| 1. |
- Estrada, Karol, et al.
(author)
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Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
- 2012
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:5, s. 491-501
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Journal article (peer-reviewed)abstract
- Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
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| 2. |
- Gurbel, Paul A., et al.
(author)
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Platelet Function During Extended Prasugrel and Clopidogrel Therapy for Patients With ACS Treated Without Revascularization The TRILOGY ACS Platelet Function Substudy
- 2012
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In: JAMA: The Journal of the American Medical Association. - : American Medical Association (AMA). - 1538-3598. ; 308:17, s. 1785-1794
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Journal article (peer-reviewed)abstract
- Context The relationship of platelet function testing measurements with outcomes in patients with acute coronary syndromes (ACS) initially managed medically without revascularization is unknown. Objective To characterize the differences and evaluate clinical outcomes associated with platelet reactivity among patients with ACS treated with clopidogrel or prasugrel. Design, Setting, and Patients Patients with medically managed unstable angina or non-ST-segment elevation myocardial infarction were enrolled in the TRILOGY ACS trial (2008 to 2011) comparing clopidogrel vs prasugrel. Of 9326 participants, 27.5% were included in a platelet function substudy: 1286 treated with prasugrel and 1278 treated with clopidogrel. Interventions Aspirin with either prasugrel (10 or 5 mg/d) or clopidogrel (75 mg/d); those 75 years or older and younger than 75 years but who weighed less than 60 kg received a 5-mg prasugrel maintenance dose. Main Outcome Measures Platelet reactivity, measured in P2Y(12) reaction units (PRUs), was performed at baseline, at 2 hours, and at 1, 3, 6, 12, 18, 24, and 30 months after randomization. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke through 30 months. Results Among participants younger than 75 years and weighing 60 kg or more, the median PRU values at 30 days were 64 (interquartile range [IQR], 33-128) in the prasugrel group vs 200 (IQR, 141-260) in the clopidogrel group (P<.001), a difference that persisted through all subsequent time points. For participants younger than 75 years and weighing less than 60 kg, the median 30-day PRU values were 139 (IQR, 86-203) for the prasugrel group vs 209 (IQR, 148-283) for the clopidogrel group (P<.001), and for participants 75 years or older, the median PRU values were 164 (IQR, 105-216) for the prasugrel group vs 222 (IQR, 148-268) for the clopidogrel group (P<.001). At 30 months the rate of the primary efficacy end point was 17.2% (160 events) in the prasugrel group vs 18.9% (180 events) in the clopidogrel group (P=.29). There were no significant differences in the continuous distributions of 30-day PRU values for participants with a primary efficacy end point event after 30 days (n=214) compared with participants without an event (n=1794; P=.07) and no significant relationship between the occurence of the primary efficacy end point and continuous PRU values (adjusted hazard ratio [HR] for increase of 60 PRUs, 1.03; 95% CI, 0.96-1.11; P=.44). Similar findings were observed with 30-day PRU cut points used to define high on-treatment platelet reactivity-PRU more than 208 (adjusted HR, 1.16; 95% CI, 0.89-1.52, P=.28) and PRU more than 230 (adjusted HR, 1.20; 95% CI, 0.90-1.61; P=.21). Conclusions Among patients with ACS without ST-segment elevation and initially managed without revascularization, prasugrel was associated with lower platelet reactivity than clopidogrel, irrespective of age, weight, and dose. Among those in the platelet substudy, no significant differences existed between prasugrel vs clopidogrel in the occurence of the primary efficacy end point through 30 months and no significant association existed between platelet reactivity and occurrence of ischemic outcomes.
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| 3. |
- Skibola, Christine F, et al.
(author)
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Genome-wide Association Study Identifies Five Susceptibility Loci for Follicular Lymphoma outside the HLA Region.
- 2014
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 95:4, s. 462-471
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Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 × 10(-20)) near CXCR5; 11q24.3 (rs4937362, p = 6.76 × 10(-11)) near ETS1; 3q28 (rs6444305, p = 1.10 × 10(-10)) in LPP; 18q21.33 (rs17749561, p = 8.28 × 10(-10)) near BCL2; and 8q24.21 (rs13254990, p = 1.06 × 10(-8)) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DRβ1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (pomnibus = 4.20 × 10(-67) to 2.67 × 10(-70)). Additional independent signals included rs17203612 in HLA class II (odds ratio [ORper-allele] = 1.44; p = 4.59 × 10(-16)) and rs3130437 in HLA class I (ORper-allele = 1.23; p = 8.23 × 10(-9)). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk.
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| 4. |
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| 5. |
- Armstrong, Paul W., et al.
(author)
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Quantitative ST-depression in Acute Coronary Syndromes : the PLATO Electrocardiographic Substudy
- 2013
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In: American Journal of Medicine. - : Elsevier BV. - 0002-9343 .- 1555-7162. ; 126:8, s. 723-
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Journal article (peer-reviewed)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.
(author)
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ST Elevation Acute Coronary Syndromes in PLATO : Insights from the ECG Substudy
- 2012
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In: Circulation. - 0009-7322 .- 1524-4539. ; 125:3, s. 514-521
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Journal article (peer-reviewed)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. |
- Beer, Tomasz M, et al.
(author)
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Enzalutamide in metastatic prostate cancer before chemotherapy
- 2014
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In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 371:5, s. 33-424
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Journal article (peer-reviewed)abstract
- BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy.METHODS: In this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival.RESULTS: The study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment.CONCLUSIONS: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas Pharma; PREVAIL ClinicalTrials.gov number, NCT01212991.).
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| 9. |
- Berndt, Sonja I., et al.
(author)
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Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia
- 2013
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:8, s. 868-U202
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Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWAS) have previously identified 13 loci associated with risk of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL). To identify additional CLL susceptibility loci, we conducted the largest meta-analysis for CLL thus far, including four GWAS with a total of 3,100 individuals with CLL (cases) and 7,667 controls. In the meta-analysis, we identified ten independent associated SNPs in nine new loci at 10q23.31 (ACTA2 or FAS (ACTA2/FAS), P = 1.22 x 10(-14)), 18q21.33 (BCL2, P = 7.76 x 10(-11)), 11p15.5 (C11orf21, P = 2.15 x 10(-10)), 4q25 (LEF1, P = 4.24 x 10(-10)), 2q33.1 (CASP10 or CASP8 (CASP10/CASP8), P = 2.50 x 10(-9)), 9p21.3 (CDKN2B-AS1, P = 1.27 x 10(-8)), 18q21.32 (PMAIP1, P = 2.51 x 10(-8)), 15q15.1 (BMF, P = 2.71 x 10(-10)) and 2p22.2 (QPCT, P = 1.68 x 10(-8)), as well as an independent signal at an established locus (2q13, ACOXL, P = 2.08 x 10(-18)). We also found evidence for two additional promising loci below genome-wide significance at 8q22.3 (ODF1, P = 5.40 x 10(-8)) and 5p15.33 (TERT, P = 1.92 x 10(-7)). Although further studies are required, the proximity of several of these loci to genes involved in apoptosis suggests a plausible underlying biological mechanism.
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| 10. |
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| 11. |
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| 12. |
- Conde, Lucia, et al.
(author)
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Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32
- 2010
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:8, s. 661-664
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Journal article (peer-reviewed)abstract
- To identify susceptibility loci for non-Hodgkin lymphoma subtypes, we conducted a three-stage genome-wide association study. We identified two variants associated with follicular lymphoma at 6p21.32 (rs10484561, combined P = 1.12 x 10(-29) and rs7755224, combined P = 2.00 x 10(-19); r(2) = 1.0), supporting the idea that major histocompatibility complex genetic variation influences follicular lymphoma susceptibility. We also found confirmatory evidence of a previously reported association between chronic lymphocytic leukemia/small lymphocytic lymphoma and rs735665 (combined P = 4.24 x 10(-9)).
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| 13. |
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| 14. |
- Eggers, Kai M., et al.
(author)
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Clinical and prognostic implications of circulating pentraxin 3 levels in non ST-elevation acute coronary syndrome
- 2013
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In: Clinical Biochemistry. - : Elsevier BV. - 0009-9120 .- 1873-2933. ; 46:16-17, s. 1655-1659
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Journal article (peer-reviewed)abstract
- Objectives: Pentraxin 3 (PTX3) is the prototype of the long pentraxin family. PTX3 is involved in inflammatory processes affecting the cardiovascular system, and PTX3 levels have been shown to be elevated and independently prognostic in ST-elevation myocardial infarction. Data on PTX3 levels in non-ST-elevation acute coronary syndrome (NSTE-ACS), in contrast, are limited. The aim of the present analysis was to investigate the implications of PTX3 levels in a fairly large sample of NSTE-ACS patients and in comparison to levels of C-reactive protein (CRP). Design and methods: We measured levels of PTX3 and CRP in both 82 healthy controls and 401 NSTE-ACS patients from the GUSTO IV study, and studied the associations of these biomarkers to clinical data and 1-year mortality. Results: NSTE-ACS patients had significantly higher median PTX3 levels compared to healthy controls (3.8 vs. 1.9 mu g/L; p < 0.001). PTX3 levels in patients with NSTE-ACS were independently related to female sex and cardiac troponin T levels, but not to age or cardiovascular risk factors. PTX3 levels were higher in patients who died within 1 year but did not emerge as an independent predictor of 1-year mortality (adjusted OR 1,2 [95% Cl 0.6-2.31). This was in contrast to CRP (adjusted OR 1.5 [95% Cl 1.1-2.3]). Neither PTX3 nor CRP yielded significant discriminative value regarding mortality prediction. Conclusions: PTX3 levels are elevated in NSTE-ACS. However, the prognostic information provided by PTX3 levels is limited and inferior compared to CRP. Our data, thus, do not support the measurement of PTX3 in patients with NSTE-ACS.
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| 15. |
- Eggers, Kai M., 1962-, et al.
(author)
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ST2 and mortality in non-ST-segment elevation acute coronary syndrome
- 2010
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In: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 159:5, s. 788-794
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Journal article (peer-reviewed)abstract
- BACKGROUND: ST2 is a member of the interleukin-1 receptor family that is up-regulated in conditions associated with increased myocardial strain. ST2 has been shown to be independently predictive of adverse outcome in heart failure and ST-segment elevation myocardial infarction, but its prognostic value in non-ST-elevation acute coronary syndrome (NSTE-ACS) has not been established. METHODS: We measured ST2 at randomization and after 24, 48, and 72 hours in 403 NSTE-ACS patients from the GUSTO IV study, and studied its kinetics and its associations to clinical baseline factors and 1-year mortality. RESULTS: Median ST2 levels decreased from 28.4 U/mL at randomization to 21.8 U/mL at 72 hours (P < .001). Peak levels were noted 6 to 17 hours after symptom onset. Randomization ST2 levels were independently associated to N-terminal pro-B-type natriuretic peptide but otherwise exhibited only weak relations to cardiovascular risk factors and comorbidities, and biomarkers of myocardial necrosis or inflammation. ST2 was related to 1-year mortality independently of clinical risk indicators (odds ratio 2.3 [95% CI 1.1-4.6], P = .03) but lost its predictive value after additional adjustment for prognostic biomarkers, in particular N-terminal pro-B-type natriuretic peptide. CONCLUSIONS: ST2 levels are elevated early in NSTE-ACS and predict 1-year mortality. Our data indicate that ST2 represents an interesting novel pathophysiologic pathway in the setting of ischemia-related myocardial dysfunction. However, future prospective evaluations in larger populations are needed before the clinical utility of ST2 can be determined.
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| 16. |
- Gharacholou, S. Michael, et al.
(author)
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Age and Outcomes in ST-Segment Elevation Myocardial Infarction Treated With Primary Percutaneous Coronary Intervention : Findings From the APEX-AMI Trial
- 2011
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In: Archives of Internal Medicine. - : American Medical Association (AMA). - 0003-9926 .- 1538-3679. ; 171:6, s. 559-567
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Journal article (peer-reviewed)abstract
- Background: To understand the influence of age on treatment and outcomes, we analyzed the largest group of patients 75 years or older with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention (PPCI) in a clinical trial. Methods: We analyzed data from 5745 patients in the Assessment of Pexelizumab in Acute Myocardial Infarction trial from July 13, 2004, through May 11, 2006. Age was analyzed continuously and according to 3 groups: younger than 65 years (n = 3410), 65 to 74 years old (n = 1358), and 75 years or older (n = 977). The main outcome measures were 90-day mortality and the composite of congestive heart failure, shock, or death at 90 days. Results: Older patients had higher rates of hypertension, chronic obstructive lung disease, previous angina, and prior revascularization. Also notable in these patients were higher Killip class, less angiographic success after PPCI, and less ST-segment resolution with higher rates of in-hospital clinical events, including mechanical, electrical, and bleeding complications. There was less use of short-term adjunctive medications but similar use of discharge medications in older compared with younger patients. Ninety-day mortality rates were 2.3%, 4.8%, and 13.1%; composite outcome rates were 5.9%, 11.9%, and 22.8% for patients younger than 65 years, 65 to 74 years old, and 75 years or older, respectively. After multivariable adjustment, age was the strongest independent predictor of 90-day mortality (hazard ratio, 2.07 per 10-year increase; 95% confidence interval, 1.84-2.33). Conclusions: Older patients have lower rates of acute procedural success and more postinfarction complications. Age is the strongest predictor of 90-day mortality in ST-segment elevation myocardial infarction patients undergoing PPCI. Despite implementing PPCI for ST-segment elevation myocardial infarction in older patients, early risk remains high, necessitating continued focus on improving outcomes in this vulnerable population.
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| 17. |
- Guptill, Jeffrey T., et al.
(author)
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Stroke After Primary Percutaneous Coronary Intervention in Patients With ST-Segment Elevation Myocardial Infarction Timing, Characteristics, and Clinical Outcomes
- 2013
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In: Circulation. Cardiovascular Interventions. - 1941-7640 .- 1941-7632. ; 6:2, s. 176-183
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Journal article (peer-reviewed)abstract
- Background-Stroke is a rare but potentially devastating complication of acute myocardial infarction. Little is known about stroke timing, characteristics, and clinical outcomes in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention (PCI). Methods and Results-We studied 5372 patients enrolled in the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial. We analyzed stroke incidence, type, timing, and association with the prespecified 90-day clinical outcomes. Cox proportional hazards modeling was performed to assess the relationship between stroke and outcomes, after adjusting baseline characteristics and analyzing stroke as a time-dependent covariate. Stroke occurred in 69 primary patients with PCI (1.3%). A third of strokes were ischemic (n=23; 33%), 12% (n=8) were hemorrhagic, and the remaining 55% (n=38) were of uncertain type. The median (25th, 75th percentile) time of stroke occurrence was 6 (3, 14) days. Overall, 43% of strokes occurred within 48 hours of PCI, and all hemorrhagic strokes occurred within 48 hours. Stroke was associated with an increased risk of 90-day death (unadjusted hazard ratio [HR], 8.0; 95% confidence interval [CI], 4.8-13.5), congestive heart failure (unadjusted HR, 3.2; 95% CI, 1.3-7.8), and 30-day hospital readmission (unadjusted HR, 3.2; 95% CI, 2.0-5.1). After adjustment, stroke was still strongly associated with 90-day death (adjusted HR, 5.6; 95% CI, 3.2-9.8) and the combination end point of death, congestive heart failure, or cardiogenic shock at 90 days (adjusted HR, 2.4; 95% CI, 1.2-4.7). Conclusions-Stroke is an infrequent complication in the setting of ST-segment elevation myocardial infarction treated with primary PCI but is associated with increased morbidity and mortality. Studies to determine mechanisms that may be responsible for strokes that occur >48 hours from primary PCI are warranted.
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| 18. |
- Held, Claes, et al.
(author)
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Vorapaxar, a platelet thrombin-receptor antagonist, in medically managed patients with non-ST-segment elevation acute coronary syndrome: : results from the TRACER trial
- 2014
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In: European Heart Journal. - : Oxford University Press (OUP). - 2048-8726 .- 2048-8734. ; 3:3, s. 246-256
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Journal article (peer-reviewed)abstract
- Background: This study characterized a medically managed population in a non-ST-segment elevation acute coronary syndrome (NSTEACS) cohort and evaluated prognosis and outcomes of vorapaxar vs. placebo.Methods: In the TRACER study, 12,944 NSTEACS patients were treated with standard care and vorapaxar (a novel platelet protease-activated receptor-1 antagonist) or placebo. Of those, 4194 patients (32.4%) did not undergo revascularization during index hospitalization, and 8750 (67.6%) underwent percutaneous coronary intervention or coronary artery bypass grafting. Patients managed medically were heterogeneous with different risk profiles, including 1137 (27.1%) who did not undergo coronary angiography. Patients who underwent angiography but were selected for medical management included those without evidence of significant coronary artery disease (CAD), with prior CAD but no new significant lesions, and with significant lesions who were not treated with revascularization.Results: Cardiovascular event rates were highest among those without angiography and lowest in the group with angiography but without CAD. In the medically managed cohort, 2-year primary outcome (cardiovascular death, myocardial infarction, stroke, recurrent ischaemia with rehospitalization, urgent coronary revascularization) event rates were 16.3% with vorapaxar and 17.0% with placebo (HR 0.99, 95% CI 0.83–1.17), with no interaction between drug and management strategy (p=0.75). Key secondary endpoint (cardiovascular death, myocardial infarction, stroke) rates were 13.4% with vorapaxar and 14.9% with placebo (HR 0.89, 95% CI 0.74–1.07), with no interaction (p=0.58). Vorapaxar increased GUSTO moderate/severe bleeding numerically in medically managed patients (adjusted HR 1.46, 95% CI 0.99–2.15).Conclusions: NSTEACS patients who were initially medically managed had a higher risk-factor burden, and one-third had normal coronary arteries. Outcome in the medically managed cohort was significantly related to degree of CAD, highlighting the importance of coronary angiography. Efficacy and safety of vorapaxar appeared consistent with the overall trial results.
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| 19. |
- Jakobsson, Martin, et al.
(author)
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The International Bathymetric Chart of the Arctic Ocean (IBCAO) Version 3.0
- 2012
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In: Geophysical Research Letters. - 0094-8276 .- 1944-8007. ; 39
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Journal article (peer-reviewed)abstract
- The International Bathymetric Chart of the Arctic Ocean (IBCAO) released its first gridded bathymetric compilation in 1999. The IBCAO bathymetric portrayals have since supported a wide range of Arctic science activities, for example, by providing constraint for ocean circulation models and the means to define and formulate hypotheses about the geologic origin of Arctic undersea features. IBCAO Version 3.0 represents the largest improvement since 1999 taking advantage of new data sets collected by the circum-Arctic nations, opportunistic data collected from fishing vessels, data acquired from US Navy submarines and from research ships of various nations. Built using an improved gridding algorithm, this new grid is on a 500 meter spacing, revealing much greater details of the Arctic seafloor than IBCAO Version 1.0 (2.5 km) and Version 2.0 (2.0 km). The area covered by multibeam surveys has increased from similar to 6% in Version 2.0 to similar to 11% in Version 3.0. Citation: Jakobsson, M., et al. (2012), The International Bathymetric Chart of the Arctic Ocean (IBCAO) Version 3.0, Geophys. Res. Lett., 39, L12609, doi:10.1029/2012GL052219.
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| 20. |
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| 21. |
- Jones, William Schuyler, et al.
(author)
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Vorapaxar in patients with peripheral artery disease and acute coronary syndrome: : Insights from Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER)
- 2014
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In: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 168:4, s. 588-596
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Journal article (peer-reviewed)abstract
- Background In the TRACER trial, vorapaxar, a protease-activated receptor-1 antagonist, plus standard care in non-ST-segment elevation acute coronary syndrome (NSTE ACS) patients did not significantly reduce the primary composite end point but reduced a key secondary end point and significantly increased bleeding. History of peripheral artery disease (PAD) was a risk-enrichment inclusion criterion. We investigated the efficacy and safety of vorapaxar in NSTE ACS patients with documented PAD. Methods TRACER was a double-blind, randomized trial comparing vorapaxar with placebo in 12,944 patients with NSTE ACS. Results In total, 936 (7.2%) patients had a history of PAD. Ischemic events occurred more frequently among patients with PAD (25.3%) versus no PAD (12.2%, P < .001), and Global Use of Strategies to Open Occluded Coronary Arteries moderate/severe bleeding was more common in PAD (9.1%) versus no PAD (5.0%, P = .004). Similar rates of the composite end point (cardiovascular death, myocardial infarction, or stroke) occurred in patients with PAD treated with vorapaxar and placebo (21.7% vs 24.8%, P interaction = .787). Patients with PAD treated with vorapaxar, when compared with placebo, also had a numerical reduction in peripheral revascularization procedures (8.1% vs 9.0%, P = .158) and a lower extremity amputation rate (0.9% vs 1.5%, P = .107). Vorapaxar increased Global Use of Strategies to Open Occluded Coronary Arteries moderate/severe bleeding similarly in patients with PAD (hazard ratio 1.47, 95% CI 0.89-2.45) and without (hazard ratio 1.48, 95% CI 1.22-1.79; P interaction = .921). Conclusions Patients with NSTEACS and PAD were at increased risk for ischemic events. Lower rates of ischemic end points, peripheral revascularization, and amputation with vorapaxar did not reach statistical significance but warrant further investigation. Vorapaxar increased bleeding in both patients with and without PAD at a similar magnitude of risk.
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| 22. |
- Lassila, Riitta, et al.
(author)
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Practical Viewpoints on the Diagnosis and Management of Heparin-Induced Thrombocytopenia
- 2011
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In: Seminars in Thrombosis and Hemostasis. - : Georg Thieme Verlag KG. - 1098-9064 .- 0094-6176. ; 37:3, s. 328-335
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Journal article (peer-reviewed)abstract
- Heparin-induced thrombocytopenia (HIT, type II) is an immune-mediated disorder due to antibodies formed against heparin platelet factor 4 complexes, usually appearing at days 5 to 14 after initiation of heparin. It is important to recognize HIT because heparin prophylaxis or treatment paradoxically associates with new venous and/or arterial thrombosis. Early clinical suspicion and diagnosis together with proper pharmacotherapy and close laboratory monitoring are the cornerstones for successful management. This includes monitoring of Thrombocytopenia, its Timing to heparin administration, appearance of new Thrombosis or resistance to treatment, and differential diagnosis by exclusion of oTher causes (the 4T's). Specific attention should be paid to the absence or presence of thrombosis and to tailoring thromboprophylaxis or anticoagulant therapy with a nonheparin alternative. Even in the absence of HIT-associated thrombosis, an active policy for prolonged thromboprophylaxis is demanded. Rapid and reliable assays should be developed for diagnosis and anticoagulation monitoring to secure safe management with nonheparins. Semiquantitative testing for on-call hours should be available and later confirmed as clinically needed. Alternative therapeutic options are available, but because their use is infrequent, experienced coagulation treatment centers should provide guidance in the treatment and in laboratory monitoring. Most of the evidence in HIT is grade IC, and thus the best evidence is provided by clinical experience. New anticoagulants and platelet inhibitors may offer future alternatives in the management of HIT, but the current treatment options provide the best experience and benefit. The joint clinical and laboratory guidelines provided in this article along with two practical case scenarios were prepared by a Nordic expert panel. They will be valuable for hematologists and colleagues who do not routinely encounter HIT.
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| 23. |
- Leonardi, Sergio, et al.
(author)
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Effect of vorapaxar on myocardial infarction in the thrombin receptor antagonist for clinical event reduction in acute coronary syndrome (TRA·CER) trial
- 2013
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In: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 34:23, s. 1723-1731
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Journal article (peer-reviewed)abstract
- AimsThe TRA·CER trial compared vorapaxar, a novel platelet protease-activated receptor (PAR)-1 antagonist, with placebo in 12 944 patients with high-risk non–ST-segment elevation acute coronary syndromes (NSTE ACS). In this analysis, we explored the effect of vorapaxar on myocardial infarction (MI).Methods and resultsA blinded, independent central endpoint adjudication committee prospectively defined and classified MI according to the universal MI definition, including peak cardiac marker value (creatine kinase-MB [CK-MB] and/or troponin). Because the trial failed to meet its primary endpoint, these analyses are considered exploratory. During a median follow-up of 502 days, 1580 MIs occurred in 1319 patients. The majority (n = 1025, 64.9%) were type 1 (spontaneous) MI, followed by type 4a [percutaneous coronary intervention (PCI)-related] MI (n = 352; 22.3%). Compared with placebo, vorapaxar reduced the hazard of a first MI of any type by 12% [hazard ratio (HR), 0.88; 95% confidence interval (CI), 0.79–0.98; P = 0.021] and the hazard of total number of MIs (first and subsequent) by 14% (HR, 0.86; 95% CI, 0.77–0.97; P = 0.014), an effect that was sustained over time. Vorapaxar reduced type 1 MI by 17% (HR, 0.83; 95% CI, 0.73–0.95; P = 0.007). Type 4a MIs were not significantly reduced by vorapaxar (HR, 0.90; 95% CI, 0.73–1.12; P = 0.35). Vorapaxar effect was consistent across MI sizes defined by peak cardiac marker elevations and across key clinical subgroups; however, in patients not treated with thienopyridine at baseline (HR, 0.65; 95% CI, 0.46–0.92) compared with patients who received thienopyridine (HR, 0.91; 95% CI, 0.81–1.02), there was a trend towards a higher effect (Pint = 0.077).ConclusionThe PAR-1 antagonist vorapaxar was associated with a reduction of MI, including total number of infarctions. This reduction was sustained over time and was mostly evident in type 1 MI, the most common type of MI observed.
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| 24. |
- Lopes, Renato D., et al.
(author)
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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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In: Journal of Thrombosis and Thrombolysis. - : Springer Science and Business Media LLC. - 0929-5305 .- 1573-742X. ; 32:2, s. 242-266
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Journal article (peer-reviewed)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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| 25. |
- Lopes, Renato D., et al.
(author)
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Warfarin Use and Outcomes in Patients with Atrial Fibrillation Complicating Acute Coronary Syndromes
- 2010
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In: American Journal of Medicine. - : Elsevier BV. - 0002-9343 .- 1555-7162. ; 123:2, s. 134-140
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Journal article (peer-reviewed)abstract
- BACKGROUND: We examined warfarin use at discharge (according to Congestive heart failure, Hypertension, Age > 75 years, Diabetes, Prior Stroke/transient ischemic attack score and bleeding risk) and its association with 6-month death or myocardial infarction in patients with post-acute coronary syndrome atrial fibrillation. METHODS: Of the 23,208 patients enrolled in the Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy, Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network A, and Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors trials, 4.0% (917 patients) had atrial fibrillation as an in-hospital complication and were discharged alive. Cox proportional hazards models were performed to assess 6-month outcomes after discharge. RESULTS: Overall, 13.5% of patients with an acute coronary syndrome complicated by atrial fibrillation received warfarin at discharge. Warfarin use among patients with atrial fibrillation had no relation with estimated stroke risk; similar rates were observed across Congestive heart failure, Hypertension, Age > 75 years, Diabetes, Prior Stroke/transient ischemic attack (CHADS(2)) scores (0, 13%; 1, 14%: >= 2, 13%) and across different bleeding risk categories (low risk, 11.9%: intermediate risk, 13.3%; high risk, 11.1%). Among patients with in-hospital atrial fibrillation, warfarin use at discharge was independently associated with a lower risk of death or myocardial infarction within 6 months of discharge (hazard ratio 0.39; 95% confidence interval, 0.15-0.98). CONCLUSION: Warfarin is associated with better 6-month outcomes among patients with atrial fibrillation complicating an acute coronary syndrome, but its use is not related to CHADS(2) score or bleeding risk.
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