| 1021. |
- Varenhorst, Christoph, et al.
(författare)
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Factors Contributing to the Lower Mortality With Ticagrelor Compared With Clopidogrel in Patients Undergoing Coronary Artery Bypass Surgery
- 2012
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 60:17, s. 1623-1630
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Tidskriftsartikel (refereegranskat)abstract
- Objectives This study investigated the differences in specific causes of post-coronary artery bypass graft surgery (CABG) deaths in the PLATO (Platelet Inhibition and Patient Outcomes) trial. Background In the PLATO trial, patients assigned to ticagrelor compared with clopidogrel and who underwent CABG had significantly lower total and cardiovascular mortality. Methods In the 1,261 patients with CABG performed within 7 days after stopping study drug, reviewers blinded to treatment assignment classified causes of death into subcategories of vascular and nonvascular, and specifically identified bleeding or infection events that either caused or subsequently contributed to death. Results Numerically more vascular deaths occurred in the clopidogrel versus the ticagrelor group related to myocardial infarction (14 vs. 10), heart failure (9 vs. 6), arrhythmia or sudden death (9 vs. 3), and bleeding, including hemorrhagic stroke (7 vs. 2). Clopidogrel was also associated with an excess of nonvascular deaths related to infection (8 vs. 2). Among factors directly causing or contributing to death, bleeding and infections were more common in the clopidogrel group compared with the ticagrelor group (infections: 16 vs. 6, p < 0.05, and bleeding: 27 vs. 9, p < 0.01, for clopidogrel and ticagrelor, respectively). Conclusions The mortality reduction with ticagrelor versus clopidogrel following CABG in the PLATO trial was associated with fewer deaths from cardiovascular, bleeding, and infection complications.
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| 1022. |
- Varenhorst, Christoph, 1977-, et al.
(författare)
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Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease
- 2009
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 30:14, s. 1744-1752
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Tidskriftsartikel (refereegranskat)abstract
- Aims The metabolic pathways leading to the formation of prasugrel and clopidogrel active metabolites differ. We hypothesized that decreased CYP2C19 activity affects the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. Methods and results Ninety-eight patients with coronary artery disease (CAD) taking either clopidogrel 600 mg loading dose (LD)/75 mg maintenance dose (MD) or prasugrel 60 mg LD/10 mg MD were genotyped for variation in six CYP genes. Based on CYP genotype, patients were segregated into two groups: normal function (extensive) metabolizers (EM) and reduced function metabolizers (RM). Plasma active metabolite concentrations were measured at 30 min, 1, 2, 4, and 6 h post-LD and during the MD period on Day 2, Day 14, and Day 29 at 30 min, 1, 2, and 4 h. Vasodilator-stimulated phosphoprotein (VASP) and VerifyNow P2Y12 were measured predose, 2, and 24 +/- 4 h post-LD and predose during the MD period on Day 14 +/- 3 and Day 29 +/- 3. For clopidogrel, active metabolite exposure was significantly lower (P = 0.0015) and VASP platelet reactivity index (PRI, %) and VerifyNow P2Y(12) reaction unit (PRU) values were significantly higher (P < 0.05) in the CYP2C19 RM compared with the EM group. For prasugrel, there was no statistically significant difference in active metabolite exposure or pharmacodynamic response between CYP2C19 EM and RM. Variation in the other five genes demonstrated no statistically significant differences in pharmacokinetic or pharmacodynamic responses. Conclusion Variation in the gene encoding CYP2C19 in patients with stable CAD contributes to reduced exposure to clopidogrel's active metabolite and a corresponding reduction in P2Y(12) inhibition, but has no significant influence on the response to prasugrel.
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| 1023. |
- Varenhorst, Christoph, 1977-
(författare)
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Platelet Inhibition in Coronary Artery Disease – Mechanisms and Clinical Importance : Studies with Focus on P2Y12 Inhibition
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Despite the currently recommended dual antiplatelet treatment (DAT) with aspirin and P2Y12 inhibition in patients with coronary artery disease (CAD) there is a risk of adverse clinical outcome. Pharmacodynamic (PD) poor response to clopidogrel occurs in ~ 30% of clopidogrel-treated patients and is associated with an increased risk of recurrent thrombotic events. The aims of this thesis were to compare the PD and pharmacokinetic effects of clopidogrel 600 mg loading dose (LD)/ 75 mg standard maintenance dose (MD) with the novel P2Y12 inhibitor prasugrel 60 mg LD/10 mg MD, in 110 patients with CAD. The mechanisms behind clopidogrel poor response were investigated by assessing the pharmacodynamics after adding clopidogrel active metabolite (AM) and genotyping for variation in CYP-genes involved in thienopyridine metabolism. In another study, we compared the on-clopidogrel platelet reactivity of patients with stent thrombosis (ST) (n=48) or myocardial infarction (MI) (n=30) while on DAT and their matched controls (n=50 + 28). Prasugrel achieved a faster and greater P2Y12-mediated platelet inhibition than clopidogrel measured with light transmission aggregometry, VASP and VerifyNow® P2Y12. Prasugrel’s greater platelet inhibition was associated with higher exposure of AM. The addition of clopidogrel AM led to maximal platelet inhibition in all subjects, suggesting that prasugrel’s greater antiplatelet effect was related to more efficient AM generation compared to that of clopidogrel. Lower levels of AM as well as less platelet inhibition were seen in clopidogrel-treated patients with reduced-metabolizer genotype CYP2C19 compared to those with normal genotype. Patients with ST while on DAT showed higher on-clopidogrel platelet reactivity compared to matched stented controls. Patients with spontaneous MI after stenting did not. In conclusion, these results showed a high rate PD poor response to a high bolus dose of clopidogrel because of a partly genetically caused lower generation of AM which could be overcome by prasugrel treatment. In patients after coronary stenting, clopidogrel poor response was related to ST but not to spontaneous MI, illustrating difficulties in optimizing treatment with clopidogrel based on platelet function or genetic testing in individual patients.
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| 1024. |
- Varenhorst, Christoph, 1977-, et al.
(författare)
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Relationship between Clopidogrel-Induced Platelet P2Y12 Inhibition and Stent Thrombosis or Myocardial Infarction after Percutaneous Coronary Intervention : A Case-Control Study
- 2011
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Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 162:2, s. 363-371
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Platelet inhibition levels were investigated in patients with previous angiographically confirmed stent thrombosis (ST), myocardial infarction (MI) and controls.Methods and Results: Using The Swedish Coronary Angiography and Angioplasty Registry we identified patients with angiographically confirmed ST (n=48) or MI (n=30) while on dual antiplatelet therapy within 6 months of percutaneous coronary intervention (PCI) and matched control patients (n=78) with none of these events in the same setting. On-clopidogrel platelet reactivity was measured with VerifyNow™ P2Y12 and vasodilator stimulated phosphoprotein phosphorylation (VASP-P) assay.The mean P2Y12 reaction units (PRU) was higher (246.8 ± 75.9 vs. 200.0 ± 82.7, p=0.001) in ST patients compared to controls. The optimal cut-off for ST was ≥222 PRU (area under the curve 0.69, p<0.0001) in a receiver operating characteristics (ROC) analysis, which was identical to the cut-off level defined as the proportion of controls below the 30th percentile of P2Y12 inhibition distribution in patients with ST. The cut-off level resulted in 70.2% sensitivity and 67.3% specificity. There was no significant difference in mean PRU but a higher device-reported % inhibition (45.1 ± 23.8 vs 32.1 ± 23.2, p=0.04) in patients with MI compared to controls. Results with the VASP-P assay were not related to the occurrence of ST or MI.Conclusion: Stent thrombosis was associated with high on-clopidogrel platelet reactivity measured with VerifyNow™. Spontaneous MI in stented patients on clopidogrel treatment was not. There was, however, a substantial overlap in clopidogrel platelet reactivity response between patients with and without on-treatment ST.
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| 1025. |
- Varenhorst, Christoph, 1977-, et al.
(författare)
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Stent thrombosis rates the first year and beyond with new- and old-generation drug-eluting stents compared to bare metal stents
- 2018
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Ingår i: Clinical Research in Cardiology. - : Springer. - 1861-0684 .- 1861-0692. ; 107:9, s. 816-823
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Tidskriftsartikel (refereegranskat)abstract
- Old-generation drug-eluting coronary stents (o-DES) have despite being safe and effective been associated with an increased propensity of late stent thrombosis (ST). We evaluated ST rates in o-DES, new-generation DES (n-DES) and bare metal stents (BMS) the first year (< 1 year) and beyond 1 year (> 1 year). We evaluated all implantations with BMS, o-DES (Cordis Cypher, Boston Scientific Taxus Libert, and Medtronic Endeavor) and n-DES in the Swedish coronary angiography and angioplasty registry (SCAAR) between 1 January 2007 and 8 January 2014 (n = 207 291). All cases of ST (n = 2 268) until 31 December 2014 were analyzed. The overall risk of ST was lower in both n-DES and o-DES compared with BMS up to 1 year (n-DES versus BMS: adjusted risk ratio (RR) 0.48 (0.41-0.58) and o-DES versus BMS: 0.56 (0.46-0.67), both p < 0.001). From 1 year after stent implantation and onward, the risk for ST was higher in o-DES compared with BMS [adjusted RR, 1.82 (1.47-2.25], p < 0.001). N-DES were associated with similar low ST rates as BMS from 1 year and onward [adjusted RR 1.21 (0.94-1.56), p = 0.135]. New-generation DES were associated with lower ST rates in comparison to BMS during the first-year post-stenting. After 1 year, n-DES and BMS were associated with similar ST rates. This study was a retrospective observational study and as such did not require clinical trial database registration.
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| 1026. |
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| 1027. |
- Varenhorst, Christoph, et al.
(författare)
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Timing Of Pci In Patients With Non-St-Elevation Myocardial Infarction : A Swedeheart Study
- 2016
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Ingår i: Journal of the American College of Cardiology. - Uppsala Univ, Dept Med Sci, Cardiol, Uppsala, Sweden. Uppsala Univ, Uppsala Clin Res Ctr, Uppsala, Sweden.. - 0735-1097 .- 1558-3597. ; 67:13, s. 44-44
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 1028. |
- Varenhorst, Christoph, et al.
(författare)
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Which antiplatelet agent for whom? Which patient populations benefit most from novel antiplatelet agents (ticagrelor, prasugrel)?
- 2012
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Ingår i: Current Cardiology Reports. - : Springer Science and Business Media LLC. - 1523-3782 .- 1534-3170. ; 14:4, s. 486-492
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Tidskriftsartikel (refereegranskat)abstract
- Antiplatelet treatment is a cornerstone for patients with acute coronary syndromes treated invasively or conservatively to reduce the risk of early and late occurring ischemic complications and to improve survival. Compared to clopidogrel, the novel antiplatelet agents prasugrel and ticagrelor provide faster and more consistent inhibition of platelet aggregation and result in substantially improved clinical outcome in patients with acute coronary syndromes but also an increased bleeding risk. Therefore, balancing the rope between safety and efficacy of treatment is crucial for optimizing outcome. An understanding of the similarities but also differences in pharmacological effect, clinical trial design, and outcome is crucial for understanding which patient populations benefit the most from novel antiplatelet treatments. This review provides recommendations for their optimal use.
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| 1029. |
- Veiseh, Mandana, et al.
(författare)
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Imaging of Homeostatic, Neoplastic, and Injured Tissues by HA-Based Probes
- 2012
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Ingår i: Biomacromolecules. - : American Chemical Society (ACS). - 1525-7797 .- 1526-4602. ; 13:1, s. 12-22
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Tidskriftsartikel (refereegranskat)abstract
- An increase in hyaluronan (HA) synthesis, cellular uptake, and metabolism occurs during the remodeling of tissue microenvironments following injury and during disease processes such as cancer. We hypothesized that multimodality HA-based probes selectively target and detectably accumulate at sites of high HA metabolism, thus providing a flexible imaging strategy for monitoring disease and repair processes. Kinetic analyses confirmed favorable available serum levels of the probe following intravenous (i.v.) or subcutaneous (s.c.) injection. Nuclear (technetium-HA, Tc-99m-HA, and iodine-HA, I-125-HA), optical (fluorescent Texas Red-HA, TR-HA), and magnetic resonance (gadolinium-HA, Gd-HA) probes imaged liver (Tc-99m-HA), breast cancer. cells/xenografts (TR-HA, Gd-HA), and vascular injury (I-125-HA, TR-HA). Targeting of HA probes to these sites. appeared to result from selective HA receptor-dependent localization. Our results suggest that HA-based probes, which do not require, polysaccharide backbone modification to achieve favorable half-life and distribution, can detect elevated HA metabolism in homeostatic, injured, and diseased tissues.
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| 1030. |
- Velders, Matthijs A., et al.
(författare)
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Biomarkers for risk stratification of patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention : Insights from the Platelet Inhibition and Patient Outcomes trial
- 2015
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Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 169:6, s. 879-889.e7
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Tidskriftsartikel (refereegranskat)abstract
- Background The incremental prognostic value of admission measurements of biomarkers beyond clinical characteristics and extent of coronary artery disease (CAD) in patients treated with primary percutaneous coronary intervention (PPCI) for ST-elevation myocardial infarction (STEMI) is unclear. Methods Centrally analyzed plasma for biomarker measurements was available in 5,385 of the STEMI patients treated with PPCI in the PLATO trial. Extent of CAD was graded by operators in association with PPCI. We evaluated the prognostic value of high-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and growth differentiation factor 15 (GDF-15) beyond clinical characteristics and extent of CAD using Cox proportional hazards analyses, C-index, and net reclassification improvement (NRI). Outcomes were cardiovascular death (CVD) and spontaneous myocardial infarction (MI). Results Angiographic data on extent of CAD improved the prediction of CVD compared to clinical risk factors alone, increasing the C-index from 0.760 to 0.778, total NRI of 0.31. Biomarker information provided additional prognostic value for CVD beyond clinical risk factors and extent of CAD, C-indices ranging from 0.792 to 0.795 for all biomarkers, but with a higher NRI for NT-proBNP. Extent of CAD and high-sensitivity cardiac troponin T were not associated with spontaneous MI. The prediction of spontaneous MI beyond clinical characteristics and extent of CAD (C-index 0.647) was improved by both NT-proBNP (C-index 0.663, NRI 0.22) and GDF-15 (C-index 0.652, NRI 0.05). Conclusions Biomarker measurement on admission is feasible and provides incremental risk stratification in patients with STEMI treated with PPCI, with NT-proBNP and GDF-15 being most valuable due to the association with both CVD and spontaneous MI.
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