Cost-effectiveness of ticagrelor plus aspirin versus aspirin in acute ischaemic stroke or transient ischaemic attack: an economic evaluation of the THALES trial.

Objective: THALES demonstrated that ticagrelor plus aspirin reduced the risk of stroke or death but increased bleeding versus aspirin during the 30 days following a mild-to-moderate acute non-cardioembolic ischaemic stroke (AIS) or high-risk transient ischaemic attack (TIA). There are no cost-effectiveness analyses supporting this combination in Europe. To address this, a cost-effectiveness analysis was performed. Methods: Cost-effectiveness was evaluated using a decision tree and Markov model with a short-term and long-term (30-year) horizon. Stroke, mortality, bleeding and EuroQol-5 Dimension (EQ-5D) data from THALES were used to estimate short-term outcomes. Model transitions were based on stroke severity (disabling stroke was defined as modified Rankin Scale >2). Healthcare resource utilisation and EQ-5D data beyond 30 days were based on SOCRATES, another trial in AIS/TIA that compared ticagrelor with aspirin. Long-term costs, survival and disutilities were based on published literature. Unit costs were derived from national databases and discounted at 3% annually from a Swedish healthcare perspective. Results: One-month treatment with ticagrelor plus aspirin resulted in 12 fewer strokes, 4 additional major bleeds and cost savings of €95 000 per 1000 patients versus aspirin from a Swedish healthcare perspective. This translated into increased quality-adjusted life-years (0.04) and reduced societal costs (-€1358) per patient over a lifetime horizon. Key drivers of cost-effectiveness were number of patients experiencing subsequent disabling stroke and degree of disability. Findings were robust over a range of input assumptions. Conclusion: One month of treatment with ticagrelor plus aspirin is likely to improve outcomes and reduce costs versus aspirin in mild-to-moderate AIS or high-risk TIA. Trial registration number: NCT03354429.

Risk of Subsequent Events in Patients With Minor Ischemic Stroke or High-Risk Transient Ischemic Attack.

This study aimed to present the prognosis after minor acute ischemic stroke (AIS) or transient ischemic attack (TIA), using a definition of subsequent stroke in accordance with recent clinical trials. In total, 9,506 patients with minor AIS (National Institutes of Health Stroke Scale ≤ 5) or high-risk TIA (acute lesions or ≥ 50% cerebral artery steno-occlusion) admitted between November 2010 and October 2013 were included. The primary outcome was the composite of stroke (progression of initial event or a subsequent event) and all-cause mortality. The cumulative incidence of stroke or death was 11.2% at 1 month, 13.3% at 3 months and 16.7% at 1 year. Incidence rate of stroke or death in the first month was 12.5 per 100 person-months: highest in patients with large artery atherosclerosis (17.0). The risk of subsequent events shortly after a minor AIS or high-risk TIA was substantial, particularly in patients with large artery atherosclerosis.

Cost-effectiveness of ticagrelor in patients with type 2 diabetes and coronary artery disease: a European economic evaluation of the THEMIS trial.

AIMS: To conduct a health economic evaluation of ticagrelor in patients with type 2 diabetes and coronary artery disease (CAD) from a multinational payer perspective. Cost-effectiveness and cost-utility of ticagrelor were evaluated in the overall effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study (THEMIS) trial population and in the predefined patient group with prior percutaneous coronary intervention. METHODS AND RESULTS: A Markov model was developed to extrapolate patient outcomes over a lifetime horizon. The primary outcome was incremental cost-effectiveness ratios (ICERs), which were compared with conventional willingness-to-pay thresholds [€47 000/quality-adjusted life-year (QALY) in Sweden and €30 000/QALY in other countries].Treatment with ticagrelor resulted in QALY gains of up to 0.045 in the overall population and 0.099 in patients with percutaneous coronary intervention (PCI). Increased costs and benefits translated to ICERs ranged between €27 894 and €42 252/QALY across Sweden, Germany, Italy, and Spain in the overall population. In patients with prior PCI, estimated ICERs improved to €18 449, €20 632, €20 233, and €13 228/QALY in Sweden, Germany, Italy, and Spain, respectively, driven by higher event rates and treatment benefit. CONCLUSION: Based on THEMIS results, ticagrelor plus aspirin compared with aspirin alone may be cost-effective in some European countries in patients with T2DM and CAD and no prior myocardial infarction (MI) or stroke. Additionally, ticagrelor is likely to be cost-effective across European countries in patients with a history of PCI.

Disease Burden Following Non-Cardioembolic Minor Ischemic Stroke or High-Risk TIA: A GWTG-Stroke Study.

BACKGROUND: Limited real-world data are available on outcomes following non-cardioembolic minor ischemic stroke (IS) or high-risk transient ischemic attack (TIA), particularly in the United States (US). We examined outcomes and Medicare payments following any severity IS or TIA as well as the subgroup with minor IS or high-risk TIA. METHODS: Medicare beneficiaries >65 years were identified using US nationwide Get with the Guidelines (GWTG)-Stroke Registry linked to Medicare claims data. The cohort consisted of patients enrolled in Medicare fee-for-service plan, hospitalized with non-cardioembolic IS or TIA between 2011 and 2014, segmenting a subgroup with minor IS (National Institute of Health Stroke Scale [NIHSS] ≤5) or high-risk TIA (ABCD2-score ≥6) compatible with the THALES clinical trial population. Outcomes included functional status at discharge, clinical outcomes (all-cause mortality, ischemic stroke, and hemorrhagic stroke, individually and as a composite), hospitalizations, and population average inpatient Medicare payments following non-cardioembolic IS or TIA. RESULTS: The THALES-compatible cohort included 62,518 patients from 1471 hospitals. At discharge, 37.0% were unable to ambulate without assistance, and 96.2% were prescribed antiplatelet therapy. Cumulative incidences at 30 days, 90 days, and 1 year for the composite outcome were 3.7%, 7.6%, and 17.2% and 2.4%, 4.0%, and 7.3% for subsequent stroke. The mean Medicare payment for the index hospitalization was $7951. The cumulative all-cause inpatient Medicare spending per patient (with or without any subsequent admission) at 30 days and 1 year from discharge was $1451 and $8105, respectively. CONCLUSIONS: The burden of illness for minor IS/high-risk TIA patients indicates an important unmet need. Improved therapeutic options may offer a significant impact on both patient outcomes and Medicare spending.

Adverse Changes in HbA1c, Body Weight and Insulin Use in People with Type 1 Diabetes Mellitus Following Dapagliflozin Discontinuation in the DEPICT Clinical Trial Programme.

INTRODUCTION: Dapagliflozin is an orally active inhibitor of sodium-glucose co-transporter 2 (SGLT2) that is indicated for use in adults with type 1 diabetes (T1DM) (with a body mass index (BMI) of at least 27 kg/m2 in Europe, no such BMI limit in Japan), when insulin alone does not provide adequate glycaemic control. The aim of this study was to evaluate changes in glycated haemoglobin (HbA1c), body weight and insulin dose following discontinuation of dapagliflozin for the management of T1DM in the DEPICT clinical trial programme. METHODS: The interrelationship between treatment discontinuation, insulin requirement and outcomes post-discontinuation was evaluated using descriptive summary statistics and linear regression modelling. Data were analysed from individuals with T1DM discontinuing dapagliflozin in DEPICT-1 or DEPICT-2 (unplanned or end of study). HbA1c and body weight were measured over the 56-week study period (consisting of a 52-week treatment period and a 4-week follow-up period) at 4-8 weekly intervals. Following discontinuation of dapagliflozin, 1-year change in HbA1c (%) and weight (kg) following discontinuation of dapagliflozin was estimated; total daily insulin doses were descriptively summarised. RESULTS: Of the 1059 individuals that received dapagliflozin during the DEPICT trials 91 met the eligibility criteria and were included in the analyses of HbA1c and body weight. The mean duration of follow-up was 209 days in both analyses. Following dapagliflozin discontinuation, estimated annualised changes in HbA1c and body weight were + 0.99% (95% CI 0.39, 1.59) and + 3.75 kg (1.65, 5.86), respectively. An increase in insulin dose was observed around the time of discontinuation; insulin dose in the 2-week post-discontinuation was + 3.6 IU and + 4.4 IU higher with dapagliflozin 5 mg and 10 mg than 2 weeks pre-discontinuation, respectively. CONCLUSION: Discontinuation of dapagliflozin is predicted to lead to clinically meaningful increases in HbA1c and body weight, in addition to higher insulin doses. These findings are important in the management of people with T1DM among whom insulin is the only existing pharmacological treatment option.

Cost-effectiveness of dapagliflozin as an adjunct to insulin for the treatment of type 1 diabetes mellitus in the United Kingdom.

AIMS: To assess the cost-effectiveness of dapagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor, as an adjunct to insulin in adults with type 1 diabetes mellitus (T1DM) inadequately controlled by insulin alone in the UK setting. METHODS: A cost-utility analysis was conducted to compare dapagliflozin (5 mg or 10 mg) added to insulin versus insulin monotherapy (standard of care) over a lifetime horizon. Treatment efficacy and safety data were obtained from 52-week results of the DEPICT-1 and DEPICT-2 trials and a network meta-analysis of SGLT2 inhibitors in T1DM. Direct healthcare costs, life-years, and quality-adjusted life-years (QALYs) were estimated from a UK payer perspective and discounted at 3.5% annually, using the Cardiff T1DM Model. Sensitivity analyses assessed uncertainty in estimated incremental cost-effectiveness ratios (ICERs). RESULTS: Dapagliflozin 5 mg was associated with gains of 0.23 life-years and 0.42 QALYs, at an additional cost of £4240 per person; corresponding to an ICER of £10 143 versus standard of care. For dapagliflozin 10 mg, incremental life-years, QALYs and costs were 0.24, 0.49 and £2964, respectively; corresponding to an ICER of £6103 versus standard of care. In probabilistic sensitivity analysis, ICER estimates fell below £20 000/QALY in 78% to 90% of simulations. Cost-effectiveness results were sensitive to changes in baseline patient characteristics and treatment effects on glycated haemoglobin; however, ICERs remained below £20 000. CONCLUSIONS: At cost-effectiveness thresholds conventionally applied in the UK, dapagliflozin as an adjunct to insulin appears to be a cost-effective treatment option for people with T1DM inadequately controlled by insulin alone.

Relationship between hypoglycaemia, body mass index and quality of life among patients with type 1 diabetes: Observations from the DEPICT clinical trial programme.

AIMS: To demonstrate the relationships between hypoglycaemia, body mass index (BMI) and quality of life, and to examine the impact of dapagliflozin on patient-reported treatment satisfaction in patients with type 1 diabetes mellitus (T1DM), using data from the DEPICT (Dapagliflozin Evaluation in Patients With Inadequately Controlled Type 1 Diabetes) clinical trial programme. METHODS: A two-stage modelling approach, using a linear regression framework, was adopted to evaluate the relationship between hypoglycaemia, BMI and quality of life. Hypoglycaemia fear score (HFS) was modelled as a function of hypoglycaemic events (non-severe documented symptomatic and severe) and, subsequently, quality of life (as measured by the EQ-5D questionnaire) was modelled as a function of HFS and BMI. A linked evidence approach correlated the relationship between treatment, hypoglycaemic events and glycated haemoglobin (HbA1c), to the relationships captured within the regression models. The proportion of patients achieving increased patient-reported treatment satisfaction, as measured by the Diabetes Treatment Satisfaction Questionnaire (DTSQ) total score, was compared between study arms. RESULTS: Incident severe hypoglycaemia was associated with significantly higher HFS (coefficient estimate [CE] 14.62, P=0.004). The frequency of symptomatic hypoglycaemic events was associated with a significantly higher HFS (log transposed, CE 1.32, P=0.026). Higher HFS and higher BMI were both independently associated with a significantly lower EQ-5D score (HFS: CE -0.0024, P<0.001; BMI: CE -0.0026, P=0.016). Significantly higher proportions of dapagliflozin-treated patients achieved ≥3-point increases in DTSQ total score compared to patients in the placebo group. CONCLUSION: The results of this study demonstrated that increases in hypoglycaemia and BMI were associated with reduced quality of life in people with T1DM. Dapagliflozin-treated patients achieved a reduction in HbA1c whilst avoiding an increase in hypoglycaemic events. The results also showed that treatment with dapagliflozin was associated with an improvement in treatment satisfaction.

Systematic literature review and network meta-analysis of sodium-glucose co-transporter inhibitors vs metformin as add-on to insulin in type 1 diabetes.

AIMS: To identify and synthesize phase 3 and phase 4 randomized controlled trials (RCTs) of sodium-glucose co-transporter (SGLT) inhibitors and metformin as adjuncts to insulin in type 1 diabetes (T1DM) using network meta-analysis (NMA). MATERIALS AND METHODS: A systematic literature review (SLR) identified relevant RCTs of ≥12 Weeks duration. MEDLINE, Embase, the Cochrane Library and grey literature were searched through October 2018. NMAs indirectly compared SGLT inhibitors and metformin for change from baseline in HbA1c, weight, total daily insulin dose and systolic blood pressure at Week 24 to 26 and Week 52. Safety outcomes were also explored. RESULTS: Nine trials (N = 6780) were included in the SLR. NMAs indicated that all therapies performed better than placebo for the efficacy outcomes at both time points. Compared with metformin at Week 24 to 26, the SGLT inhibitors dapagliflozin (5 mg), sotagliflozin (200 mg) and empagliflozin (10 mg) had larger reductions in HbA1c (mean difference [MD] = -0.24, 95% credible interval [CrI], -0.41 to -0.07, MD = -0.23, 95% CrI, -0.39 to -0.08 and MD = -0.35, 95% CrI, -0.51 to -0.19, respectively) and in weight, which were sustained in sensitivity analyses. There were few differences observed in the results of safety outcomes, such as risk of diabetic ketoacidosis (DKA), which should be interpreted cautiously because of wide CrIs. CONCLUSIONS: Adjunctive use of SGLT inhibitors in T1DM can improve glycaemic control compared with metformin while enabling weight loss, with consistent efficacy across the class. However, these results are based on indirect evidence so confirmation in a head-to-head study would be valuable.