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.

Abnormal cerebral hemodynamics and blood-brain barrier permeability detected with perfusion MRI in systemic lupus erythematosus patients.

Objective: Dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) has previously shown alterations in cerebral perfusion in patients with systemic lupus erythematosus (SLE). However, the results have been inconsistent, in particular regarding neuropsychiatric (NP) SLE. Thus, we investigated perfusion-based measures in different brain regions in SLE patients with and without NP involvement, and additionally, in white matter hyperintensities (WMHs), the most common MRI pathology in SLE patients.

Results from the "Me & My Heart" (eMocial) Study: a Randomized Evaluation of a New Smartphone-Based Support Tool to Increase Therapy Adherence of Patients with Acute Coronary Syndrome.

Purpose: This study evaluated whether patient support, administered via an electronic device-based app, increased adherence to treatment and lifestyle changes in patients with acute coronary syndrome (ACS) treated with ticagrelor in routine clinical practice.

Methods: Patients (aged ≥ 18 years) with diagnosed ACS treated with ticagrelor co-administered with low-dose acetylsalicylic acid were randomized into an active group (with support tool app for medication intake reminders and motivational messages) and a control group (without support tool app), and observed for 48 weeks (ClinicalTrials.gov Identifier: NCT02615704).

Time Course for Benefit and Risk of Ticagrelor and Aspirin in Acute Ischemic Stroke or Transient Ischemic Attack.

Background And Objectives: The goal of this work was to investigate the short-term time-course benefit and risk of ticagrelor with aspirin in acute mild-moderate ischemic stroke or high-risk TIA in The Acute Stroke or Transient Ischemic Attack Treated with Ticagrelor and ASA for Prevention of Stroke and Death (THALES) trial.

Methods: In an exploratory analysis of the THALES trial, we evaluated the cumulative incidence of irreversible efficacy and safety outcomes at different time points during the 30-day treatment period. The efficacy outcome was major ischemic events defined as a composite of ischemic stroke or nonhemorrhagic death.

Extrinsic rewards and crowding-out of prosocial behaviour.

The law of supply is a fundamental principle of economics and states that any increase in price will increase the quantity supplied. In the case of prosocial behaviour, however, increasing rewards have reduced supply, posing a challenge to standard economic theory. Attempts to study such 'crowding-out' have been limited by their small scale and the inherent difficulties posed by calibration of experimental tests.

Ischemic Benefit and Hemorrhage Risk of Ticagrelor-Aspirin Versus Aspirin in Patients With Acute Ischemic Stroke or Transient Ischemic Attack.

Background And Purpose: In patients with acute mild-moderate ischemic stroke or high-risk transient ischemic attack, the THALES trial (Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and Aspirin for Prevention of Stroke and Death) demonstrated that when added to aspirin, ticagrelor reduced stroke or death but increased risk of severe hemorrhage compared with placebo. The primary efficacy outcome of THALES included hemorrhagic stroke and death, events also counted in the primary safety outcome. We sought to disentangle risk and benefit, assess their relative impact, and attempt to identify subgroups with disproportionate risk or benefit.

Ticagrelor Added to Aspirin in Acute Nonsevere Ischemic Stroke or Transient Ischemic Attack of Atherosclerotic Origin.

Background And Purpose: Among patients with a transient ischemic attack or minor ischemic strokes, those with ipsilateral atherosclerotic stenosis of cervicocranial vasculature have the highest risk of recurrent vascular events.

Methods: In the double-blind THALES (The Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and ASA for Prevention of Stroke and Death) trial, we randomized patients with a noncardioembolic, nonsevere ischemic stroke, or high-risk transient ischemic attack to ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2-30) or placebo added to aspirin (300-325 mg on day 1 followed by 75-100 mg daily for days 2-30) within 24 hours of symptom onset. The present paper reports a prespecified analysis in patients with and without ipsilateral, potentially causal atherosclerotic stenosis ≥30% of cervicocranial vasculature.

Ticagrelor Added to Aspirin in Acute Ischemic Stroke or Transient Ischemic Attack in Prevention of Disabling Stroke: A Randomized Clinical Trial.

Importance: Reduction of subsequent disabling stroke is the main goal of preventive treatment in the acute setting after transient ischemic attack (TIA) or minor ischemic stroke.

Objective: To evaluate the superiority of ticagrelor added to aspirin in preventing disabling stroke and to understand the factors associated with recurrent disabling stroke.

Design, Setting, And Participants: The Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and Aspirin for Prevention of Stroke and Death (THALES) was a randomized clinical trial conducted between January 22, 2018, and December 13, 2019, with a 30-day follow-up, at 414 hospitals in 28 countries.

Improving data integrity in regulated bioanalysis: proposal for a generic data transfer process for LC-MS from the European Bioanalysis Forum.

In this paper, the European Bioanalysis Forum reports back from the discussions with software developers, involved in regulated bioanalysis software solutions, on agreeing to data transfer specification in the bioanalytical labs' LC-MS workflows as part of today's Data Integrity (DI) challenges. The proposed specifications aim at identifying what consists of a minimum dataset, that is, which are the pre-identified fields to be included in DI proof bidirectional data transfer between LC-MS and information management systems. The proposal is an attempt from the European Bioanalysis Forum to facilitate new software solutions becoming available to increase compliance related to DI in today's LC-MS workflows.

Ticagrelor and Aspirin or Aspirin Alone in Acute Ischemic Stroke or TIA.

Background: Trials have evaluated the use of clopidogrel and aspirin to prevent stroke after an ischemic stroke or transient ischemic attack (TIA). In a previous trial, ticagrelor was not better than aspirin in preventing vascular events or death after stroke or TIA. The effect of the combination of ticagrelor and aspirin on prevention of stroke has not been well studied.

Methodologies for pragmatic and efficient assessment of benefits and harms: Application to the SOCRATES trial.

Background/aims: Standard approaches to trial design and analyses can be inefficient and non-pragmatic. Failure to consider a range of outcomes impedes evidence-based interpretation and reduces power. Traditional approaches synthesizing information obtained from separate analysis of each outcome fail to incorporate associations between outcomes and recognize the cumulative nature of outcomes in individual patients, suffer from competing risk complexities during interpretation, and since efficacy and safety analyses are often conducted on different populations, generalizability is unclear.

European Bioanalysis Forum feedback on draft ICH M10 guideline on bioanalytical method validation during the Step 2b public consultation period.

Once released, the ICH M10 Guideline on bioanalytical method validation will become one of the most important milestones in the history of regulated bioanalysis, closing a chapter on intense discussions among the industry and health authorities started in Crystal City in 2001. In this manuscript, the European Bioanalysis Forum community reports back on their feedback on the ICH M10 draft guideline gathered during the public consultation period. The comments given are intended to contribute to a guideline that combines several decades of experience and current scientific vision.

Intact protein quantification in biological samples by liquid chromatography - high-resolution mass spectrometry: somatropin in rat plasma.

The quantitative determination of intact proteins in biological samples by LC with high-resolution MS detection can be a useful alternative to ligand-binding assays or LC-MS-based quantification of a surrogate peptide after protein digestion. The 22-kDa biopharmaceutical protein somatropin (recombinant human growth hormone) was quantified down to 10 ng/mL (0.45 nM) in 75 μL of rat plasma by the combination of an immunocapture step using an anti-somatropin antibody and LC-MS on a quadrupole-time of flight instrument.

Data integrity in regulated bioanalysis: a summary from the European Bioanalysis Forum Workshop in collaboration with the MHRA.

In this conference report, we summarize the main findings and messages from a workshop on 'Data Integrity'. The workshop was held at the 11th European Bioanalysis Forum Open (EBF) Symposium in Barcelona (21-23 November 2018), in collaboration with the Medicines and Health products Regulatory Agency to provide insight and understanding of regulatory data integrity expectations. The workshop highlighted the importance of engaging with software developers to address the gap between industry's data integrity needs and current system software capabilities.

Disability after minor stroke and TIA: A secondary analysis of the SOCRATES trial.

Objective: To examine factors associated with disability following TIA and minor stroke, including poststroke complications such as stroke recurrence, major bleeding, and other adverse medical events.

Methods: The SOCRATES trial randomized patients with TIA/minor stroke (NIH Stroke Scale [NIHSS] score ≤5) within 24 hours of onset. We performed a post hoc analysis of factors associated with disability (modified Rankin Scale [mRS] score >1).

Estimated treatment effect of ticagrelor versus aspirin by investigator-assessed events compared with judgement by an independent event adjudication committee in the SOCRATES trial.

Background: Adjudication of endpoints is a standard procedure in cardiovascular clinical trials. However, several studies indicate that the benefit of adjudication in estimating treatment effect may be limited.

Aims: This post hoc analysis of SOCRATES (NCT01994720) compared the treatment effects and investigated the agreement of clinical event assessment by site investigators and independent adjudicators.

Time to Loading Dose and Risk of Recurrent Events in the SOCRATES Trial.

Background and Purpose- Recurrent ischemia risk is high in the acute period after cerebral ischemic events. Effects of antiplatelet agents may vary by time to loading dose (TLD). We explored the risk of recurrent events and safety and efficacy of ticagrelor versus aspirin in relation to TLD.

The Acute Sroke or Transient Iscemic Attack Treated with Ticgreor and Aspirin for Prvention of troke and Death (THALES) trial: Rationale and design.

Rationale: In patients with acute cerebral ischemia, the rate of stroke, myocardial infarction, or death during 90 days was reported to be non-significantly lower with ticagrelor compared with aspirin, with no increase in major hemorrhage. Dual antiplatelet therapy may be more effective in this setting.

Aim: To investigate whether ticagrelor combined with aspirin are superior to aspirin alone in preventing stroke or death in patients with non-severe, non-cardioembolic ischemic stroke or high-risk transient ischemic attack.

Improving selectivity and sensitivity of protein quantitation by LC-HR-MS/MS: determination of somatropin in rat plasma.

Aim: Protein quantitation by digestion of a biological sample followed by LC-MS analysis of a signature peptide can be a challenge because of the high complexity of the digested matrix. Results/methodology: The use of LC with high-resolution (quadrupole-TOF) MS detection allowed quantitation of the 22-kDa biopharmaceutical somatropin in 60 μl of rat plasma down to 25 ng/ml with minimal further sample treatment. Reducing the mass extraction window to 0.

Efficacy and Safety of Ticagrelor in Relation to Aspirin Use Within the Week Before Randomization in the SOCRATES Trial.

Background And Purpose: SOCRATES (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes), comparing ticagrelor with aspirin in patients with acute cerebral ischemia, found a nonsignificant 11% relative risk reduction for stroke, myocardial infarction, or death (=0.07). Aspirin intake before randomization could enhance the effect of ticagrelor by conferring dual antiplatelet effect during a high-risk period for subsequent stroke.

Tenapanor administration and the activity of the H -coupled transporter PepT1 in healthy volunteers.

Aim: Tenapanor (RDX5791/AZD1722), an inhibitor of gastrointestinal Na /H exchanger NHE3, is being evaluated for the treatment of patients with constipation-predominant irritable bowel syndrome and the treatment of hyperphosphataemia in patients with chronic kidney disease on dialysis. By reducing intestinal H secretion, inhibition of NHE3 by tenapanor could indirectly affect H -coupled transporter activity, leading to drug-drug interactions. We investigated the effect of tenapanor on the activity of the H -coupled peptide transporter PepT1 via assessment of the pharmacokinetics of cefadroxil - a compound transported by PepT1 - in healthy volunteers.

Effect of weight reduction on glycated haemoglobin in weight loss trials in patients with type 2 diabetes.

Aim: To quantify the effect of weight loss on glycated haemoglobin (HbA1c) at group level, based on data from published weight loss trials in overweight and obese patients with type 2 diabetes (T2D).

Methods: A systematic literature search in MEDLINE, EMBASE and Cochrane CENTRAL (January 1990 through December 2012) was conducted to identify prospective trials of energy-reduced diets, obesity drugs or bariatric surgery in adult, overweight and obese patients with T2D. Based on clinical data with follow-up from 3 to 24 months, a linear model was developed to describe the effect of weight reduction on HbA1c.

Effect of Food Intake on the Pharmacodynamics of Tenapanor: A Phase 1 Study.

Tenapanor (RDX5791/AZD1722) is a minimally systemic small-molecule inhibitor of the sodium/hydrogen exchanger NHE3. Tenapanor acts in the gut to reduce absorption of sodium and phosphate. This phase 1 open-label, 3-way crossover study (NCT02226783) evaluated the effect of food on the pharmacodynamics of tenapanor.