| 1. |
- Harrington, Robert A., et al.
(författare)
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The Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRA.CER) trial : study design and rationale
- 2009
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Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 158:3, s. 327-334
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Tidskriftsartikel (refereegranskat)abstract
- Background The protease-activated receptor 1 (PAR-1), the main platelet receptor for thrombin, represents a novel target for treatment of arterial thrombosis, and SCH 530348 is an orally active, selective, competitive PAR-1 antagonist. We designed TRA.CER to evaluate the efficacy and safety of SCH 530348 compared with placebo in addition to standard of care in patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS) and high-risk features. Trial design TRA.CER is a prospective, randomized, double-blind, multicenter, phase III trial with an original estimated sample size of 10,000 subjects. Our primary objective is to demonstrate that SCH 530348 in addition to standard of care will reduce the incidence of the composite of cardiovascular death, myocardial infarction (MI), stroke, recurrent ischemia with rehospitalization, and urgent coronary revascularization compared with standard of care alone. Our key secondary objective is to determine whether SCH 530348 will reduce the composite of cardiovascular death, MI, or stroke compared with standard of care alone. Secondary objectives related to safety are the composite of moderate and severe GUSTO bleeding and clinically significant TIMI bleeding. The trial will continue until a predetermined minimum number of centrally adjudicated primary and key secondary end point events have occurred and all subjects have participated in the study for at least I year. The TRA.CER trial is part of the large phase III SCH 530348 development program that includes a concomitant evaluation in secondary prevention. Conclusion TRA.CER will define efficacy and safety of the novel platelet PAR-1 inhibitor SCH 530348 in the treatment of high-risk patients with NSTE ACS in the setting of current treatment strategies.
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| 2. |
- Whellan, David J., et al.
(författare)
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Vorapaxar in Acute Coronary Syndrome Patients Undergoing Coronary Artery Bypass Graft Surgery
- 2014
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 63:11, s. 1048-1057
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Tidskriftsartikel (refereegranskat)abstract
- Objectives This study evaluated effects of protease-activated receptor-1 antagonist vorapaxar (Merck, Whitehouse Station, New Jersey) versus placebo among the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) study patients with non-ST-segment elevation acute coronary syndromes undergoing coronary artery bypass grafting (CABG). Background Platelet activation may play a key role in graft occlusion, and antiplatelet therapies may reduce ischemic events, but perioperative bleeding risk remains a major concern. Although the TRACER study did not meet the primary quintuple composite outcome in the overall population with increased bleeding, an efficacy signal with vorapaxar was noted on major ischemic outcomes, and preliminary data suggest an acceptable surgical bleeding profile. We aimed to assess efficacy and safety of vorapaxar among CABG patients. Methods Associations between treatment and ischemic and bleeding outcomes were assessed using time-to-event analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox hazards model. Event rates were estimated using the Kaplan-Meier method. Results Among 12,944 patients, 1,312 (10.1%) underwent CABG during index hospitalization, with 78% on the study drug at the time of surgery. Compared with placebo CABG patients, vorapaxar-treated patients had a 45% lower rate of the primary endpoint (i.e., a composite of death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularizationduring index hospitalization) (HR: 0.55; 95% CI: 0.36 to 0.83; p = 0.005), with a significant interaction (p = 0.012). The CABG-related Thrombolysis In Myocardial Infarction major bleeding was numerically higher with vorapaxar, but not significantly different between vorapaxar and placebo (9.7% vs. 7.3%; HR: 1.36; 95% CI: 0.92 to 2.02; p = 0.12), with no excess in fatal bleeding (0% vs. 0.3%) or need for reoperation (4.7% vs. 4.6%). Conclusions In non-ST-segment elevation acute coronary syndrome patients undergoing CABG, vorapaxar was associated with a significant reduction in ischemic events and no significant increase in major CABG-related bleeding. These data show promise for protease-activated receptor 1 antagonism in patients undergoing CABG and warrant confirmatory evidence in randomized trials. (Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Acute Coronary Syndrome [TRA.CER] [Study P04736AM3]; NCT00527943) (C) 2014 by the American College of Cardiology Foundation
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| 3. |
- Adcox, K, et al.
(författare)
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PHENIX detector overview
- 2003
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Ingår i: Nuclear Instruments & Methods in Physics Research. Section A: Accelerators, Spectrometers, Detectors, and Associated Equipment. - 0167-5087. ; 499:2-3, s. 469-479
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Tidskriftsartikel (refereegranskat)abstract
- The PHENIX detector is designed to perform a broad study of A-A, p-A, and p-p collisions to investigate nuclear matter under extreme conditions. A wide variety of probes, sensitive to all timescales, are used to study systematic variations with species and energy as well as to measure the spin structure of the nucleon. Designing for the needs of the heavy-ion and polarized-proton programs has produced a detector with unparalleled capabilities. PHENIX measures electron and muon pairs, photons, and hadrons with excellent energy and momentum resolution. The detector consists of a large number of subsystems that are discussed in other papers in this volume. The overall design parameters of the detector are presented. (C) 2002 Elsevier Science B.V. All rights reserved.
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| 4. |
- Benjamin, Daniel J., et al.
(författare)
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Redefine statistical significance
- 2018
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Ingår i: Nature Human Behaviour. - : Nature Research (part of Springer Nature). - 2397-3374. ; 2:1, s. 6-10
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 5. |
- Heerspink, Hiddo J L, et al.
(författare)
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A pre-specified analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial on the incidence of abrupt declines in kidney function.
- 2022
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Ingår i: Kidney international. - : Elsevier BV. - 1523-1755 .- 0085-2538. ; 101:1, s. 174-184
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Tidskriftsartikel (refereegranskat)abstract
- This pre-specified analysis of DAPA-CKD assessed the impact of sodium-glucose cotransporter 2 inhibition on abrupt declines in kidney function in high-risk patients based on having chronic kidney disease (CKD) and substantial albuminuria. DAPA-CKD was a randomized, double-blind, placebo-controlled trial that had a median follow-up of 2.4 years. Adults with CKD (urinary albumin-to-creatinine ratio 200-5000 mg/g and estimated glomerular filtration rate 25-75 mL/min/1.73m2) were randomized to dapagliflozin 10 mg/day matched to placebo (2152 individuals each). An abrupt decline in kidney function was defined as a pre-specified endpoint of doubling of serum creatinine between two subsequent study visits. We also assessed a post-hoc analysis of investigator-reported acute kidney injury-related serious adverse events. Doubling of serum creatinine between two subsequent visits (median time-interval 100 days) occurred in 63 (2.9%) and 91 (4.2%) participants in the dapagliflozin and placebo groups, respectively (hazard ratio 0.68 [95% confidence interval 0.49, 0.94]). Accounting for the competing risk of mortality did not alter our findings. There was no heterogeneity in the effect of dapagliflozin on abrupt declines in kidney function based on baseline subgroups. Acute kidney injury-related serious adverse events were not significantly different and occurred in 52 (2.5%) and 69 (3.2%) participants in the dapagliflozin and placebo groups, respectively (0.77 [0.54, 1.10]). Thus, in patients with CKD and substantial albuminuria, dapagliflozin reduced the risk of abrupt declines in kidney function.
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| 6. |
- Heerspink, Hiddo J L, et al.
(författare)
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Effects of dapagliflozin on mortality in patients with chronic kidney disease : a pre-specified analysis from the DAPA-CKD randomized controlled trial.
- 2021
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Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 42:13, s. 1216-1227
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Mortality rates from chronic kidney disease (CKD) have increased in the last decade. In this pre-specified analysis of the DAPA-CKD trial, we determined the effects of dapagliflozin on cardiovascular and non-cardiovascular causes of death.METHODS AND RESULTS: DAPA-CKD was an international, randomized, placebo-controlled trial with a median of 2.4 years of follow-up. Eligible participants were adult patients with CKD, defined as a urinary albumin-to-creatinine ratio (UACR) 200-5000 mg/g and an estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m2. All-cause mortality was a key secondary endpoint. Cardiovascular and non-cardiovascular death was adjudicated by an independent clinical events committee. The DAPA-CKD trial randomized participants to dapagliflozin 10 mg/day (n = 2152) or placebo (n = 2152). The mean age was 62 years, 33% were women, the mean eGFR was 43.1 mL/min/1.73 m2, and the median UACR was 949 mg/g. During follow-up, 247 (5.7%) patients died, of whom 91 (36.8%) died due to cardiovascular causes, 102 (41.3%) due to non-cardiovascular causes, and in 54 (21.9%) patients, the cause of death was undetermined. The relative risk reduction for all-cause mortality with dapagliflozin (31%, hazard ratio [HR] [95% confidence interval (CI)] 0.69 [0.53, 0.88]; P = 0.003) was consistent across pre-specified subgroups. The effect on all-cause mortality was driven largely by a 46% relative risk reduction of non-cardiovascular death (HR [95% CI] 0.54 [0.36, 0.82]). Deaths due to infections and malignancies were the most frequently occurring causes of non-cardiovascular deaths and were reduced with dapagliflozin vs. placebo.CONCLUSION: In patients with CKD, dapagliflozin prolonged survival irrespective of baseline patient characteristics. The benefits were driven largely by reductions in non-cardiovascular death.
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| 7. |
- Mark, Daniel B., et al.
(författare)
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Comprehensive Quality-of-Life Outcomes With Invasive Versus Conservative Management of Chronic Coronary Disease in ISCHEMIA
- 2022
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Ingår i: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 0009-7322 .- 1524-4539. ; 145:17, s. 1294-1307
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) compared an initial invasive treatment strategy (INV) with an initial conservative strategy in 5179 participants with chronic coronary disease and moderate or severe ischemia. The ISCHEMIA research program included a comprehensive quality-of-life (QOL) substudy.METHODS: In 1819 participants (907 INV, 912 conservative strategy), we collected a battery of disease-specific and generic QOL instruments by structured interviews at baseline; at 3, 12, 24, and 36 months postrandomization; and at study closeout. Assessments included angina-related QOL (19-item Seattle Angina Questionnaire), generic health status (EQ-5D), depressive symptoms (Patient Health Questionnaire-8), and, for North American patients, cardiac functional status (Duke Activity Status Index).RESULTS: Median age was 67 years, 19.2% were female, and 15.9% were non-White. The estimated mean difference for the 19-item Seattle Angina Questionnaire Summary score favored INV (1.4 points [95% CI, 0.2-2.5] over all follow-up). No differences were observed in patients with rare/absent baseline angina (SAQ Angina Frequency score >80). Among patients with more frequent angina at baseline (SAQ Angina Frequency score <80, 744 patients, 41%), those randomly assigned to INV had a mean 3.7-point higher 19-item Seattle Angina Questionnaire Summary score than conservative strategy (95% CI, 1.6-5.8) with consistent effects across SAQ subscales: Physical Limitations 3.2 points (95% CI, 0.2-6.1), Angina Frequency 3.2 points (95% CI, 1.2-5.1), Quality of Life/Health Perceptions 5.3 points (95% CI, 2.8-7.8). For the Duke Activity Status Index, no difference was estimated overall by treatment, but in patients with baseline SAQ Angina Frequency scores <80, Duke Activity Status Index scores were higher for INV (3.2 points [95% CI, 0.6-5.7]), whereas patients with rare/absent baseline angina showed no treatment-related differences. Moderate to severe depression was infrequent at randomization (11.5%-12.8%) and was unaffected by treatment assignment.CONCLUSIONS: In the ISCHEMIA comprehensive QOL substudy, patients with more frequent baseline angina reported greater improvements in the symptom, physical functioning, and psychological well-being dimensions of QOL when treated with an invasive strategy, whereas patients who had rare/absent angina at baseline reported no consistent treatment-related QOL differences.
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| 8. |
- Maron, David J., et al.
(författare)
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Initial Invasive or Conservative Strategy for Stable Coronary Disease
- 2020
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 382:15, s. 1395-1407
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Tidskriftsartikel (refereegranskat)abstract
- Background: Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain.Methods: We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction.Results: Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32).Conclusions: Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, .) Patients with stable coronary disease were randomly assigned to an initial invasive strategy with angiography and revascularization if appropriate or to medical therapy alone. At 3.2 years, there was no significant difference between the groups with respect to the estimated rate of ischemic events. The findings were sensitive to the definition of myocardial infarction.
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| 9. |
- McMurray, John J. V., et al.
(författare)
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Effect of Dapagliflozin on Clinical Outcomes in Patients with Chronic Kidney Disease, With and Without Cardiovascular Disease
- 2021
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Ingår i: Circulation. - : Wolters Kluwer. - 0009-7322 .- 1524-4539. ; 143:5, s. 438-448
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Tidskriftsartikel (refereegranskat)abstract
- Background:Dapagliflozin reduces the risk of end-stage renal disease in patients with chronic kidney disease. We examined the relative risk of cardiovascular and renal events in these patients and the effect of dapagliflozin on either type of event, taking account of history of cardiovascular disease.Methods:In the DAPA-CKD trial (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease), 4304 participants with chronic kidney disease were randomly assigned to dapagliflozin 10 mg once daily or placebo. The primary end point was a composite of sustained decline in estimated glomerular filtration rate ≥50%, end-stage kidney disease, or kidney or cardiovascular death. The secondary end points were a kidney composite outcome (primary end point, minus cardiovascular death), the composite of hospitalization for heart failure or cardiovascular death, and all-cause death. In a prespecified subgroup analysis, we divided patients into primary and secondary prevention subgroups according to history of cardiovascular disease.Results:Secondary prevention patients (n=1610; 37.4%) were older, were more often male, had a higher blood pressure and body mass index, and were more likely to have diabetes. Mean estimated glomerular filtration rate and median urinary albumin-to-creatinine ratio were similar in the primary and secondary prevention groups. The rates of adverse cardiovascular outcomes were higher in the secondary prevention group, but kidney failure occurred at the same rate in the primary and secondary prevention groups. Dapagliflozin reduced the risk of the primary composite outcome to a similar extent in both the primary (hazard ratio, 0.61 [95% CI, 0.48–0.78]) and secondary (0.61 [0.47–0.79]) prevention groups (P-interaction=0.90). This was also true for the composite of heart failure hospitalization or cardiovascular death (0.67 [0.40–1.13] versus 0.70 [0.52–0.94], respectively; P-interaction=0.88), and all-cause mortality (0.63 [0.41–0.98] versus 0.70 [0.51–0.95], respectively; P-interaction=0.71). Rates of adverse events were low overall and did not differ between patients with and without cardiovascular disease.Conclusions:Dapagliflozin reduced the risk of kidney failure, death from cardiovascular causes or hospitalization for heart failure, and prolonged survival in people with chronic kidney disease, with or without type 2 diabetes, independently of the presence of concomitant cardiovascular disease.Registration:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036150.
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| 10. |
- Schunk, Stefan J., et al.
(författare)
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Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality
- 2021
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Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 42:18, s. 1742-1756
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Tidskriftsartikel (refereegranskat)abstract
- AimsInflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown.Methods and resultsWe explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality.ConclusionThe NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.
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