SummaryBackgroundIntensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy.MethodsWe did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388.Findings3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67–1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05–3·16, p<0·0001).InterpretationAmong patients with recent cerebral ischaemia, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did significantly increase the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice.FundingNational Institutes of Health Research Health Technology Assessment Programme, British Heart Foundation.

Background CYP2C19 loss-of-function (LOF) alleles impair clopidogrel effectiveness after percutaneous coronary intervention (PCI). The feasibility, sustainability and clinical impact of using CYP2C19 genotype-guided dual antiplatelet therapy (DAPT) selection in practice remains unclear. Methods and Results A single-center observational study was conducted in 1193 patients who underwent PCI and received DAPT following implementation of an algorithm that recommends CYP2C19 testing in high-risk patients and alternative DAPT (prasugrel or ticagrelor) in LOF allele carriers. The frequency of genotype testing and alternative DAPT selection were the primary implementation endpoints. Risk of major adverse cardiovascular or cerebrovascular (MACCE) and clinically significant bleeding events over 12 months were compared across genotype and DAPT groups by proportional hazards regression. CYP2C19 genotype was obtained in 868 (72.8%) patients. Alternative DAPT was prescribed in 186 (70.7%) LOF allele carriers. CYP2C19 testing (P<0.001) and alternative DAPT use in LOF allele carriers (P=0.001) varied over time. Risk for MACCE was significantly higher in LOF carriers prescribed clopidogrel versus alternative DAPT (adjusted hazard ratio [HR] 4.65, 95% confidence interval [CI] 2.22–10.0, P<0.001), whereas no significant difference was observed in those without a LOF allele (adjusted HR 1.37, 95% CI 0.72–2.85, P=0.347). Bleeding event rates were similar across groups (log-rank P=0.816). Conclusions Implementing CYP2C19 genotype-guided DAPT is feasible and sustainable in a real-world setting, but challenging to maintain at a consistently high level of fidelity. The higher risk of MACCE associated with clopidogrel use in CYP2C19 LOF allele carriers suggests that use of genotype-guided DAPT in practice may improve clinical outcomes.

The two branches of the autonomic nervous system (ANS) have been individually linked to changes in cognitive functioning: The parasympathetic nervous system (PNS) has been associated with healthy cognitive aging, whereas excessive sympathetic nervous system (SNS) activity has been linked to heightened cognitive decline. Despite these separate findings and despite the integrative nature of the ANS, little work has examined the two branches simultaneously to better understand their interactive effects on changes in cognitive functioning in midlife adults. We examined cognitive change in two waves of the Midlife in the United States (MIDUS) study cognitive project and indexed PNS and SNS activity from heart rate variability and epinephrine levels, respectively, from the MIDUS biomarker project (minimum n = 843, 57.9% female, mean age at first wave = 53.8 years). Our findings indicate that greater PNS responsivity (i.e., greater withdrawal and greater recovery) in response to cognitive challenge is associated with attenuated cognitive decline, but only among individuals with low SNS levels; at higher SNS levels, the effects of the PNS on cognitive decline are attenuated. These results suggest that future research targeting the ANS and cognitive aging should consider both ANS branch's effects simultaneously.

Purpose-To evaluate the frequency and clinical impact of switches in antiplatelet therapy following implementation of CYP2C19 genotyping after percutaneous coronary intervention (PCI). Methods-The frequency of escalation (clopidogrel switched to prasugrel/ticagrelor) and deescalation (prasugrel/ticagrelor switched to clopidogrel) was evaluated in 1063 PCI patients who underwent CYP2C19 genotyping. Risk of major adverse cardiovascular or cerebrovascular (MACCE) and bleeding events over one-year was evaluated. Results-Antiplatelet therapy switches were common (19%), with escalation (101/115: 88%) and de-escalation (77/84: 92%) occurring predominantly in patients with and without a CYP2C19 nonfunctional allele, respectively. Nonfunctional allele carriers initiated and continued on clopidogrel had a significantly higher risk of experiencing either a MACCE or bleeding event Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Background: The beverage hydration index (BHI) is a composite measure of fluid balance after consuming a test beverage relative to water. BHI is a relatively new measure that has been explored in young, but not yet older, adults. Objective: The aim of this study was to investigate potential differences in BHI between euhydrated younger and older adults after drinking 4 different commercial beverages. We hypothesized that 1) older subjects would remain in positive fluid balance longer than young subjects after ingestion of each test beverage due to decreased urinary excretion rates, 2) glucose (glu)-and amino acid (AA)-based hydration beverages with sodium would have a BHI greater than water in both groups, and 3) the traditional 2-h postingestion BHI may be inappropriate for older adults. Methods: On 5 separate visits, 12 young (23 ± 3 yr, 7 M/5F) and 12 older (67 ± 6 yr, 5 M/7F) subjects consumed 1 L of distilled water, G-20 (6% CHO, 20 mmol/L Na +), G-45 (2.5% CHO, 45 mmol/L Na +), AA-30 (5 AAs, 30 mmol/L Na +), or AA-60 (8 AAs, 60 mmol/L Na +) over 30 min. Blood and urine samples were collected before ingestion and at 0, 60, 120, 180, and 240 min postingestion with additional venous blood sampling at 5, 10, 15, and 30 min postingestion. Results: In young subjects, BHI increased with increasing beverage Na + concentration, and AA-60 had the highest BHI (AA-60 = 1.24 ± 0.10 compared with water = 1.00, P = 0.01). For older subjects, BHI was highest in AA-30 (AA-30; 1.20 ± 0.13 compared with water, P < 0.01) and was still in flux beyond 2 h in AA-60 (P < 0.05). Conclusions: Beverage Na + content progressively increased BHI in young adults independent of glucose or AA content. For older adults, the AA-30 beverage had the highest BHI. A 4-h BHI may be more appropriate for older adults due to attenuated urine excretion rates. This trial was registered at clinicaltrials.gov as NCT03559101.