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. The main safety objective was assessment of PLATO (Platelet Inhibition and Patient Outcomes)-defined major bleeds on treatment, with special focus on intracranial hemorrhage (ICrH). METHODS: An independent adjudication committee blinded to study treatment classified bleeds according to the PLATO, TIMI (Thrombolysis in Myocardial Infarction), and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) definitions. The definitions of ICrH and major bleeding excluded cerebral microbleeds and asymptomatic hemorrhagic transformations of cerebral infarctions so that the definitions better discriminated important events in the acute stroke population. RESULTS: A total of 13 130 of 13 199 randomized patients received at least 1 dose of study drug and were included in the safety analysis set. PLATO major bleeds occurred in 31 patients (0.5%) on ticagrelor and 38 patients (0.6%) on aspirin (hazard ratio, 0.83; 95% confidence interval, 0.52-1.34). The most common locations of major bleeds were intracranial and gastrointestinal. ICrH was reported in 12 patients (0.2%) on ticagrelor and 18 patients (0.3%) on aspirin. Thirteen of all 30 ICrHs (4 on ticagrelor and 9 on aspirin) were hemorrhagic strokes, and 4 (2 in each group) were symptomatic hemorrhagic transformations of brain infarctions. The ICrHs were spontaneous in 6 and 13, traumatic in 3 and 3, and procedural in 3 and 2 patients on ticagrelor and aspirin, respectively. In total, 9 fatal bleeds occurred on ticagrelor and 4 on aspirin. The composite of ICrH or fatal bleeding included 15 patients on ticagrelor and 18 on aspirin. Independently of bleeding classification, PLATO, TIMI, or GUSTO, the relative difference between treatments for major/severe bleeds was similar. Nonmajor bleeds were more common on ticagrelor. CONCLUSIONS: Antiplatelet therapy with ticagrelor in patients with acute ischemic stroke or transient ischemic attack showed a bleeding profile similar to that of aspirin for major bleeds. There were few ICrHs. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01994720.

Acid control cannot be improved with a modified-release formulation of a proton pump inhibitor compared with twice-daily dosing of the conventional formulation.

AIM: The aim of this study was to compare acid control with a once-daily (od) modified-release (MR) formulation of esomeprazole vs. the conventional formulation (CF) dosed twice-daily (bid). METHODS: In a randomized, five-way crossover study, 55 healthy volunteers underwent 24-h intragastric pH monitoring after 5-day treatment with MR esomeprazole (40, 60 or 80 mg od) and CF esomeprazole (20 or 40 mg bid). RESULTS: Modified-release 60 and 80 mg od resulted in a significantly longer time with intragastric pH > 4 than MR 40 mg od (77.1 and 79.0% vs. 66.4%, respectively; both p < 0.05). At equivalent total daily doses, CF 20 mg bid led to a significantly longer time with intragastric pH > 4 than MR 40 mg od (72.3 vs. 66.4%; p < 0.05), and CF 40 mg bid led to a significantly longer time with pH > 4 than MR 80 mg od (85.5 vs. 79.0%; p < 0.05). CONCLUSIONS: At equivalent total daily doses, the MR formulation of esomeprazole provides less 24-h acid control than the conventional formulation dosed twice-daily.

Pharmacokinetic Profiles of Ticagrelor Orodispersible Tablets in Healthy Western and Japanese Subjects.

BACKGROUND AND OBJECTIVES: Ticagrelor is an antiplatelet agent for patients with acute coronary syndrome or a history of myocardial infarction. Two studies compared pharmacokinetic profiles of orodispersible (OD) ticagrelor tablets versus immediate-release (IR) tablets in Western and Japanese subjects. METHODS: Both studies were open-label, randomized, crossover, single-center trials. Thirty-six healthy subjects (94% white, 6% other race; Western study NCT02400333) and 42 Japanese healthy subjects (Japanese study NCT02436577) received a single 90-mg ticagrelor dose as an OD tablet [with/without water, and via a nasogastric tube (Western study only)], and an IR tablet; washout between treatments was ≥7 days. Assessments included ticagrelor and AR-C124910XX (active metabolite) plasma concentrations for pharmacokinetic analyses, and safety evaluations. RESULTS: In the Western study, the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) for ticagrelor and AR-C124910XX maximum plasma concentration (C max) and area under the plasma concentration-time curve (AUC) were within the acceptance interval (80%-125%) for OD tablets (with/without water, via a nasogastric tube) versus the IR tablet; except for an ~15% lowering of ticagrelor C max (90% CI: 76.77%-93.78%) for the OD tablet taken with water. In the Japanese study, 90% CIs of the GMRs for AUC and C max of both ticagrelor and AR-C124910XX were all within the acceptance intervals for the OD (with/without water) versus IR tablet. No new safety issues were identified. CONCLUSIONS: Ticagrelor administered as an OD tablet to Western (without water, and via a nasogastric tube) and Japanese (with/without water) subjects was bioequivalent to the IR tablet.