Cost-Effectiveness of Canagliflozin Added to Standard of Care for Treating Diabetic Kidney Disease (DKD) in Patients with Type 2 Diabetes Mellitus (T2DM) in England: Estimates Using the CREDEM-DKD Model.

INTRODUCTION: On the basis of reductions in diabetic kidney disease (DKD) progression and major adverse cardiovascular events observed in the landmark CREDENCE trial, canagliflozin 100 mg received an extension to its EU marketing authorisation in July 2020 to include the treatment of DKD in people with type 2 diabetes mellitus (T2DM) making it the first pharmacological therapy to receive regulatory authorisation for treatment of DKD since the RENAAL and IDNT trials in nearly 20 years. Efficient allocation of limited healthcare resources requires evaluation not only of clinical safety and efficacy but also economic consequences. The study aim was to estimate the cost-effectiveness of canagliflozin when added to current standard of care (SoC) versus SoC alone from the perspective of the NHS in England. METHODS: A microsimulation model was developed using patient-level data from CREDENCE, including risk equations for the key clinical outcomes of start of dialysis, hospitalisation for heart failure, nonfatal myocardial infarction, nonfatal stroke, and all-cause mortality. DKD progression was modelled using estimated glomerular filtration rate and urinary albumin-to-creatinine ratio evolution equations. Risk for kidney transplant was sourced from UK-specific sources given the near absence of events in CREDENCE. Patient characteristics and treatment effects were sourced from CREDENCE. Unit costs (£2019) and disutility weights were sourced from the literature and discounted at 3.5% annually. The time horizon was 10 years in the base case, and sensitivity analysis was performed. RESULTS: Canagliflozin was associated with sizable gains in life-years and quality-adjusted life-year (QALYs) over 10 years, with gains increasing with simulation duration. Cost offsets associated with reductions in cardiovascular and renal complications were sufficient to achieve overall net cost savings. The findings were generally confirmed in the sensitivity analyses. CONCLUSION: Model results suggest that adding canagliflozin 100 mg to SoC can improve patient outcomes while reducing overall net costs from the NHS perspective in England. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02065791.

Focused Ultrasound Thalamotomy and Other Interventions for Medication-Refractory Essential Tremor: An Indirect Comparison of Short-Term Impact on Health-Related Quality of Life.

BACKGROUND: Up to 50% of essential tremor patients are refractory to medication and require alternative treatment to achieve tremor relief. This study aimed to identify and analyze evidence supporting the use of the emerging magnetic resonance-guided focused ultrasound (MRgFUS) compared to alternative stimulatory and ablative interventions for the treatment of medication-refractory essential tremor: radiofrequency thalamotomy, unilateral deep brain stimulation (DBS), and stereotactic radiosurgery. METHODS: A systematic literature review was conducted to identify clinical, health-related quality of life (HRQoL), and economic evidence for each intervention. Because of the lack of comparative evidence captured, a feasibility assessment was performed to determine possible comparisons between interventions, and newly established matching-adjusted indirect comparison and simulated treatment comparison techniques were used to conduct a comparison between unilateral DBS aggregate data and MRgFUS individual patient data. RESULTS: The systematic literature review identified 1,559 records, and screening yielded 46 relevant articles. The captured studies demonstrated that radiofrequency thalamotomy, DBS, stereotactic radiosurgery, and MRgFUS all exhibit clinical efficacy, with variation in onset and duration of tremor relief, and are each associated with a unique safety profile. The matching-adjusted indirect comparison and simulated treatment comparison results demonstrated no evidence of a difference in efficacy (measured by Clinical Rating Scale for Tremor Total) and HRQoL (measured by Clinical Rating Scale for Tremor Part C) outcomes between MRgFUS and unilateral DBS in the short term (≤12 months). CONCLUSIONS: This study provides preliminary evidence that MRgFUS could elicit similar short-term tremor- and HRQoL-related benefits to DBS, the current standard of care, and allowed for the first robust statistical comparison between these interventions.

Long-term retention rates for antiepileptic drugs: A review of long-term extension studies and comparison with brivaracetam.

Antiepileptic drug (AED) retention rates are frequently reported in the literature and used to inform clinical decision-making, but methodological differences in the determination of retention rates make comparisons between trials difficult. Open-label extension (OLE) studies of AEDs in patients with focal epilepsy were identified from the literature. Retention calculation methods were reviewed, and published AED retention rates qualitatively compared with corresponding data for brivaracetam (BRV), a synaptic vesicle protein 2A ligand. The search identified 40 publications (corresponding to 17 studies of nine AEDs: eslicarbazepine, gabapentin, lacosamide, levetiracetam, oxcarbazepine, perampanel, pregabalin, topiramate and zonisamide) meeting eligibility criteria for inclusion in the review. Three methodologies to estimate retention rate were identified, which differed in whether patients randomised to placebo in the preceding randomised controlled trials (RCTs) were included or analysed separately, and whether retention was measured from the start of the OLE or of active treatment exposure. The most robust, conservative approach included all patients and measured retention from start of active treatment exposure, whether during the blinded RCT or at the start of the OLE (placebo RCT patients). Data using this method was available for five AEDs in this review, including BRV. The corresponding BRV 52week retention rate (modal doses 50-200mg/day; therapeutic range) was 69.8% (63.3-66.7% for other AEDs at this time point). No statistical indirect comparison was performed, as study populations were clinically heterogeneous. To avoid inconsistencies in methodologies, and allow comparison between AEDs when OLE data are the only long-term data available, retention rate analyses would benefit from the development of consistent reporting standards and guidelines.

Matrikines are key regulators in modulating the amplitude of lung inflammation in acute pulmonary infection.

Bioactive matrix fragments (matrikines) have been identified in a myriad of disorders, but their impact on the evolution of airway inflammation has not been demonstrated. We recently described a pathway where the matrikine and neutrophil chemoattractant proline-glycine-proline (PGP) could be degraded by the enzyme leukotriene A4 hydrolase (LTA4H). LTA4H classically functions in the generation of pro-inflammatory leukotriene B4, thus LTA4H exhibits opposing pro- and anti-inflammatory activities. The physiological significance of this secondary anti-inflammatory activity remains unknown. Here we show, using readily resolving pulmonary inflammation models, that loss of this secondary activity leads to more pronounced and sustained inflammation and illness owing to PGP accumulation. PGP elicits an exacerbated neutrophilic inflammation and protease imbalance that further degrades the extracellular matrix, generating fragments that perpetuate inflammation. This highlights a critical role for the secondary anti-inflammatory activity of LTA4H and thus has consequences for the generation of global LTA4H inhibitors currently being developed.