest follow-up studies indicate similar or lower incidence for spironolactone non-users. Most results consistently reported a higher incidence of hyperkalemia among patients on steroidal MRAs in all CKD stages, and side effects led to high discontinuation rates in the real-world setting. CONCLUSIONS: Despite the limited availability of evidence on the effectiveness and safety of steroidal MRAs in CKD patients and subgroups with diabetes, HF or history of cardiovascular disease, MRAs were shown to have a limited effect on renal and cardiovascular outcomes. Gaps in the evidence regarding the efficacy and safety of MRAs are particularly relevant in diabetic CKD patients; therefore, further research is warranted.

High unmet treatment needs in patients with chronic kidney disease and type 2 diabetes: real-world evidence from a US claims database.

BACKGROUND: Chronic kidney disease (CKD), a serious complication of type 2 diabetes (T2D) increases the comorbid risk of cardiovascular disease (CVD) and end-stage kidney disease(ESKD). Treatment guidelines recommend renin-angiotensin blockade and antihyperglycemic treatment with metformin and sodium-glucose cotransporter 2 inhibitors (SGLT2is) as first-line treatment. We evaluated treatment initiation and discontinuation overall and in subgroups of T2D patients with incident CKD (incident cohort) and rates of clinical and economic outcomes in patients with T2D and any CKD (prevalent cohort). METHODS: In this retrospective study of administrative claims in the USA between 1 January 2007 and 31 March 2019, we evaluated the proportion of patients with concomitant, newly initiated and discontinued use of antihypertensive [angiotensin-converting enzyme inhibitor (ACEi)/angiotensin II receptor blockers (ARBs), steroidal mineralocorticoid receptor antagonists (sMRAs)] and antidiabetic [SGLT2is, dipeptidyl peptidase-4 inhibitors (DPP4is), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), insulin and sulfonylureas] medications, rates of clinical outcomes per 1000 person-years and mean total healthcare costs. RESULTS: We identified 63 127 and 326 763 patients in the incident and prevalent CKD cohorts, respectively. Low initiation and high discontinuation rates were observed with 17.8% and 56.0% for ACEi/ARBs, 1.3% and 66.0% for sMRAs, 2.5% and 65.0% for SGLT2is, 3.7% and 66.8% for DPP4is, 2.31% and 69.0% for GLP-1 RAs, 4% and 75.7% for insulin and 5.5% and 56.9% for sulfonylureas. Similar results were seen by subgroups. Rates of clinical outcomes ranged from 35.07 per 1000 person-years for all-cause mortality to 104.19 for ESKD, with rates of hospitalization ranging from 36.61 for kidney hospitalizations to 283.14 for all-cause hospitalizations. Among patients with comorbidities, higher clinical and economic outcomes were found. CONCLUSION: Our results highlight high unmet needs of CKD and T2D, particularly subgroups of patients with multimorbid CVD, high-risk CKD (low estimated glomerular filtration rate or high urinary albumin:creatinine ratio) or rapidly progressing CKD. Low initiation and high discontinuation of recommended treatments suggest that adherence to guidelines for halting CKD progression is suboptimal. These high-risk patients may benefit from further treatment options to improve morbidity and mortality and reduce the economic burden.

Validation of the FINE-CKD model for future health technology assessments for finerenone in patients with chronic kidney disease and type 2 diabetes.

BACKGROUND: The FINE-CKD model was developed to estimate the cost-effectiveness of finerenone in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). OBJECTIVE: To perform internal and external validation by comparing the model estimates with trial results and outcomes from other models. METHODS: Incidence rates from trials were compared with the model predictions. Statistical tests were then performed to assess whether modeled event rates aligned with trial observations. A cross-validation was also performed using the online version of the SHARP CKD-Cardiovascular Disease (SHARP CKD-CVD) model, with population characteristics from the finerenone trials analyzed. Where no finerenone data were available, the default SHARP CKD-CVD values were used. Comparison of the results considered the ranges from both models. RESULTS: The outcomes of the FINE-CKD model reflect the event rates observed in the trials. Based on the results of the statistical tests, the hypothesis of no difference between observed and modeled events cannot be rejected for any of the outcomes. The results of the FINE-CKD model are within the ranges from the SHARP CKD-CVD model. Disease progressions align across the models; however, incident kidney failure events in the SHARP CKD-CVD model were higher. This can be explained by simulation of more severely affected patients in the SHARP CKD-CVD model. CONCLUSIONS: This study demonstrates that the FINE-CKD model adequately reflects the clinical data and provides reliable extrapolation relative to the existing predictive tools while also being conservative in its approach.

Predictors of cardio-kidney complications and treatment failure in patients with chronic kidney disease and type 2 diabetes treated with SGLT2 inhibitors.

BACKGROUND: Clinical practice guidelines recommend sodium-glucose co-transporter 2 inhibitors (SGLT2is) to mitigate adverse kidney and cardiovascular outcomes in patients with type 2 diabetes (T2D), including patients with comorbid chronic kidney disease (CKD), also referred to as diabetic kidney disease (DKD), who are at even higher risk. In this study, we sought to identify predictors of cardio-kidney events, cardio-kidney complications, and treatment failure (i.e., addition/initiation of a new T2D class, insulin, or discontinuation of SGLT2is) after new initiation of SGLT2is in patients with CKD and T2D (DKD). METHODS: In this retrospective cohort study, we identified adult patients with DKD who initiated SGLT2is between April 1, 2012, and June 30, 2019, in Optum claims data. Outcome rates per 1000 person-years (PY) are reported with 95% confidence intervals (CIs). Cox proportional hazards regression identified patient characteristics associated with each outcome. RESULTS: The study population consisted of 6389 initiators of SGLT2is. The rate of CV hospitalization was 26.0 (95% CI 21.6, 30.4) per 1000 PY. Baseline characteristics associated with higher risk of CV hospitalization included age, atrial fibrillation, peripheral vascular disease (PVD), and cancer. The rate of kidney hospitalization was 12.0 (95% CI 9.0, 15.0) per 1000 PY. The risk increased significantly with baseline evidence of heart failure, hyperkalemia, respiratory failure, depression, and use of loop diuretics. In total, 55.0% of all SGLT2i initiators discontinued treatment during the follow-up period. The rate of treatment failure was 510.5 (95% CI 492.9, 528.1) per 1000 PY. Analysis of key time-dependent SGLT2i-associated adverse events showed that experiencing diabetic ketoacidosis and volume depletion were associated with risk of treatment failure. CONCLUSIONS: Our study demonstrated high rates of residual cardio-kidney outcomes and treatment failure in patients with DKD treated with SGLT2is. Patients with high baseline CV risk and the presence of certain conditions, such as atrial fibrillation, PVD, and heart failure, were at higher risk for cardio-kidney events. Further research is needed to assess the potential relationship between adverse events and SGLT2i treatment failure.

ACE inhibitor or ARB treatment among patients with diabetes and chronic kidney disease.

OBJECTIVES: Many patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) experience a delay in treatment or fail to initiate treatment with guideline-recommended angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs) after CKD diagnosis. This study aimed to describe treatment patterns and treatment initiation after initial CKD diagnosis among patients with T2D. STUDY DESIGN: Retrospective analysis using data from the Optum Clinformatics Data Mart administrative claims database (January 2014-September 2018). METHODS: Adult patients with T2D entered the cohort if they met the criteria for CKD, defined as 2 laboratory test results 90 to 365 days apart (January 2014-September 2017) indicating CKD. Included were patients with no prior use of ACEis or ARBs or evidence of kidney disease in the 365 days prior to cohort entry (baseline). Patients were followed for a maximum of 365 days and were censored on death, disenrollment, or end of data. Patient demographics, comorbidities, and medication use were assessed at baseline, and treatments were assessed over a 1-year followup period. Multivariate logistic regression was used to identify factors associated with ACEi or ARB initiation. RESULTS: Among 15,400 eligible patients without prior ACEi or ARB treatment, only 17% initiated such therapy within a year after meeting CKD criteria. Patients who were White, resided in the northeastern United States, had more comorbidities, had less advanced albuminuria, or used sodium-glucose cotransporter 2 inhibitors were less likely to initiate treatment. CONCLUSIONS: A large proportion of patients with T2D meeting criteria for CKD do not initiate the recommended therapy within 1 year of CKD diagnosis, highlighting a need for new therapies that can slow the progression of CKD.

FINE-CKD model to evaluate economic value of finerenone in patients with chronic kidney disease and type 2 diabetes.

BACKGROUND: Chronic kidney disease (CKD) is a progressive and irreversible disease often associated with type 2 diabetes (T2D). CKD is associated with an elevated risk of cardiovascular (CV) events, increased mortality, and diminished quality of life. Finerenone is a new treatment for patients with CKD and T2D that delays CKD progression and reduces CV complications. OBJECTIVE: To describe the approach and structure of a costeffectiveness model for finerenone for patients with CKD and T2D and compare it with existing economic models in CKD. METHODS: A de novo cost-effectiveness model (FINE-CKD model), reflective of FIDELIO-DKD results, was developed for finerenone. The FINE-CKD model was designed and implemented in accordance with published guidance on modeling and was developed with input from economic and clinical experts. The final model approach was evaluated against existing modeling structures in CKD identified through a systematic literature review. RESULTS AND CONCLUSIONS: The FINE-CKD model structure follows recommended modeling guidelines and has been designed in accordance with the best practices of modeling in CKD, while also incorporating important features of the FIDELIO-DKD design and results. The approach is consistent with the published literature, ensuring transparency and minimizing uncertainty that can arise from unnecessary complexity. The FINE-CKD model allows for reliable assessment of benefits and costs related to the use of finerenone in patients with CKD and T2D, and it is a reliable assessment of cost-effectiveness.

Chronic kidney disease progression among patients with type 2 diabetes identified in US administrative claims: a population cohort study.

BACKGROUND: Chronic kidney disease (CKD), one of the most common complications of type 2 diabetes (T2D), is associated with poor health outcomes and high healthcare expenditures. As the CKD population increases, a better understanding of the prevalence and progression of CKD is critical. However, few contemporary studies have explored the progression of CKD relative to its onset in T2D patients using established markers derived from real-world care settings. METHODS: This retrospective, population-based cohort study assessed CKD progression among adults with T2D and with newly recognized CKD identified from US administrative claims data between 1 January 2008 and 30 September 2018. Included were patients with T2D and laboratory evidence of CKD as indicated by the established estimated glomerular filtration rate (eGFR) and urine albumin:creatinine ratio (UACR) criteria. Disease progression was described as transitions across the eGFR- and UACR-based stages. RESULTS: A total of 65 731 and 23 035 patients with T2D contributed to the analysis of eGFR- and UACR-based CKD stage progression, respectively. CKD worsening was observed in approximately 10-17% of patients over a median follow-up of 2 years. Approximately one-third of patients experienced an increase in eGFR values or a decrease in UACR values during follow-up. CONCLUSIONS: A relatively high proportion of patients were observed with disease progression over a short period of time, highlighting the need for better identification of patients at risk of rapidly progressive CKD. Future studies are needed to determine the clinical characteristics of these patients to inform earlier diagnostic and therapeutic interventions aimed at slowing disease progression.

Targeted literature review of the burden of illness in patients with chronic kidney disease and type 2 diabetes.

OBJECTIVES: Chronic kidney disease (CKD) is increasingly prevalent among patients with type 2 diabetes (T2D). CKD is associated with increased mortality rates, clinical and humanistic burden, and substantial health care costs in the T2D population. The objective of this review was to summarize the burden of illness among patients with CKD and T2D, including the profile of patients, incidence, prevalence, mortality, progression, diagnosis and screening rates, and cardiovascular (CV) events. METHODS: A targeted literature review of published studies was conducted using Embase; Medline; Medline In-Process Citations, Daily Update, and Epub Ahead of Print; Igaku Chuo Zasshi databases; and 7 websites. Methods recommended by the Cochrane collaboration handbook, the Centre for Reviews and Dissemination, and the Joanna Briggs Institute critical appraisal checklist were employed. RESULTS: A total of 1290 full-text articles were reviewed for eligibility and 73 were included in this analysis. Patient profiles indicated older age was associated with more severe disease and number of comorbidities. The definition of kidney disease varied between studies reporting incidence and prevalence, with reported values up to 37.0% and 43.5% for incidence and prevalence, respectively. CKD among patients with T2D contributed to higher mortality rates. Higher disease progression rates were associated with higher albuminuria and lower estimated glomerular filtration rate levels. The available literature suggested annual screening rates for CKD declined over time. CV events were reported to have a substantial effect on morbidity and resource use. CONCLUSIONS: This review highlights the burden of CKD among patients with T2D and underscores a need for new treatment alternatives to reduce the burden of disease.

Adherence to Chronic Kidney Disease Screening Guidelines Among Patients With Type 2 Diabetes in a US Administrative Claims Database.

OBJECTIVE: To examine the screening rates for kidney damage and function among patients with type 2 diabetes (T2D) and chronic kidney disease stage at diabetes diagnosis using a US administrative claims database. PATIENTS AND METHODS: This cohort study used a claims database enriched with laboratory results data. Patients with T2D (defined as 1 inpatient or 2 outpatient claims for diabetes), aged 18 years or older, and with at least 1 year of follow-up enrollment were identified. Patients with type 1 diabetes, kidney disease, or other related conditions at baseline were excluded. We estimated screening rates using laboratory orders for serum creatinine and estimated glomerular filtration rate (eGFR) measurement and urine albumin to creatinine ratio (UACR). Chronic kidney disease severity was reported using the Kidney Disease: Improving Global Outcomes classification based on laboratory results. RESULTS: A total of 1,881,447 patients with T2D were eligible for analysis. Mean ± SD age was 63.1±13.1 years; 947,150 patients (50.3%) were male. Serum creatinine tests were ordered within 14 days of the index date among 290,722 patients of 622,915 (46.7%) patients with newly-recognized T2D. Overall, 1,595,964 patients (84.8%) had at least one serum creatinine test ordered during the 1-year follow-up period. Fewer patients received a UACR test during follow-up (814,897 [43.3%]). Less than half of all patients with T2D received a laboratory test order for both serum creatinine and urine albumin measurements during the follow-up period. CONCLUSION: Physicians treating patients with diabetes are selectively adhering to chronic kidney disease screening guidelines, as indicated by high rates of eGFR testing, but less frequent UACR testing. Despite recommendations to monitor both eGFR and UACR, less than half of patients were screened for albuminuria during the 1-year follow-up.

Cardiovascular and Renal Outcomes in Patients with Type-2 Diabetes and Chronic Kidney Disease Identified in a United States Administrative Claims Database: A Population Cohort Study.

INTRODUCTION: CKD, a common complication of type-2 diabetes (T2D), causes considerable disease burden. Patients with T2D and CKD are considered high-risk for complications; however, studies describing patients with T2D and incident CKD identified from real-world data using the diagnostic gold-standard criteria - estimated glomerular filtration rate and urine albumin-to-creatinine ratio (UACR) - are scarce. METHODS: In this population-based cohort study, we sought to estimate the rates of cardiovascular and renal outcomes among patients with T2D and CKD by comorbidity subgroups and CKD severity. Patients were sampled between 2008 and 2017 from de-identified US administrative claims enriched with laboratory data. Analyses were stratified by prevalent heart failure (HF), anemia, and resistant hypertension and the KDIGO categories at index. RESULTS: We identified 106,369 patients with T2D and incident CKD. The rate of all-cause hospitalization was 189 [95% CI: 187, 191] per 1,000 person-years with cardiovascular-related hospitalizations being more frequent than kidney-related outcomes. The rate of acute kidney failure was 77.3 [95% CI: 76.2, 78.5] per 1,000 person-years. Patients with HF experienced a 4-times higher rate for cardiovascular events compared to those without. Rates of hospitalization increased from 5- to 6-fold with increasing KDIGO severity. CONCLUSIONS: Multimorbidity and advance stages of CKD increase the risk of cardiovascular and renal complications among patients with T2D diabetes. Earlier CKD diagnosis as well as interventions and coordinated care addressing other comorbid conditions present at diagnosis may reduce the overall disease burden in this population.

Annual health care resource utilization and cost among type 2 diabetes patients with newly recognized chronic kidney disease within a large U.S. administrative claims database.

BACKGROUND: Chronic kidney disease (CKD) is one of the most common complications of type 2 diabetes mellitus (T2D) and results in considerable economic burden. Current studies describing cost and health care resource utilization (HCRU) in T2D patients with CKD in real-world data are few. Even more scarce is evidence that takes into account disease severity and other comorbidities. OBJECTIVES: To (a) describe T2D patients with CKD identified in U.S. administrative claims data using laboratory test results for kidney function that are considered the gold standard criteria for kidney disease diagnosis and (b) estimate the annual HCRU and costs among these patients, overall and by disease severity and comorbidity subgroup. METHODS: Optum CDM data between the years 2008 and 2017 were used to identify T2D patients with newly recognized CKD, using laboratory test results for estimated glomerular filtration rate (eGFR) or urine albumin-to-creatinine ratio (UACR). The study estimated annualized total, inpatient, outpatient, and pharmacy costs and the number of outpatient, inpatient, and emergency room visits in the first year after CKD identification. Analyses were stratified by prevalent anemia, heart failure (HF), resistant hypertension, and by CKD stages. RESULTS: T2D patients with newly recognized CKD (n = 106,369) had a high prevalence of cardiovascular comorbidities and incurred on average $24,029 of total cost per person per year in the first year after CKD identification. Patients with HF and anemia incurred on average $41,951 and $31,127 of total annual cost, respectively. Patients identified at stage 5 CKD incurred on average $110,210 of total annual cost and had roughly a 7-fold higher annual inpatient hospitalization rate compared with patients identified at stage 1 CKD. CONCLUSIONS: Administrative claims data linked to laboratory results provide an opportunity to identify CKD patients using the gold standard criteria from clinical practice, minimizing potential misclassification of patients. Identified CKD patients, particularly those with HF, anemia, and more advanced CKD stage, incur high HCRU and cost. Better monitoring, earlier CKD diagnosis, and interventions that are effective in halting or slowing the progression of CKD, as well as at managing comorbid conditions, could be effective means to reduce the economic burden of CKD in T2D. DISCLOSURES: This study was funded by Bayer. Kelly is an employee of, and owns stock options in, Aetion, which was contracted by Bayer to conduct the study. Petruski-Ivleva was an employee of Aetion during the planning, analysis, and interpretation stages of the study. Kovesdy received honoraria from Amgen, Astra Zeneca, Bayer, Cara Therapeutics, Reata, Takeda, and Tricida. Fried received consultant fees from Bayer, Novo Nordisk, and Bristol-Meyers Squibb. Folkerts, Blankenburg, and Gay are Bayer employees. This work was presented as a poster at the annual European Association for the Study of Diabetes (EASD) conference held in Barcelona, Spain, on September 16-20, 2019.

Cost-effectiveness of rivaroxaban versus apixaban for the initial treatment of venous thromboembolism and extended prevention of recurrences in the UK.

Aim: To evaluate the relative cost-effectiveness of using rivaroxaban vs apixaban for the initial treatment plus extended prevention of venous thromboembolism (VTE) in the UK. Extended prevention was assessed using a 10-mg rivaroxaban dose, as the 20-mg dose has already been evaluated. Methods: A Markov model compared the health outcomes and costs of treating VTE patient cohorts with either rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily for 6 months, then extended prevention with 10 mg once daily) or apixaban (10 mg twice daily for 1 week, followed by 5 mg twice daily for 6 months, then extended prevention with 2.5 mg twice daily) over a lifetime horizon. The model included an initial acute treatment and prevention phase (0-6 months) and an extended prevention phase (6-18 months). Efficacy and safety data were derived from two network meta-analyses. Reference treatment comparators were derived from the EINSTEIN-Pooled study and EINSTEIN-CHOICE trial. Healthcare costs and utility data were derived from published literature. Results: The rivaroxaban regimen was associated with increased quality-adjusted life years (QALYs) and slightly lower total costs compared with apixaban over a lifetime horizon. Deterministic and probabilistic sensitivity analyses demonstrated that rivaroxaban remained a cost-effective alternative to apixaban over a wide range of parameters. Incremental cost-effectiveness ratio estimates were below the £20,000 per QALY threshold in 74.1% of 2,000 model simulations. Scenario analyses further supported that rivaroxaban is a cost-effective alternative to apixaban. Limitations: Clinical and safety inputs were derived from network meta-analysis, which are subject to inherent limitations whereby small differences between study designs may severely impact efficacy and safety outcomes. Furthermore, these inputs were based on data from clinical trials, which may not reflect real-world data. Conclusions: Rivaroxaban was associated with a slightly lower total cost and increased QALYs compared with apixaban for VTE management in the UK over a lifetime horizon.

Healthcare resource use in XALIA: A subgroup analysis of a non-interventional study of rivaroxaban versus standard anticoagulation for deep vein thrombosis.

INTRODUCTION: The non-interventional XALIA study compared the safety and effectiveness of rivaroxaban with standard anticoagulation for the treatment of venous thromboembolism in routine clinical practice. This substudy assessed the effect of treatment with rivaroxaban on healthcare resource use, hospital length of stay (LOS) and frequency of hospitalisation. METHODS: In XALIA, patients aged ≥18 years scheduled to receive ≥3 months of rivaroxaban or standard anticoagulation treatment for deep vein thrombosis (DVT) were eligible. Treatment decisions were at the physician's discretion. Healthcare resource use, including hospital admission for the index DVT and initial LOS, was documented. The main analyses in this substudy were conducted in a 1:1 propensity score-matched set (PMS) of patients, with adjustment for cancer at baseline. RESULTS: In the PMS analysis, 1124 rivaroxaban-treated patients and 1124 standard anticoagulation-treated patients were included. Baseline characteristics were similar between groups (mean age 60.8 years vs. 61.2 years, DVT only rates of 89.7% vs. 90.2% and cancer rates of 8.4% vs. 8.5%, respectively). Of these, 433/1124 (38.5%) rivaroxaban-treated patients and 438/1124 (39.0%) standard anticoagulation-treated patients were hospitalised. Index event LOS in the PMS analysis was a least-squares mean of 2.6 days shorter with rivaroxaban vs. standard anticoagulation (5.4 vs. 8.0 days; geometric means ratio = 0.67 [95% confidence interval 0.61-0.74, P < 0.001]). CONCLUSIONS: In XALIA, hospital LOS was shorter with rivaroxaban than with standard anticoagulation, consistent with the phase III study results. DVT treatment with rivaroxaban in routine clinical practice may reduce the cost per patient vs. standard anticoagulation.

Real-world clinical evidence on rivaroxaban, dabigatran, and apixaban compared with vitamin K antagonists in patients with nonvalvular atrial fibrillation: a systematic literature review.

INTRODUCTION: Several comparative real-world effectiveness studies on direct oral anticoagulants (DOACs) have been conducted, but an overview of the available evidence remains to be developed, which could provide a better understanding of the value of DOACs relative to vitamin K antagonists (VKAs). AREAS COVERED: A systematic literature review was conducted on the available real-world evidence (RWE) of three DOACs (rivaroxaban, dabigatran, and apixaban) compared with VKAs (e.g. warfarin), in patients with nonvalvular atrial fibrillation (NVAF).This systematic literature review included RWE published up to December 2016. Studies with > 50 patients reporting on incident and prevalent NVAF cases were included. The following databases were searched: Medline, Embase, and the Cochrane Library. Outcomes of interest included thromboembolic events, all-cause mortality, bleeding events, and nonpersistence. Of the 562 RWE DOACs articles retrieved, 49 presented results for rivaroxaban versus VKAs, 79 for dabigatran versus VKAs, and 18 for apixaban versus VKAs. Substantial heterogeneity was found across patient population, outcome definition, and follow-up period. Major bleeding, ischemic stroke, and intracranial hemorrhage were the most frequent outcomes analyzed. EXPERT COMMENTARY: Overall, the RWE studies were aligned with the Phase 3 trials. However, conflicting results were reported for several outcomes of interest.

Thirteen-year trend in the persistence with vitamin K antagonists for venous thromboembolism in the UK: a cohort study.

BACKGROUND: Venous thromboembolism (VTE) comprises deep vein thrombosis (DVT) and pulmonary embolism (PE) and is associated with significant recurrence and mortality risk. Standard VTE treatment includes at least 3 months anticoagulation. The objective was to describe time trends in the duration of oral anticoagulation in patients initially treated with vitamin K antagonists (VKAs). METHODS: A retrospective cohort study was conducted on patients with first VTE and VKA treatment initiation within 30 days, identified from the UK Clinical Practice Research Datalink from 2001 to 2014. VKA users were followed for the duration of oral anticoagulation which included switching to non-VKA oral anticoagulants. The probability of remaining on anticoagulation treatment (persistence) was estimated using Kaplan-Meier survival functions. RESULTS: A total of 16,018 patients with VTE initiated VKA; 48.2% males, mean age 62.1 years, median VKA treatment duration 6.5 months. The 90-day persistence increased from 75.6% in 2001 to 91.2% in 2013 (p < .0001) and the 180-day persistence from 39.3% in 2001 to 61.1% in 2013 (p < .0001). This time trend was also shown for patients with DVT, PE, provoked VTE, unprovoked VTE, provoked DVT, unprovoked DVT, provoked PE and unprovoked PE. There were no major differences in persistence between patients with provoked and unprovoked VTE, but persistence was lower following DVT than PE (p < .0001). CONCLUSIONS: The increase in persistence was independent of the presentation of the first VTE (provoked or unprovoked), but higher for first PE. Whether the increasing persistence resulted in decreasing risk of recurrent VTE needs to be confirmed.

Patient-Reported Treatment Experience with Oral Rivaroxaban: Results from the Noninterventional XALIA Study of Deep-Vein Thrombosis.

For venous thromboembolism (VTE) treatment, patient satisfaction was shown to improve with rivaroxaban versus standard anticoagulation in the phase III EINSTEIN DVT and EINSTEIN PE trials. This substudy of the prospective, noninterventional XALIA study of rivaroxaban for deep-vein thrombosis treatment assessed if this was also observed in routine clinical practice. Patients enrolled in XALIA who received rivaroxaban or standard anticoagulation treatment were eligible for inclusion in this substudy. Treatment decisions were at the physician's discretion. Patients completed the 17-item Anti-Clot Treatment Scale (ACTS, comprising a 12-item Burdens subscale, a 3-item Benefits subscale and one global item per subscale) during follow-up. The propensity score-matched set (PMS) was used for the main analysis; the adjusted safety analysis (ASAF) set was used for confirmatory purposes. Analyses by follow-up visit and subgroup, including age, sex, and previous VTE, were also conducted. The PMS-ACTS analysis included 458 rivaroxaban-treated and 434 standard anticoagulation-treated patients. Baseline demographic and clinical characteristics were generally similar across treatment arms. ACTS Burdens scores significantly improved with rivaroxaban versus standard anticoagulation (least-squares mean difference of 2.4 ± 0.4 points; p < 0.0001); ACTS Benefits scores were numerically higher with rivaroxaban (least-squares mean difference of 0.2 ± 0.1 points; p = 0.2). Similar findings occurred across follow-up visits and subgroups. Results were confirmed in the ASAF-ACTS analysis. Consistent with phase III analyses, rivaroxaban was associated with improved ACTS Burdens scores; ACTS Benefits scores numerically favored rivaroxaban, although without reaching statistical significance.

The Burden of Major Adverse Cardiac Events and Antiplatelet Prevention in Patients with Coronary or Peripheral Arterial Disease.

BACKGROUND: Patients with a history of a cardiovascular (CV) disease are at high risk of suffering secondary major adverse cardiac events (MACE), namely death, nonfatal myocardial infarction (MI), stroke, symptomatic pulmonary embolism, CV and all-cause hospitalization, and bleeding. METHODS: A comprehensive review of the literature was conducted to review the epidemiology and burden of MACE in patients with coronary or peripheral arterial disease (CAD or PAD) in Europe and other ex-US regions. Relevant articles published between 2003 and 2013 were retrieved from PubMed and other sites. RESULTS: MACE incidence and prevalence in patients with CAD or PAD were increased by at least 1.4-fold compared with matched controls with no CV disease. In patients with CAD, MACE mostly occurred within 30 days of primary percutaneous coronary intervention; incidence decreased with time. Increased oxidative stress in coronary and peripheral arteries, diabetes, and chronic kidney disease were identified as the main risk factors for MACE in patients with CAD and PAD. Registry data showed that, although preventive antiplatelet therapy was prescribed at high rates, a large proportion (9-56%) of patients did not receive treatment. Furthermore, adherence to treatment declined over time, potentially leading to disease worsening. CONCLUSION: Despite gaps in the literature, this assessment showed that MACE's risk is substantial among patients with CAD or PAD and that the use of preventive therapies is suboptimal. Development of additional preventive therapies for these patients is warranted.