Browsing by Subject "Ischemic Attack, Transient"
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Item Open Access Characterization of cardiovascular clinical events and impact of event adjudication on the treatment effect of darapladib versus placebo in patients with stable coronary heart disease: Insights from the STABILITY trial.(American heart journal, 2019-02) Held, Claes; White, Harvey D; Stewart, Ralph AH; Davies, Richard; Sampson, Shani; Chiswell, Karen; Silverstein, Adam; Lopes, Renato D; Heldestad, Ulrika; Budaj, Andrzej; Mahaffey, Kenneth W; Wallentin, Lars; STABILITY InvestigatorsBackground
Clinical Endpoint Classification (CEC) in clinical trials allows FOR standardized, systematic, blinded, and unbiased adjudication of investigator-reported events. We quantified the agreement rates in the STABILITY trial on 15,828 patients with stable coronary heart disease.Methods
Investigators were instructed to report all potential events. Each reported event was reviewed independently by 2 reviewers according to prespecified processes and prespecified end point definitions. Concordance between reported and adjudicated cardiovascular (CV) events was evaluated, as well as event classification influence on final study results.Results
In total, CEC reviewed 7,096 events: 1,064 deaths (696 CV deaths), 958 myocardial infarctions (MI), 433 strokes, 182 transient ischemic attacks, 2,052 coronary revascularizations, 1,407 hospitalizations for unstable angina, and 967 hospitalizations for heart failure. In total, 71.8% events were confirmed by CEC. Concordance was high (>80%) for cause of death and nonfatal MI and lower for hospitalization for unstable angina (25%) and heart failure (50%). For the primary outcome (composite of CV death, MI, and stroke), investigators reported 2,086 events with 82.5% confirmed by CEC. The STABILITY trial treatment effect of darapladib versus placebo on the primary outcome was consistent using investigator-reported events (hazard ratio 0.96 [95% CI 0.87-1.06]) or adjudicated events (hazard ratio 0.94 [95% CI 0.85-1.03]).Conclusions
The primary outcome results of the STABILITY trial were consistent whether using investigator-reported or CEC-adjudicated events. The proportion of investigator-reported events confirmed by CEC varied by type of event. These results should help improve event identification in clinical trials to optimize ascertainment and adjudication.Item Open Access Characterization of the ubiquitin-modified proteome regulated by transient forebrain ischemia.(Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 2014-03) Iwabuchi, Masahiro; Sheng, Huaxin; Thompson, J Will; Wang, Liangli; Dubois, Laura G; Gooden, David; Moseley, Marthur; Paschen, Wulf; Yang, WeiUbiquitylation is a posttranslational protein modification that modulates various cellular processes of key significance, including protein degradation and DNA damage repair. In animals subjected to transient cerebral ischemia, ubiquitin-conjugated proteins accumulate in Triton-insoluble aggregates. Although this process is widely considered to modulate the fate of postischemic neurons, few attempts have been made to characterize the ubiquitin-modified proteome in these aggregates. We performed proteomics analyses to identify ubiquitylated proteins in postischemic aggregates. Mice were subjected to 10 minutes of forebrain ischemia and 4 hours of reperfusion. The hippocampi were dissected, aggregates were isolated, and trypsin-digested after spiking with GG-BSA as internal standard. K-ɛ-GG-containing peptides were immunoprecipitated and analyzed by label-free quantitative liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. We identified 1,664 peptides to 520 proteins containing at least one K-ɛ-GG. Sixty-six proteins were highly ubiquitylated, with 10 or more K-ɛ-GG peptides. Based on selection criteria of greater than fivefold increase and P<0.001, 763 peptides to 272 proteins were highly enriched in postischemic aggregates. These included proteins involved in important neuronal functions and signaling pathways that are impaired after ischemia. Results of this study could serve as an important platform to uncover the mechanisms linking insoluble ubiquitin aggregates to the functions of postischemic neurons.Item Open Access Medication coaching program for patients with minor stroke or TIA: a pilot study.(BMC Public Health, 2012-07-25) Sides, Elizabeth G; Zimmer, Louise O; Wilson, Leslie; Pan, Wenqin; Olson, Daiwai M; Peterson, Eric D; Bushnell, CherylBACKGROUND: Patients who are hospitalized with a first or recurrent stroke often are discharged with new medications or adjustment to the doses of pre-admission medications, which can be confusing and pose safety issues if misunderstood. The purpose of this pilot study was to assess the feasibility of medication coaching via telephone after discharge in patients with stroke. METHODS: Two-arm pilot study of a medication coaching program with 30 patients (20 intervention, 10 control). Consecutive patients admitted with stroke or TIA with at least 2 medications changed between admission and discharge were included. The medication coach contacted intervention arm patients post-discharge via phone call to discuss risk factors, review medications and triage patients' questions to a stroke nurse and/or pharmacist. Intervention and control participants were contacted at 3 months for outcomes. The main outcomes were feasibility (appropriateness of script, ability to reach participants, and provide requested information) and participant evaluation of medication coaching. RESULTS: The median lengths of the coaching and follow-up calls with requested answers to these questions were 27 minutes and 12 minutes, respectively, and participant evaluations of the coaching were positive. The intervention participants were more likely to have seen their primary care provider than were control participants by 3 months post discharge. CONCLUSIONS: This medication coaching study executed early after discharge demonstrated feasibility of coaching and educating stroke patients with a trained coach. Results from our small pilot showed a possible trend towards improved appointment-keeping with primary care providers in those who received coaching.Item Open Access Metabolic Markers to Predict Incident Diabetes Mellitus in Statin-Treated Patients (from the Treating to New Targets and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels Trials).(The American journal of cardiology, 2016-11) Kohli, Payal; Knowles, Joshua W; Sarraju, Ashish; Waters, David D; Reaven, GeraldThe goal of this analysis was to evaluate the ability of insulin resistance, identified by the presence of prediabetes mellitus (PreDM) combined with either an elevated triglyceride (TG >1.7 mmol/l) or body mass index (BMI ≥27.0 kg/m2), to identify increased risk of statin-associated type 2 diabetes mellitus (T2DM). Consequently, a retrospective analysis of data from subjects without diabetes in the Treating to New Targets and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels randomized controlled trials was performed, subdividing participants into 4 experimental groups: (1) normal fasting glucose (NFG) and TG ≤1.7 mmol/l (42%); (2) NFG and TG >1.7 mmol/l (22%); (3) PreDM and TG ≤1.7 mmol/l (20%); and (4) PreDM and TG >1.7 mmol/l (15%). Comparable groupings were created substituting BMI values (kg/m2 <27.0 and ≥27.0) for TG concentrations. Patients received atorvastatin or placebo for a median duration of 4.9 years. Incident T2DM, defined by developing at least 2 fasting plasma glucose (FPG) concentrations ≥126 mg/dl, an increase in FPG ≥37 mg/dl, or a clinical diagnosis of T2DM, was observed in 8.2% of the total population. T2DM event rates (statin or placebo) varied from a low of 2.8%/3.2% (NFG and TG ≤1.7 mmol/l) to a high of 22.8%/7.6% (PreDM and TG >1.7 mmol/l) with intermediate values for only an elevated TG >1.7 mmol/l (5.2%/4.3%) or only PreDM (12.8%/7.6%). Comparable differences were observed when BMI values were substituted for TG concentrations. In conclusion, these data suggest that (1) the diabetogenic impact of statin treatment is relatively modest in general; (2) the diabetogenic impact is accentuated relatively dramatically as FPG and TG concentrations and BMI increase; and (3) PreDM, TG concentrations, and BMI identify people at highest risk of statin-associated T2DM.Item Open Access Off-label closure during CLOSURE study.(J Invasive Cardiol, 2012-11) Stackhouse, Kathryn A; Goel, Sachin S; Qureshi, Athar M; Prieto, Lourdes; Kapadia, Samir; Tuzcu, E Murat; Krasuski, Richard ABACKGROUND: The role of percutaneous closure of patent foramen ovale (PFO) in patients with cryptogenic stroke or transient ischemic attack remains controversial. Registry data have suggested considerable benefit of closure over medical therapy, but the prospective, randomized CLOSURE I trial found no benefit for device closure. METHODS: We compared patients enrolled into CLOSURE I to off-label closures performed during the study recruitment period at a single large institution and prospectively enrolled into an institutional registry of PFO closure. We also compared CLOSURE I patients at our institution to the reported characteristics of the entire study to ensure generalizability. RESULTS: Between 11/3/2003 and 4/16/2007, there were 100 off-label closures and 33 patients randomized into CLOSURE I. Compared with off-label closure, patients in CLOSURE I were younger (41.6 ± 10.1 years vs 50.0 ± 14.0 years; P<.001) and had fewer cardiovascular risks including hypertension (12% vs 36%; P=.009), hyperlipidemia (24% vs 53%; P=.008), and coronary disease (3% vs 44%; P<.001). Degree of right-to-left shunting was considerably higher in off-label closures (28%, 14%, and 58% vs 45%, 30%, and 25% for mild, moderate, and severe, respectively; P=.026). CONCLUSION: Off-label closures outnumbered patient recruitment into CLOSURE 3:1 at our institution during study recruitment. Certain demographic differences were expected (age over 60 was an exclusion for CLOSURE I), but vascular risks were considerably greater in the off-label group and may be important mechanistically. Large shunts were considerably more common in off-label patients, suggesting that higher-risk patients may have been preferentially closed off-label. These results suggest that the results of CLOSURE I may not apply to all patients with initial cryptogenic stroke.Item Open Access Small ubiquitin-like modifier 3-modified proteome regulated by brain ischemia in novel small ubiquitin-like modifier transgenic mice: putative protective proteins/pathways.(Stroke, 2014-04) Yang, Wei; Sheng, Huaxin; Thompson, J Will; Zhao, Shengli; Wang, Liangli; Miao, Pei; Liu, Xiaozhi; Moseley, M Arthur; Paschen, WulfBackground and purpose
Small ubiquitin-like modifier (SUMO) conjugation is a post-translational modification associated with many human diseases. Characterization of the SUMO-modified proteome is pivotal to define the mechanistic link between SUMO conjugation and such diseases. This is particularly evident for SUMO2/3 conjugation, which is massively activated after brain ischemia/stroke, and is believed to be a protective response. The purpose of this study was to perform a comprehensive analysis of the SUMO3-modified proteome regulated by brain ischemia using a novel SUMO transgenic mouse.Methods
To enable SUMO proteomics analysis in vivo, we generated transgenic mice conditionally expressing tagged SUMO1-3 paralogues. Transgenic mice were subjected to 10 minutes forebrain ischemia and 1 hour of reperfusion. SUMO3-conjugated proteins were enriched by anti-FLAG affinity purification and analyzed by liquid chromatography-tandem mass spectrometry.Results
Characterization of SUMO transgenic mice demonstrated that all 3 tagged SUMO paralogues were functionally active, and expression of exogenous SUMOs did not modify the endogenous SUMOylation machinery. Proteomics analysis identified 112 putative SUMO3 substrates of which 91 candidates were more abundant in the ischemia group than the sham group. Data analysis revealed processes/pathways with putative neuroprotective functions, including glucocorticoid receptor signaling, RNA processing, and SUMOylation-dependent ubiquitin conjugation.Conclusions
The identified proteins/pathways modulated by SUMOylation could be the key to understand the mechanisms linking SUMOylation to neuroprotection, and thus provide new promising targets for therapeutic interventions. The new transgenic mouse will be an invaluable platform for analyzing the SUMO-modified proteome in models of human disorders and thereby help to mechanistically link SUMOylation to the pathological processes.Item Open Access Treatment Effect of Clopidogrel Plus Aspirin Within 12 Hours of Acute Minor Stroke or Transient Ischemic Attack.(Journal of the American Heart Association, 2016-03-21) Li, Zixiao; Wang, Yilong; Zhao, Xingquan; Liu, Liping; Wang, David; Wang, Chunxue; Meng, Xia; Li, Hao; Pan, Yuesong; Wang, Xianwei; Wang, Chunjuan; Yang, Xiaomeng; Zhang, Changqing; Jing, Jing; Xian, Ying; Johnston, S Claiborne; Wang, Yongjun; CHANCE InvestigatorsBACKGROUND:The aim of this study was to analyze the benefits and safety associated with the combination therapy of clopidogrel and aspirin among minor stroke or transient ischemic attack patients treated within 12 hours. METHODS AND RESULTS:This was a subanalysis of the CHANCE (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events) trial, mainly limited to the prespecified group of patients randomized within 12 hours to either the combination of clopidogrel plus aspirin or aspirin alone. The primary outcome was ischemic stroke during 90-day follow-up. Recurrent ischemic stroke and progressive ischemic stroke were analyzed. Multivariable Cox modeling showed that randomization within 12 hours was an independent predictor of ischemic stroke events (hazard ratio [95% CI] 1.25 [1.04-1.49], P=0.02). Among 2573 patients randomized within 12 hours, 282 (10.96%) patients had ischemic stroke events. Among them, 158 (12.34%) of 1280 patients taking aspirin experienced ischemic stroke compared with 124 (9.59%) of 1293 patients taking clopidogrel-aspirin (P=0.02). The dual antiplatelet was more effective than aspirin alone in reducing the risk of recurrent ischemic stroke (6.57% versus 8.91%, P=0.03) but not progressive ischemic stroke (3.02% versus 3.43%, P=0.28). There was no significant difference in hemorrhagic events (P=0.39). CONCLUSIONS:Among patients treated within 12 hours, the combination of clopidogrel and aspirin was more effective than aspirin alone in reducing the risk of recurrent ischemic stroke during the 90-day follow-up and did not increase the hemorrhagic risk. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00979589.