| 1. |
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| 2. |
- Marquis-Gravel, Guillaume, et al.
(author)
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Post-Discharge Bleeding and Mortality Following Acute Coronary Syndromes With or Without PCI
- 2020
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In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 76:2, s. 162-171
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Journal article (peer-reviewed)abstract
- BACKGROUND The long-term prognostic impact of post-discharge bleeding in the unique population of patients with acute coronary syndrome (ACS) treated without percutaneous coronary intervention (PCI) remains unexplored.OBJECTIVES The aim of this study was to assess the association between post-discharge bleeding and subsequent mortality after ACS according to index strategy (PCI or no PCI) and to contrast with the association between post-discharge myocardial infarction (MI) and subsequent mortality.METHODS In a harmonized dataset of 4 multicenter randomized trials (APPRAISE-2 [Apixaban for Prevention of Acute Ischemic Events-2], PLATO [Study of Platelet Inhibition and Patient Outcomes], TRACER [Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome], and TRILOGY ACS [Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes]), the association between post-discharge noncoronary artery bypass graft-related GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) moderate, severe, or life-threatening bleeding (landmark 7 days post-ACS) and subsequent all-cause mortality was evaluated in a time-updated Cox proportional hazards analysis. Interaction with index treatment strategy was assessed. Results were contrasted with risk for mortality following post-discharge MI.RESULTS Among 45,011 participants, 1,133 experienced post-discharge bleeding events (2.6 per 100 patient-years), and 2,149 died during follow-up. The risk for mortality was significantly higher <30 days (adjusted hazard ratio: 15.7; 95% confidence interval: 12.3 to 20.0) and 30 days to 12 months (adjusted hazard ratio: 2.7; 95% confidence interval: 2.1 to 3.4) after bleeding, and this association was consistent in participants treated with or without PCI for their index ACS (p for interaction = 0.240). The time-related association between post-discharge bleeding and mortality was similar to the association between MI and subsequent mortality in participants treated with and without PCI (p for interaction = 0.696).CONCLUSIONS Post-discharge bleeding after ACS is associated with a similar increase in subsequent all-cause mortality in participants treated with or without PCI and has an equivalent prognostic impact as post-discharge MI.
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| 3. |
- Whellan, David J., et al.
(author)
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Vorapaxar in Acute Coronary Syndrome Patients Undergoing Coronary Artery Bypass Graft Surgery
- 2014
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In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 63:11, s. 1048-1057
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Journal article (peer-reviewed)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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| 4. |
- Capodanno, Davide, et al.
(author)
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Dual-pathway inhibition for secondary and tertiary antithrombotic prevention in cardiovascular disease
- 2020
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In: Nature Reviews Cardiology. - : Springer Science and Business Media LLC. - 1759-5002 .- 1759-5010. ; 17:4, s. 242-257
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Research review (peer-reviewed)abstract
- Advances in antiplatelet therapies for patients with cardiovascular disease have improved patient outcomes over time, but the challenge of balancing the risks of ischaemia and bleeding remains substantial. Moreover, many patients with cardiovascular disease have a residual risk of ischaemic events despite receiving antiplatelet therapy. Therefore, novel strategies are needed to prevent clinical events through mechanisms beyond platelet inhibition and with an acceptable associated risk of bleeding. The advent of non-vitamin K antagonist oral anticoagulants, which attenuate fibrin formation by selective inhibition of factor Xa or thrombin, has renewed the interest in dual-pathway inhibition strategies that combine an antiplatelet agent with an anticoagulant drug. In this Review, we highlight the emerging pharmacological rationale and clinical development of dual-pathway inhibition strategies for the prevention of atherothrombotic events in patients with different manifestations of cardiovascular disease, such as coronary artery disease, cerebrovascular disease and peripheral artery disease. Many patients with cardiovascular disease have a residual risk of ischaemic events despite receiving antiplatelet therapy. In this Review, Angiolillo and colleagues discuss the pharmacological rationale and clinical development of dual-pathway inhibition strategies for the prevention of atherothrombotic events in patients with cardiovascular disease.
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| 5. |
- Harrington, Robert A., et al.
(author)
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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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In: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 158:3, s. 327-334
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Journal article (peer-reviewed)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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| 6. |
- Hijazi, Ziad, et al.
(author)
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Apixaban or Vitamin K Antagonists and Aspirin or Placebo According to Kidney Function in Patients With Atrial Fibrillation After Acute Coronary Syndrome or Percutaneous Coronary Intervention : Insights From the AUGUSTUS Trial
- 2021
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In: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 143:12, s. 1215-1223
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Journal article (peer-reviewed)abstract
- Background: In the AUGUSTUS trial (An Open-Label, 2x2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of Apixaban Versus Vitamin K Antagonist and Aspirin Versus Aspirin Placebo in Patients With Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention), apixaban resulted in less bleeding and fewer hospitalizations than vitamin K antagonists, and aspirin caused more bleeding than placebo in patients with atrial fibrillation and acute coronary syndrome or percutaneous coronary intervention treated with a P2Y(12) inhibitor. We evaluated the risk-benefit balance of antithrombotic therapy according to kidney function.Methods: In 4456 patients, the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula was used to calculate baseline estimated glomerular filtration rate (eGFR). The effect of apixaban versus vitamin K antagonists and aspirin versus placebo was assessed across kidney function categories by using Cox models. The primary outcome was International Society on Thrombosis and Haemostasis major or clinically relevant nonmajor bleeding. Secondary outcomes included death or hospitalization and ischemic events (death, stroke, myocardial infarction, stent thrombosis [definite or probable], or urgent revascularization). Creatinine clearanceResults: Overall, 30%, 52%, and 19% had an eGFR of >80, >50 to 80, and 30 to 50 mL.min(-1).1.73 m(-2), respectively. At the 6-month follow-up, a total of 543 primary outcomes of bleeding, 1125 death or hospitalizations, and 282 ischemic events occurred. Compared with vitamin K antagonists, patients assigned apixaban had lower rates for all 3 outcomes across most eGFR categories without significant interaction. The absolute risk reduction with apixaban was most pronounced in those with an eGFR of 30 to 50 mL.min(-1).1.73 m(-2) for bleeding events with rates of 13.1% versus 21.3% (hazard ratio, 0.59; 95% CI, 0.41-0.84). Patients assigned aspirin had a higher risk of bleeding in all eGFR categories with an even greater increase among those with eGFR >80 mL.min(-1).1.73 m(-2): 16.6% versus 5.6% (hazard ratio, 3.22; 95% CI, 2.19-4.74; P for interaction=0.007). The risk of death or hospitalization and ischemic events were comparable to aspirin and placebo across eGFR categories with hazard ratios ranging from 0.97 (95% CI, 0.76-1.23) to 1.28 (95% CI, 1.02-1.59) and from 0.75 (95% CI, 0.48-1.17) to 1.34 (95% CI, 0.81-2.22), respectively.Conclusions: The safety and efficacy of apixaban was consistent irrespective of kidney function, compared with warfarin, and in accordance with the overall trial results. The risk of bleeding with aspirin was consistently higher across all kidney function categories.
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| 7. |
- Käll, Lukas, 1969-, et al.
(author)
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Assigning significance to peptides identified by tandem mass spectrometry using decoy databases
- 2008
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In: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 7:1, s. 29-34
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Journal article (peer-reviewed)abstract
- Automated methods for assigning peptides to observed tandem mass spectra typically return a list of peptide-spectrum matches, ranked according to an arbitrary score. In this article, we describe methods for converting these arbitrary scores into more useful statistical significance measures. These methods employ a decoy sequence database as a model of the null hypothesis, and use false discovery rate (FDR) analysis to correct for multiple testing. We first describe a simple FDR inference method and then describe how estimating and taking into account the percentage of incorrectly identified spectra in the entire data set can lead to increased statistical power.
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| 8. |
- Käll, Lukas, et al.
(author)
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Non-parametric estimation of posterior error probabilities associated with peptides identified by tandem mass spectrometry
- 2008
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In: Bioinformatics. - : Oxford University Press (OUP). - 1367-4803 .- 1367-4811. ; 24:16, s. i42-i48
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Journal article (peer-reviewed)abstract
- Motivation: A mass spectrum produced via tandem mass spectrometry can be tentatively matched to a peptide sequence via database search. Here, we address the problem of assigning a posterior error probability (PEP) to a given peptide-spectrum match (PSM). This problem is considerably more difficult than the related problem of estimating the error rate associated with a large collection of PSMs. Existing methods for estimating PEPs rely on a parametric or semiparametric model of the underlying score distribution. Results: We demonstrate how to apply non-parametric logistic regression to this problem. The method makes no explicit assumptions about the form of the underlying score distribution; instead, the method relies upon decoy PSMs, produced by searching the spectra against a decoy sequence database, to provide a model of the null score distribution. We show that our non-parametric logistic regression method produces accurate PEP estimates for six different commonly used PSM score functions. In particular, the estimates produced by our method are comparable in accuracy to those of PeptideProphet, which uses a parametric or semiparametric model designed specifically to work with SEQUEST. The advantage of the non-parametric approach is applicability and robustness to new score functions and new types of data.
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| 9. |
- Käll, Lukas, 1969-, et al.
(author)
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Posterior error probabilities and false discovery rates : two sides of the same coin
- 2008
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In: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 7:1, s. 40-44
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Journal article (peer-reviewed)abstract
- A variety of methods have been described in the literature for assigning statistical significance to peptides identified via tandem mass spectrometry. Here, we explain how two types of scores, the q-value and the posterior error probability, are related and complementary to one another.
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| 10. |
- Käll, Lukas, 1969-, et al.
(author)
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QVALITY : non-parametric estimation of q-values and posterior error probabilities
- 2009
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In: Bioinformatics. - : Oxford University Press (OUP). - 1367-4803 .- 1367-4811. ; 25:7, s. 964-966
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Journal article (peer-reviewed)abstract
- Qvality is a C++ program for estimating two types of standard statistical confidence measures: the q-value, which is an analog of the p-value that incorporates multiple testing correction, and the posterior error probability (PEP, also known as the local false discovery rate), which corresponds to the probability that a given observation is drawn from the null distribution. In computing q-values, qvality employs a standard bootstrap procedure to estimate the prior probability of a score being from the null distribution; for PEP estimation, qvality relies upon non-parametric logistic regression. Relative to other tools for estimating statistical confidence measures, qvality is unique in its ability to estimate both types of scores directly from a null distribution, without requiring the user to calculate p-values.
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| 11. |
- Lopes, Renato D., et al.
(author)
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Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation
- 2019
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In: New England Journal of Medicine. - : MASSACHUSETTS MEDICAL SOC. - 0028-4793 .- 1533-4406. ; 380:16, s. 1509-1524
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Journal article (peer-reviewed)abstract
- Background Appropriate antithrombotic regimens for patients with atrial fibrillation who have an acute coronary syndrome or have undergone percutaneous coronary intervention (PCI) are unclear. Methods In an international trial with a two-by-two factorial design, we randomly assigned patients with atrial fibrillation who had an acute coronary syndrome or had undergone PCI and were planning to take a P2Y(12) inhibitor to receive apixaban or a vitamin K antagonist and to receive aspirin or matching placebo for 6 months. The primary outcome was major or clinically relevant nonmajor bleeding. Secondary outcomes included death or hospitalization and a composite of ischemic events. Results Enrollment included 4614 patients from 33 countries. There were no significant interactions between the two randomization factors on the primary or secondary outcomes. Major or clinically relevant nonmajor bleeding was noted in 10.5% of the patients receiving apixaban, as compared with 14.7% of those receiving a vitamin K antagonist (hazard ratio, 0.69; 95% confidence interval [CI], 0.58 to 0.81; P<0.001 for both noninferiority and superiority), and in 16.1% of the patients receiving aspirin, as compared with 9.0% of those receiving placebo (hazard ratio, 1.89; 95% CI, 1.59 to 2.24; P<0.001). Patients in the apixaban group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group (23.5% vs. 27.4%; hazard ratio, 0.83; 95% CI, 0.74 to 0.93; P=0.002) and a similar incidence of ischemic events. Patients in the aspirin group had an incidence of death or hospitalization and of ischemic events that was similar to that in the placebo group. Conclusions In patients with atrial fibrillation and a recent acute coronary syndrome or PCI treated with a P2Y(12) inhibitor, an antithrombotic regimen that included apixaban, without aspirin, resulted in less bleeding and fewer hospitalizations without significant differences in the incidence of ischemic events than regimens that included a vitamin K antagonist, aspirin, or both.
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| 12. |
- Mahaffey, Kenneth W., et al.
(author)
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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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In: American Journal of Cardiology. - : Elsevier BV. - 0002-9149 .- 1879-1913. ; 113:6, s. 936-944
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Journal article (peer-reviewed)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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| 13. |
- Morales-Rosado, Joel A, et al.
(author)
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Next-Generation Sequencing of CYP2C19 in Stent Thrombosis : Implications for Clopidogrel Pharmacogenomics.
- 2020
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In: Cardiovascular Drugs and Therapy. - : Springer Science and Business Media LLC. - 0920-3206 .- 1573-7241. ; 35:3 SI, s. 549-559
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Journal article (peer-reviewed)abstract
- PURPOSE: Describe CYP2C19 sequencing results in the largest series of clopidogrel-treated cases with stent thrombosis (ST), the closest clinical phenotype to clopidogrel resistance. Evaluate the impact of CYP2C19 genetic variation detected by next-generation sequencing (NGS) with comprehensive annotation and functional studies.METHODS: Seventy ST cases on clopidogrel identified from the PLATO trial (n = 58) and Mayo Clinic biorepository (n = 12) were matched 1:1 with controls for age, race, sex, diabetes mellitus, presentation, and stent type. NGS was performed to cover the entire CYP2C19 gene. Assessment of exonic variants involved measuring in vitro protein expression levels. Intronic variants were evaluated for potential splicing motif variations.RESULTS: Poor metabolizers (n = 4) and rare CYP2C19*8, CYP2C19*15, and CYP2C19*11 alleles were identified only in ST cases. CYP2C19*17 heterozygote carriers were observed more frequently in cases (n = 29) than controls (n = 18). Functional studies of CYP2C19 exonic variants (n = 11) revealed 3 cases and only 1 control carrying a deleterious variant as determined by in vitro protein expression studies. Greater intronic variation unique to ST cases (n = 169) compared with controls (n = 84) was observed with predictions revealing 13 allele candidates that may lead to a potential disruption of splicing and a loss-of-function effect of CYP2C19 in ST cases.CONCLUSION: NGS detected CYP2C19 poor metabolizers and paradoxically greater number of so-called rapid metabolizers in ST cases. Rare deleterious exonic variation occurs in 4%, and potentially disruptive intronic alleles occur in 16% of ST cases. Additional studies are required to evaluate the role of these variants in platelet aggregation and clopidogrel metabolism.
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| 16. |
- Tricoci, Pierluigi, et al.
(author)
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Thrombin-receptor antagonist vorapaxar in acute coronary syndromes
- 2012
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In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 366:1, s. 20-33
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Journal article (peer-reviewed)abstract
- BACKGROUND:Vorapaxar is a new oral protease-activated-receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation.METHODS:In this multinational, double-blind, randomized trial, we compared vorapaxar with placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization.RESULTS:Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (Kaplan-Meier 2-year rate, 18.5% vs. 19.9%; hazard ratio, 0.92; 95% confidence interval [CI], 0.85 to 1.01; P=0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P=0.02). Rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58; P<0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (hazard ratio, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Rates of nonhemorrhagic adverse events were similar in the two groups.CONCLUSIONS:In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage. (Funded by Merck; TRACER ClinicalTrials.gov number, NCT00527943.).
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