Budget Impact Analysis of Metformin Sustained Release for the Treatment of Type 2 Diabetes in The Netherlands

BACKGROUND: Adverse drug reactions and medication nonadherence are well-known causes of sub-optimal disease control and worsened disease outcomes in patients who are treated for type 2 diabetes. Metformin sustained release (SR) might reduce these adverse events and improve medication adherence via a simplified treatment regimen for metformin immediate release (IR)-intolerant patients. OBJECTIVES: The aim of this study is to estimate the budget impact of metformin SR for the treatment of type 2 diabetes in the Netherlands, compared to the current standard of care (SoC) with metformin IR. METHODS: A budget impact model was built to represent the course of the disease and treatment pathway of type 2 diabetes patients eligible for metformin SR from a healthcare payer's perspective. Patients were considered eligible if they used less than 2000 mg metformin IR per day, but suffered from adverse events that might lead to therapy discontinuation, and if they were newly diagnosed with type 2 diabetes. The costs of type 2 diabetes treatment and related complications over a time horizon of 3 years were calculated. Univariate sensitivity analyses were conducted to show which parameters have the biggest influence on the budget impact. RESULTS: The budget impact analysis showed cost-savings of - €1,962,335 over a period of 3 years through implementation of metformin SR as an alternative to SoC with metformin IR. Savings were mostly driven by the delay of other, more expensive type 2 diabetes treatments, such as insulin. In sensitivity analyses, medication adherence and persistence appeared to have the biggest influence on the budget impact. CONCLUSION: Metformin SR could potentially be a cost-saving alternative to metformin IR for the treatment of type 2 diabetes in the Netherlands, especially in patients experiencing adverse events with metformin IR. However, more research is needed to better predict the effect of using once-daily metformin, compared to multiple dosages, on medication adherence and persistence and to evaluate whether metformin SR really decreases the amount of adverse events

Rivaroxaban for non-valvular atrial fibrillation and venous thromboembolism in the Netherlands:a real-world data based cost-effectiveness analysis

BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) have been included in international guidelines as important alternatives to vitamin K antagonists (VKAs) for the treatment of venous thromboembolism (VTE) and stroke prevention in non-valvular atrial fibrillation (NVAF). Meanwhile, in the Netherlands, NOACs are widely used next to VKAs. The objective of our study is to estimate the cost-effectiveness of treatment with rivaroxaban compared to VKAs in NVAF and VTE patients in the Netherlands, using data from international prospective observational phase IV studies. METHODS: Two models were developed to represent NVAF and VTE patients, populated with patients from the XANTUS (NCT01606995) and XALIA (NCT01619007) international prospective observational studies. The one-year cost-effectiveness of rivaroxaban use, compared to VKAs, was explored in a population consisting of NVAF and VTE patients (base case) as well as for four scenarios with subpopulations: NVAF patients only, VTE patients only, NVAF patients with unstable international normalized ratio (INR), and NVAF patients using an INR self-measuring device. RESULTS: In the base case, rivaroxaban saved €72,350 and gained 21 quality-adjusted life-years (QALYs) in a simulation of 2,000 patients over the use of VKAs. Ergo, rivaroxaban was dominant over VKAs. The probabilistic sensitivity analysis showed a probability of 85% for rivaroxaban being dominant and 100% at a willingness-to-pay threshold of €20,000/QALY. Rivaroxaban appeared to be dominant in all scenarios as well, except for the NVAF-patients-only scenario where the incremental cost-effectiveness ratio (ICER) was €157/QALY. CONCLUSIONS: In patients with NVAF or VTE, rivaroxaban treatment is likely to be cost-effective and potentially cost-saving alternative to VKA in the Netherlands

Extended Treatment with Apixaban for Venous Thromboembolism Prevention in the Netherlands:Clinical and Economic Effects

Background ?Dutch guidelines advise extended anticoagulant treatment with direct oral anticoagulants or vitamin K antagonists for patients with idiopathic venous thromboembolism (VTE) who do not have high bleeding risk. Objectives ?The aim of this study was to analyze the economic effects of extended treatment of apixaban in the Netherlands, based on an updated and adapted previously published model. Methods ?We performed a cost-effectiveness analysis simulating a population of 1,000 VTE patients. The base-case analysis compared extended apixaban treatment to no treatment after the first 6 months. Five additional scenarios were conducted to evaluate the effect of different bleeding risks and health care payers' perspective. The primary outcome of the model is the incremental cost-effectiveness ratio (ICER) in costs (€) per quality-adjusted life-year (QALY), with one QALY defined as 1 year in perfect health. To account for any influence of the uncertainties in the model, probabilistic and univariate sensitivity analyses were conducted. The treatment was considered cost-effective with an ICER less than €20,000/QALY, which is the most commonly used willingness-to-pay (WTP) threshold for preventive drugs in the Netherlands. Results ?The model showed a reduction in recurrent VTE and no increase in major bleeding events for extended treatment in all scenarios. The base-case analysis showed an ICER of €9,653/QALY. The probability of being cost-effective for apixaban in the base-case was 70.0% and 91.4% at a WTP threshold of €20,000/QALY and €50,000/QALY, respectively. Conclusion ?Extended treatment with apixaban is cost-effective for the prevention of recurrent VTE in Dutch patients

Loss of p53 triggers Wnt-dependent systemic inflammation to drive breast cancer metastasis

Cancer-associated systemic inflammation is strongly linked to poor disease outcome in patients with cancer1,2. For most human epithelial tumour types, high systemic neutrophil-to-lymphocyte ratios are associated with poor overall survival3, and experimental studies have demonstrated a causal relationship between neutrophils and metastasis4,5. However, the cancer-cell-intrinsic mechanisms that dictate the substantial heterogeneity in systemic neutrophilic inflammation between tumour-bearing hosts are largely unresolved. Here, using a panel of 16 distinct genetically engineered mouse models for breast cancer, we uncover a role for cancer-cell-intrinsic p53 as a key regulator of pro-metastatic neutrophils. Mechanistically, loss of p53 in cancer cells induced the secretion of WNT ligands that stimulate tumour-associated macrophages to produce IL-1β, thus driving systemic inflammation. Pharmacological and genetic blockade of WNT secretion in p53-null cancer cells reverses macrophage production of IL-1β and subsequent neutrophilic inflammation, resulting in reduced metastasis formation. Collectively, we demonstrate a mechanistic link between the loss of p53 in cancer cells, secretion of WNT ligands and systemic neutrophilia that potentiates metastatic progression. These insights illustrate the importance of the genetic makeup of breast tumours in dictating pro-metastatic systemic inflammation, and set the stage for personalized immune intervention strategies for patients with cancer

Loss of p53 triggers Wnt-dependent systemic inflammation to drive breast cancer metastasis

Cancer-associated systemic inflammation is strongly linked to poor disease outcome in patients with cancer1,2. For most human epithelial tumour types, high systemic neutrophil-to-lymphocyte ratios are associated with poor overall survival3, and experimental studies have demonstrated a causal relationship between neutrophils and metastasis4,5. However, the cancer-cell-intrinsic mechanisms that dictate the substantial heterogeneity in systemic neutrophilic inflammation between tumour-bearing hosts are largely unresolved. Here, using a panel of 16 distinct genetically engineered mouse models for breast cancer, we uncover a role for cancer-cell-intrinsic p53 as a key regulator of pro-metastatic neutrophils. Mechanistically, loss of p53 in cancer cells induced the secretion of WNT ligands that stimulate tumour-associated macrophages to produce IL-1β, thus driving systemic inflammation. Pharmacological and genetic blockade of WNT secretion in p53-null cancer cells reverses macrophage production of IL-1β and subsequent neutrophilic inflammation, resulting in reduced metastasis formation. Collectively, we demonstrate a mechanistic link between the loss of p53 in cancer cells, secretion of WNT ligands and systemic neutrophilia that potentiates metastatic progression. These insights illustrate the importance of the genetic makeup of breast tumours in dictating pro-metastatic systemic inflammation, and set the stage for personalized immune intervention strategies for patients with cancer

Clinical characteristics of women captured by extending the definition of severe postpartum haemorrhage with 'refractoriness to treatment': a cohort study

Background: The absence of a uniform and clinically relevant definition of severe postpartum haemorrhage hampers comparative studies and optimization of clinical management. The concept of persistent postpartum haemorrhage, based on refractoriness to initial first-line treatment, was proposed as an alternative to common definitions that are either based on estimations of blood loss or transfused units of packed red blood cells (RBC). We compared characteristics and outcomes of women with severe postpartum haemorrhage captured by these three types of definitions. Methods: In this large retrospective cohort study in 61 hospitals in the Netherlands we included 1391 consecutive women with postpartum haemorrhage who received either ≥4 units of RBC or a multicomponent transfusion. Clinical characteristics and outcomes of women with severe postpartum haemorrhage defined as persistent postpartum haemorrhage were compared to definitions based on estimated blood loss or transfused units of RBC within 24 h following birth. Adverse maternal outcome was a composite of maternal mortality, hysterectomy, arterial embolisation and intensive care unit admission. Results: One thousand two hundred sixty out of 1391 women (90.6%) with postpartum haemorrhage fulfilled the definition of persistent postpartum haemorrhage. The majority, 820/1260 (65.1%), fulfilled this definition within 1 h following birth, compared to 819/1391 (58.7%) applying the definition of ≥1 L blood loss and 37/845 (4.4%) applying the definition of ≥4 units of RBC. The definition persistent postpartum haemorrhage captured 430/471 adverse maternal outcomes (91.3%), compared to 471/471 (100%) for ≥1 L blood loss and 383/471 (81.3%) for ≥4 units of RBC. Persistent postpartum haemorrhage did not capture all adverse outcomes because of missing data on timing of initial, first-line treatment. Conclusion: The definition persistent postpartum haemo

SUGAR-DIP trial: Oral medication strategy versus insulin for diabetes in pregnancy, study protocol for a multicentre, open-label, non-inferiority, randomised controlled trial

Introduction In women with gestational diabetes mellitus (GDM) requiring pharmacotherapy, insulin was the established first-line treatment. More recently, oral glucose lowering drugs (OGLDs) have gained popularity as a patient-friendly, less expensive and safe alternative. Monotherapy with metformin or glibenclamide (glyburide) is incorporated in several international guidelines. In women who do not reach sufficient glucose control with OGLD monotherapy, usually insulin is added, either with or without continuation of OGLDs. No reliable data from clinical trials, however, are available on the effectiveness of a treatment strategy using all three agents, metformin, glibenclamide and insulin, in a stepwise approach, compared with insulin-only therapy for improving pregnancy outcomes. In this trial, we aim to assess the clinical effectiveness, cost-effectiveness and patient experience of a stepwise combined OGLD treatment protocol, compared with conventional insulin-based therapy for GDM. Methods The SUGAR-DIP trial is an open-label, multicentre randomised controlled non-inferiority trial. Participants are women with GDM who do not reach target glycaemic control with modification of diet, between 16 and 34 weeks of gestation. Participants will be randomised to either treatment with OGLDs, starting with metformin and supplemented as needed with glibenclamide, or randomised to treatment with insulin. In women who do not reach target glycaemic control with combined metformin and glibenclamide, glibenclamide will be substituted with insulin, while continuing metformin. The primary outcome will be the incidence of large-for-gestational-age infants (birth weight >90th percentile). Secondary outcome measures are maternal diabetes-related endpoints, obstetric complications, neonatal complications and cost-effectiveness analysis. Outcomes will be analysed according to the intention-to-treat principle. Ethics and dissemination The study protocol was approved by the Ethics Committee of the Utrecht University Medical Centre. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted for publication in peer-reviewed journals

Budget Impact Analysis of Metformin Sustained Release for the Treatment of Type 2 Diabetes in The Netherlands

BACKGROUND: Adverse drug reactions and medication nonadherence are well-known causes of sub-optimal disease control and worsened disease outcomes in patients who are treated for type 2 diabetes. Metformin sustained release (SR) might reduce these adverse events and improve medication adherence via a simplified treatment regimen for metformin immediate release (IR)-intolerant patients. OBJECTIVES: The aim of this study is to estimate the budget impact of metformin SR for the treatment of type 2 diabetes in the Netherlands, compared to the current standard of care (SoC) with metformin IR. METHODS: A budget impact model was built to represent the course of the disease and treatment pathway of type 2 diabetes patients eligible for metformin SR from a healthcare payer's perspective. Patients were considered eligible if they used less than 2000 mg metformin IR per day, but suffered from adverse events that might lead to therapy discontinuation, and if they were newly diagnosed with type 2 diabetes. The costs of type 2 diabetes treatment and related complications over a time horizon of 3 years were calculated. Univariate sensitivity analyses were conducted to show which parameters have the biggest influence on the budget impact. RESULTS: The budget impact analysis showed cost-savings of - €1,962,335 over a period of 3 years through implementation of metformin SR as an alternative to SoC with metformin IR. Savings were mostly driven by the delay of other, more expensive type 2 diabetes treatments, such as insulin. In sensitivity analyses, medication adherence and persistence appeared to have the biggest influence on the budget impact. CONCLUSION: Metformin SR could potentially be a cost-saving alternative to metformin IR for the treatment of type 2 diabetes in the Netherlands, especially in patients experiencing adverse events with metformin IR. However, more research is needed to better predict the effect of using once-daily metformin, compared to multiple dosages, on medication adherence and persistence and to evaluate whether metformin SR really decreases the amount of adverse events