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.

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.

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.

Efficacy and Safety of Ticagrelor and Aspirin in Patients With Moderate Ischemic Stroke: An Exploratory Analysis of the THALES Randomized Clinical Trial.

Importance: Prior trials of dual antiplatelet therapy excluded patients with moderate ischemic stroke. These patients were included in the Acute Stroke or Transient Ischaemic Attack Treated With Ticagrelor and ASA for Prevention of Stroke and Death (THALES) trial, but results have not been reported separately, raising concerns about safety and efficacy in this subgroup.

Objective: To evaluate the efficacy and safety of ticagrelor plus aspirin in patients with moderate ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score of 4 to 5).

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.

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.

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.

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.

Ticagrelor Versus Aspirin in Acute Embolic Stroke of Undetermined Source.

Background And Purpose: Ticagrelor is an effective antiplatelet therapy among patients with atherosclerotic disease and, therefore, could be more effective than aspirin in preventing recurrent stroke and cardiovascular events among patients with embolic stroke of unknown source (ESUS), which includes patients with ipsilateral stenosis <50% and aortic arch atherosclerosis.

Methods: We randomized 13 199 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 2-90) or aspirin (300 mg on day 1 followed by 100 mg daily for days 2-90) within 24 hours of symptom onset. In all patients, investigators informed on the presence of ipsilateral stenosis ≥50%, small deep infarct <15 mm, and on cardiac source of embolism detected after enrollment or rare causes, which allowed to construct an ESUS category in all other patients with documented brain infarction.

Risk for Major Bleeding in Patients Receiving Ticagrelor Compared With Aspirin After Transient Ischemic Attack or Acute Ischemic Stroke in the SOCRATES Study (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes).

Background: Patients with minor acute ischemic stroke or transient ischemic attack are at high risk for subsequent stroke, and more potent antiplatelet therapy in the acute setting is needed. However, the potential benefit of more intense antiplatelet therapy must be assessed in relation to the risk for major bleeding. The SOCRATES trial (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes) was the first trial with ticagrelor in patients with acute ischemic stroke or transient ischemic attack in which the efficacy and safety of ticagrelor were compared with those of aspirin.

Efficacy and safety of ticagrelor versus aspirin in acute stroke or transient ischaemic attack of atherosclerotic origin: a subgroup analysis of SOCRATES, a randomised, double-blind, controlled trial.

Background: Ticagrelor is an effective antiplatelet therapy for patients with coronary atherosclerotic disease and might be more effective than aspirin in preventing recurrent stroke and cardiovascular events in patients with acute cerebral ischaemia of atherosclerotic origin. Our aim was to test for a treatment-by-ipsilateral atherosclerotic stenosis interaction in a subgroup analysis of patients in the Acute Stroke or Transient Ischaemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial.

Methods: SOCRATES was a randomised, double-blind, controlled trial of ticagrelor versus aspirin in patients aged 40 years or older with a non-cardioembolic, non-severe acute ischaemic stroke, or high-risk transient ischaemic attack from 674 hospitals in 33 countries.

Ticagrelor in Acute Stroke or Transient Ischemic Attack in Asian Patients: From the SOCRATES Trial (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes).

Background And Purpose: In the SOCRATES trial (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes), ticagrelor was not superior to aspirin. Because of differences in patient demographics and stroke disease pattern in Asia, outcomes of ticagrelor versus aspirin were assessed among Asian patients in a prespecified exploratory analysis.

Methods: Baseline demographics, treatment effects, and safety of ticagrelor and aspirin were assessed among Asian patients.

Ticagrelor versus Aspirin in Acute Stroke or Transient Ischemic Attack.

Background: Ticagrelor may be a more effective antiplatelet therapy than aspirin for the prevention of recurrent stroke and cardiovascular events in patients with acute cerebral ischemia.

Methods: We conducted an international double-blind, controlled trial in 674 centers in 33 countries, in which 13,199 patients with a nonsevere ischemic stroke or high-risk transient ischemic attack who had not received intravenous or intraarterial thrombolysis and were not considered to have had a cardioembolic stroke were randomly assigned within 24 hours after symptom onset, in a 1:1 ratio, to receive either ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2 through 90) or aspirin (300 mg on day 1 followed by 100 mg daily for days 2 through 90). The primary end point was the time to the occurrence of stroke, myocardial infarction, or death within 90 days.

Reducing Adverse Effects During Drug Development: The Example of Lesogaberan and Paresthesia.

Purpose: Lesogaberan, a γ-aminobutyric acid (GABA)B receptor agonist, was developed for the treatment of gastroesophageal reflux disease in patients with a partial response to proton pump inhibitor therapy. A high prevalence of paresthesia was observed in healthy individuals after dosing with lesogaberan in early-phase clinical trials. The aim of this review was to gain further insight into paresthesia caused by lesogaberan by summarizing the relevant preclinical and clinical data.

Acute Stroke or Transient Ischemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial: rationale and design.

Rationale: The risk of recurrent ischemia is high in the acute period after ischemic stroke and transient ischemic attack. Aspirin is recommended by guidelines for this indication, but more intensive antiplatelet therapy may be justified.

Aims: We aim to evaluate whether ticagrelor, a potent antiplatelet agent that blocks the P2Y12 receptor without requiring metabolic activation, reduces the risk of major vascular events compared with aspirin when randomization occurs within 24 h after symptom onset of a nonsevere ischemic stroke or high-risk transient ischemic attack.

Symptom profile in partial responders to a proton pump inhibitor compared with treatment-naïve patients with gastroesophageal reflux disease: a post hoc analysis of two study populations.

Background: Partial response to proton pump inhibitor (PPI) therapy poses a healthcare challenge. This study aimed to compare symptom profiles in partial PPI responders and treatment-naïve patients with gastroesophageal reflux disease (GERD).

Methods: A post hoc analysis of data from two studies was performed.

Development and validation of a patient-reported outcome instrument in partial responders to proton pump inhibitors.

Objective: The Reflux Symptom Questionnaire 7-day recall (RESQ-7) was developed, in line with the US Food and Drug Administration (FDA) guidelines, to address the need for a patient-reported outcome (PRO) instrument assessing symptoms specifically in patients with gastroesophageal reflux disease (GERD) who are only partially responsive to proton pump inhibitor (PPI) therapy.

Materials And Methods: The RESQ-7 was constructed using patient interviews and expert consensus. The instrument was psychometrically validated in a clinical trial setting in patients with persistent GERD symptoms despite PPI therapy.

Impact of regurgitation on health-related quality of life in gastro-oesophageal reflux disease before and after short-term potent acid suppression therapy.

Objective: Limited data exist on the impact of regurgitation on health-related quality of life (HRQOL) in gastro-oesophageal reflux disease (GORD). We assessed the relationship between regurgitation frequency and HRQOL before and after acid suppression therapy in GORD.

Method: We used data from two randomised trials of AZD0865 25-75 mg/day versus esomeprazole 20 or 40 mg/day in non-erosive reflux disease (NERD) (n=1415) or reflux oesophagitis (RO) (n=1460).

Esophageal mucosal breaks in gastroesophageal reflux disease partially responsive to proton pump inhibitor therapy.

Objectives: Approximately 20-30% of patients with gastroesophageal reflux disease (GERD) do not experience complete symptom resolution during proton pump inhibitor (PPI) therapy. The aim of this study was to determine the prevalence of esophageal mucosal breaks among patients who have a partial response to PPI therapy.

Methods: This was an analysis of data from a phase 2b clinical trial carried out to assess the efficacy and safety of a reflux inhibitor, lesogaberan (AZD3355), as an add-on to PPI therapy in this patient population (clinicaltrials.

Validation of the reflux symptom questionnaire electronic diary in partial responders to proton pump inhibitor therapy.

Objectives: We aimed to develop and validate the Reflux Symptom Questionnaire electronic Diary (RESQ-eD) for use in clinical trials in patients with a partial response to proton pump inhibitor (PPI) therapy, using methods that meet US Food & Drug Administration (FDA) regulatory standards.

Methods: Patient interviews were performed to elicit new items and evaluate existing items from the Reflux Disease Questionnaire. The instrument's measurement properties were evaluated, based on data from two clinical trials of patients with gastroesophageal reflux disease (GERD) with a partial response to PPIs who received lesogaberan or placebo as an add-on to PPI therapy.