| 1. |
- Melloni, Chiara, et al.
(författare)
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Safety and efficacy of adjusted-dose eptifibatide in patients with acute coronary syndromes and reduced renal function
- 2011
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Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 162:5, s. 884-892
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Tidskriftsartikel (refereegranskat)abstract
- Background Dose adjustment of renally excreted antithrombotic drugs is recommended for patients with reduced renal function. We examined the influence of dose modification on bleeding and efficacy. Methods Based on initial study drug infusion rate, Early GP IIb/IIIa Inhibition in non-ST-segment elevation acute coronary syndromes (EARLY ACS) patients were categorized into groups: standard dose (2 mu g/kg/min; estimated creatinine clearance [eCrCl] >= 50 ml/min), adjusted dose (1 mu g/kg/min; eCrCl <50 ml/min, per protocol), excess dose (2 mu g/kg/min; eCrCl <50 ml/min). We explored relationships among initial dosing, randomized treatment assignment, and bleeding and ischemic end points (96-h composite of death, myocardial infarction [MI], recurrent ischemia requiring urgent revascularization or thrombotic bailout, and 30-d death or MI). Results Of 8,708 patients with eCrCl and dosing data, 19% had eCrCl <50 ml/min. Of these, 13% received adjusted dose eptifibatide and 6% received an excess dose. Across all dosing groups, no significant reductions were found in ischemic end points between early versus delayed provisional eptifibatide (OR 1.14, 95% CI 0.80-1.65; OR 1.13, 95% CI 0.81-1.56, respectively, for 96-h and 30-d composite end points). Bleeding risk was not significantly increased in the early versus delayed provisional treatment group in either the adjusted (OR 1.50, 95% CI 0.95-2.39) or excess dose group (OR 1.67, 95% CI 0.85-3.39). There were no significant interactions between dose group and treatment strategy on bleeding or efficacy. Conclusion Similar to observations in practice, despite guidelines recommendations and protocol guidance, 34% of EARLY ACS patients with reduced renal function failed to receive an appropriately adjusted study drug infusion. Use of an appropriately adjusted eptifibatide infusion was not associated with expected reductions in bleeding among patients with renal insufficiency.
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| 2. |
- Roe, Matthew T., et al.
(författare)
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Regional Patterns of Use of a Medical Management Strategy for Patients With Non-ST-Segment Elevation Acute Coronary Syndromes : Insights From the EARLY ACS Trial
- 2012
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Ingår i: Circulation. Cardiovascular Quality and Outcomes. - 1941-7713 .- 1941-7705. ; 5:2, s. 205-213
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Tidskriftsartikel (refereegranskat)abstract
- Background: Regional differences in the profile and prognosis of non-ST-segment elevation acute coronary syndrome (NSTE ACS) patients treated with medical management after angiography remain uncertain.Methods and Results: Using data from the Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndromes (EARLY ACS) trial, we examined regional variations in the use of an in-hospital medical management strategy in NSTE ACS patients who had significant coronary artery disease (CAD) identified during angiography, factors associated with the use of a medical management strategy, and 1-year mortality rates. Of 9406 patients, 8387 (89%) underwent angiography and had significant CAD; thereafter, 1766 (21%) were treated solely with a medical management strategy (range: 18% to 23% across 4 major geographic regions). Factors most strongly associated with a medical management strategy were negative baseline troponin values, prior coronary artery bypass grafting, lower baseline hemoglobin values, and greater number of diseased vessels; region was not a significant factor. One-year mortality was higher among patients treated with a medical management strategy compared with those who underwent revascularization (7.8% versus 3.6%; adjusted hazard ratio, 1.46; 95% CI, 1.21-1.76), with no significant interaction by region (interaction probability value=0.42).Conclusions: Approximately 20% of NSTE ACS patients with significant CAD in an international trial were treated solely with an in-hospital medical management strategy after early angiography, with no regional differences in factors associated with medical management or the risk of 1-year mortality. These findings have important implications for the conduct of future clinical trials, and highlight global similarities in the profile and prognosis of medically managed NSTE ACS patients.
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| 3. |
- Sun, Xiangqing, et al.
(författare)
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A variable age of onset segregation model for linkage analysis, with correction for ascertainment, applied to glioma
- 2012
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 21:12, s. 2242-2251
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Tidskriftsartikel (refereegranskat)abstract
- Background: We propose a two-step model-based approach, with correction for ascertainment, to linkage analysis of a binary trait with variable age of onset and apply it to a set of multiplex pedigrees segregating for adult glioma.Methods: First, we fit segregation models by formulating the likelihood for a person to have a bivariate phenotype, affection status and age of onset, along with other covariates, and from these we estimate population trait allele frequencies and penetrance parameters as a function of age (N=281 multiplex glioma pedigrees). Second, the best fitting models are used as trait models in multipoint linkage analysis (N=74 informative multiplex glioma pedigrees). To correct for ascertainment, a prevalence constraint is used in the likelihood of the segregation models for all 281 pedigrees. Then the trait allele frequencies are re-estimated for the pedigree founders of the subset of 74 pedigrees chosen for linkage analysis.Results: Using the best fitting segregation models in model-based multipoint linkage analysis, we identified two separate peaks on chromosome 17; the first agreed with a region identified by Shete et al. (1) who used model-free affected-only linkage analysis, but with a narrowed peak: and the second agreed with a second region they found but had a larger maximum LOD.Conclusions/Impact: Our approach has the advantage of not requiring markers to be in linkage equilibrium unless the minor allele frequency is small (markers which tend to be uninformative for linkage), and of using more of the available information for LOD-based linkage analysis.
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| 4. |
- Wang, Tracy Y., et al.
(författare)
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Upstream Clopidogrel Use and the Efficacy and Safety of Early Eptifibatide Treatment in Patients With Acute Coronary Syndrome An Analysis From the Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) Trial
- 2011
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 126:7, s. 722-730
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Tidskriftsartikel (refereegranskat)abstract
- Background-In the Early Glycoprotein IIb/IIIa Inhibition in Patients with Non-ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) trial, routine preangiography eptifibatide use was not superior to delayed provisional use but led to more bleeding. This analysis examines efficacy and safety of early eptifibatide in the setting of concurrent upstream clopidogrel use. Methods and Results-In EARLY-ACS, clopidogrel use and timing were determined by treating physicians, but randomization to early eptifibatide versus placebo was stratified by the intent to use upstream clopidogrel. Among 9166 non-ST-elevation acute coronary syndrome patients who underwent coronary angiography, intent to use upstream clopidogrel was declared in 6895 (75%), and 7068 (77%) received upstream clopidogrel. After multivariable adjustment, intended upstream clopidogrel use did not differentially influence the effect of early eptifibatide on the primary end point of 96-hour death/myocardial infarction/recurrent ischemia requiring urgent revascularization/thrombotic bailout (interaction P = 0.988). Early eptifibatide use reduced 30-day death/myocardial infarction among patients with intended upstream clopidogrel (adjusted odds ratio 0.85; 95% confidence interval 0.73 to 0.99) but not among those without intended upstream clopidogrel use (adjusted odds ratio 1.02; 95% confidence interval 0.80 to 1.30). However, the clopidogrel by randomized treatment interaction term was not significant (P = 0.23). Thrombolysis in Myocardial Infarction major bleeding risk was increased with early eptifibatide in the setting of upstream clopidogrel use. Results were similar using actual clopidogrel treatment strata. Conclusions-Routine early eptifibatide use, compared with delayed provisional use, may be associated with lower 30-day ischemic risk in non-ST-elevation acute coronary syndrome patients also treated with clopidogrel before angiography. The benefit-risk ratio of intensive platelet inhibition with combined early use of antiplatelet agents needs further evaluation in prospective randomized trials.
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| 5. |
- Armstrong, Paul W., et al.
(författare)
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Quantitative ST-depression in Acute Coronary Syndromes : the PLATO Electrocardiographic Substudy
- 2013
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Ingår i: American Journal of Medicine. - : Elsevier BV. - 0002-9343 .- 1555-7162. ; 126:8, s. 723-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: We evaluated whether electrocardiogram (ECG) characteristics were aligned with clinical outcomes and the effect of ticagrelor within the diverse spectrum of non-ST-elevation acute coronary syndrome patients enrolled in the PLATelet inhibition and patient Outcomes (PLATO) trial. METHODS: There were 8884 PLATO patients who had baseline ECGs assessed by a core laboratory; of these, 4935 had an ECG at hospital discharge that also was assessed. Associations with study treatment on vascular death or myocardial infarction within 1 year were examined. RESULTS: At baseline, most patients had either no or <= 0.5 mm of ST-segment depression (57%); 26% had 1.0 mm, and 17% had more extensive depression (>1.0 mm). Across the baseline ST-segment depression strata, there was a consistent treatment benefit with ticagrelor versus clopidogrel on vascular death/myocardial infarction. The extent of residual ST-segment depression at discharge was similar in the treatment groups, and the treatment effect did not differ by the extent of discharge ST-segment depression. There was a progressive increase in vascular death/myocardial infarction with increasing extent of baseline ST-segment depression (1.0 mm [vs no/0.5 mm]: hazard ratio [HR] 1.22; 95% confidence interval [CI], 1.03-1.45; > 1.0 mm: HR 1.49; 95% CI, 1.24-1.78; P < .001) and at discharge (HR 1.28; 95% CI, 1.02-1.61; HR 2.13; 95% CI, 1.54-2.95; P <. 001). CONCLUSION: The treatment effect of ticagrelor among non-ST-segment-elevation acute coronary syndrome patients was consistently expressed across all baseline ST-segment depression strata. There was no indication of an anti-ischemic benefit of ticagrelor as reflected on the discharge ECG. Our data affirm the independent prognostic relationship of both baseline and hospital discharge ST-segment depression on outcomes within 1 year in non-ST-segment-elevation acute coronary syndrome patients.
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| 6. |
- Armstrong, Paul W, et al.
(författare)
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ST Elevation Acute Coronary Syndromes in PLATO : Insights from the ECG Substudy
- 2012
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 125:3, s. 514-521
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Ticagrelor, when compared with clopidogrel, reduced the 12-month risk of vascular death/myocardial infarction (MI) and stroke in patients with ST-elevation acute coronary syndromes (ST-E ACS) intended to undergo primary percutaneous coronary intervention (PCI) in the PLATelet inhibition and patient Outcomes (PLATO) trial. This pre-specified electrocardiogram (ECG) substudy explored whether ticagrelor's association with vascular death and MI within one year would be amplified by: 1) the extent of baseline ST shift; and 2) subsequently associated with less residual ST changes at hospital discharge. METHODS AND RESULTS: ECGs were evaluated centrally in a core laboratory in 3,122 ticagrelor- and 3,084 clopidogrel-assigned patients having at least 1mm ST-E in two contiguous leads as identified by site investigators on the qualifying ECG. Patients with greater ST-segment shift at baseline had higher rates of vascular death/MI within one year. Amongst those who also had an ECG at hospital discharge (n=4,798), patients with ≥50% ∑ST-deviation (∑ST-dev) resolution had higher event-free survival than those with incomplete resolution (6.4% vs. 8.8%, adjusted hazard ratio 0.69 (0.54-0.88), p=0.003). The extent of ∑ST-dev resolution was similar irrespective of treatment assignment. The benefit of ticagrelor versus clopidogrel on clinical events was consistent irrespective of the extent of baseline ∑ST-dev (p(interaction)=0.728). When stratified according to conventional times from symptom onset i.e. ≤3 hours, 3-6 hours, >6 hours, the extent of baseline ∑ST-dev declined progressively over time. As time from symptom onset increased beyond three hours, the benefit of ticagrelor appeared to be more pronounced; however, the interaction between time and treatment was not significant (p=0.175). CONCLUSIONS: Ticagrelor did not modify ∑ST-dev resolution at discharge nor was its benefit affected by the extent of baseline ∑ST-dev. These hypothesis-generating observations suggest that the main effects of ticagrelor may not relate to the rapidity or the completeness of acute reperfusion, but rather the prevention of recurrent vascular events by more powerful platelet inhibition or other mechanisms.
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| 7. |
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| 8. |
- Lopes, Renato D., et al.
(författare)
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Highlights from the III International Symposium of Thrombosis and Anticoagulation (ISTA), October 14-16, 2010, Sao Paulo, Brazil
- 2011
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Ingår i: Journal of Thrombosis and Thrombolysis. - : Springer Science and Business Media LLC. - 0929-5305 .- 1573-742X. ; 32:2, s. 242-266
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Tidskriftsartikel (refereegranskat)abstract
- To discuss and share knowledge around advances in the care of patients with thrombotic disorders, the Third International Symposium of Thrombosis and Anticoagulation was held in So Paulo, Brazil, from October 14-16, 2010. This scientific program was developed by clinicians for clinicians, and was promoted by four major clinical research institutes: the Brazilian Clinical Research Institute, the Duke Clinical Research Institute of the Duke University School of Medicine, the Canadian VIGOUR Centre, and the Uppsala Clinical Research Center. Comprising 3 days of academic presentations and open discussion, the symposium had as its primary goal to educate, motivate, and inspire internists, cardiologists, hematologists, and other physicians by convening national and international visionaries, thought-leaders, and dedicated clinician-scientists. This paper summarizes the symposium proceedings.
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| 9. |
- Mahaffey, Kenneth W., et al.
(författare)
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Association of Aspirin Dose and Vorapaxar Safety and Efficacy in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome (from the TRACER Trial)
- 2014
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Ingår i: American Journal of Cardiology. - : Elsevier BV. - 0002-9149 .- 1879-1913. ; 113:6, s. 936-944
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Tidskriftsartikel (refereegranskat)abstract
- Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial compared vorapaxar and placebo in 12,944 high-risk patients with non ST-segment elevation acute coronary syndrome. We explored aspirin (ASA) use and its association with outcomes. Kaplan-Meier event rates were compared in groups defined by ASA dose (low, medium, and high). Landmark analyses with covariate adjustment were performed for 0 to 30, 31 to 180, and 181 to 365 days. Of 12,515 participants, 7,523, 1,049, and 3,943 participants were treated with low-, medium-, and high-dose ASA at baseline, respectively. Participants enrolled in North America versus elsewhere were more often treated with a high dose at baseline (66% vs 19%) and discharge (60% vs 3%). Unadjusted cardiovascular death, myocardial infarction, stroke, hospitalization for ischemia, or urgent revascularization event rates tended to be higher with higher baseline ASA (18.45% low, 19.13% medium, and 20.27% high; p for trend = 0.15573). Unadjusted and adjusted hazard ratios (95% confidence intervals) for effect of vorapaxar on cardiovascular (unadjusted p for interaction = 0.065; adjusted p for interaction = 0.140) and bleeding (unadjusted p for interaction = 0.915; adjusted p for interaction = 0.954) outcomes were similar across groups. Landmark analyses showed similar safety and efficacy outcomes with vorapaxar and placebo by ASA dose at each time point except for 0 to 30 days, when vorapaxar tended to be worse for efficacy (hazard ratio 1.13, 95% confidence interval 0.89 to 1.44, p for interaction = 0.0157). In conclusion, most TRACER participants were treated with low-dose ASA, although a high dose was common in North America. High-dose participants tended to have higher rates of ischemic and bleeding outcomes. Although formal statistical testing did not reveal heterogeneity in vorapaxar's effect across dose subgroups, consistent trends support use of low-dose ASA with other antiplatelet therapies.(c) 2014 Elsevier Inc. All rights reserved.
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| 10. |
- Shete, Sanjay, et al.
(författare)
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Genome-wide high-density SNP linkage search for glioma susceptibility loci : results from the gliogene consortium
- 2011
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 71:24, s. 7568-7575
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Tidskriftsartikel (refereegranskat)abstract
- Gliomas, which generally have a poor prognosis, are the most common primary malignant brain tumors in adults. Recent genome-wide association studies have shown that inherited susceptibility plays a role in the development of glioma. Although first-degree relatives of patients exhibit a two-fold increased risk of glioma, the search for susceptibility loci in familial forms of the disease has been challenging because the disease is relatively rare, fatal, and heterogeneous, making it difficult to collect sufficient biosamples from families for statistical power. To address this challenge, the Genetic Epidemiology of Glioma International Consortium (Gliogene) was formed to collect DNA samples from families with two or more cases of histologically confirmed glioma. In this study, we present results obtained from 46 U.S. families in which multipoint linkage analyses were undertaken using nonparametric (model-free) methods. After removal of high linkage disequilibrium single-nucleotide polymorphism, we obtained a maximum nonparametric linkage score (NPL) of 3.39 (P = 0.0005) at 17q12-21.32 and the Z-score of 4.20 (P = 0.000007). To replicate our findings, we genotyped 29 independent U.S. families and obtained a maximum NPL score of 1.26 (P = 0.008) and the Z-score of 1.47 (P = 0.035). Accounting for the genetic heterogeneity using the ordered subset analysis approach, the combined analyses of 75 families resulted in a maximum NPL score of 3.81 (P = 0.00001). The genomic regions we have implicated in this study may offer novel insights into glioma susceptibility, focusing future work to identify genes that cause familial glioma. Cancer Res; 71(24); 7568-75. (C) 2011 AACR.
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