| 461. |
- vanderPals, Jesper, et al.
(author)
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Treatment with the C5a receptor antagonist ADC-1004 reduces myocardial infarction in a porcine ischemia-reperfusion model
- 2010
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In: BMC Cardiovascular Disorders. - : Springer Science and Business Media LLC. - 1471-2261. ; 10
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Journal article (peer-reviewed)abstract
- Background: Polymorphonuclear neutrophils, stimulated by the activated complement factor C5a, have been implicated in cardiac ischemia/reperfusion injury. ADC-1004 is a competitive C5a receptor antagonist that has been shown to inhibit complement related neutrophil activation. ADC-1004 shields the neutrophils from C5a activation before they enter the reperfused area, which could be a mechanistic advantage compared to previous C5a directed reperfusion therapies. We investigated if treatment with ADC-1004, according to a clinically applicable protocol, would reduce infarct size and microvascular obstruction in a large animal myocardial infarct model. Methods: In anesthetized pigs (42-53 kg), a percutaneous coronary intervention balloon was inflated in the left anterior descending artery for 40 minutes, followed by 4 hours of reperfusion. Twenty minutes after balloon inflation the pigs were randomized to an intravenous bolus administration of ADC-1004 (175 mg, n = 8) or saline (9 mg/ml, n = 8). Area at risk (AAR) was evaluated by ex vivo SPECT. Infarct size and microvascular obstruction were evaluated by ex vivo MRI. The observers were blinded to the treatment at randomization and analysis. Results: ADC-1004 treatment reduced infarct size by 21% (ADC-1004: 58.3 +/- 3.4 vs control: 74.1 +/- 2.9% AAR, p = 0.007). Microvascular obstruction was similar between the groups (ADC-1004: 2.2 +/- 1.2 vs control: 5.3 +/- 2.5% AAR, p = 0.23). The mean plasma concentration of ADC-1004 was 83 +/- 8 nM at sacrifice. There were no significant differences between the groups with respect to heart rate, mean arterial pressure, cardiac output and blood-gas data. Conclusions: ADC-1004 treatment reduces myocardial ischemia-reperfusion injury and represents a novel treatment strategy of myocardial infarct with potential clinical applicability.
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| 462. |
- Varenhorst, Christoph, et al.
(author)
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Assessment of P2Y(12) inhibition with the point-of-care device VerifyNow P2Y12 in patients treated with prasugrel or clopidogrel coadministered with aspirin
- 2009
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In: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 157:3, s. 562.e1-9
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Journal article (peer-reviewed)abstract
- BACKGROUND: Variability in response to thienopyridines has led to the development of point-of-care devices to assess adenosine diphosphate (ADP)-induced platelet aggregation. These tests need to be evaluated in comparison to reference measurements of P2Y(12) function during different thienopyridine treatments. METHODS: After a run-in on 75 mg aspirin, 110 subjects were randomized to double-blind treatment with clopidogrel 600 mg loading dose (LD)/75 mg maintenance dose (MD) or prasugrel 60 mg LD/10 mg MD. Antiplatelet effects were evaluated by VerifyNow P2Y12 (VN-P2Y12) device (Accumetrics, San Diego, CA), vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay, and light transmission aggregometry (LTA). Prasugrel's and clopidogrel's active metabolite concentration were also determined. RESULTS: Dose- and time-dependent inhibition of P2Y(12) was evident with VN-P2Y12. There was strong correlation with VN-P2Y12 and VASP or LTA for all treatments through a wide range of P2Y(12) function. At high levels of P2Y(12) inhibition, platelet function measured by VN-P2Y12 was maximally inhibited and could not reflect further changes seen with VASP or LTA methods. Correlation was also observed between exposure to clopidogrel's active metabolite and VN-P2Y12 during MD and LD, whereas it was observed only with prasugrel MD. CONCLUSION: The VN-P2Y12 correlated strongly with inhibition of P2Y(12) function, as measured with either VASP or LTA. VN-P2Y12 also correlated to exposure to the active metabolite of prasugrel and clopidogrel up to levels associated with assumed saturation of the P2Y(12) receptor.
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| 463. |
- Varenhorst, Christoph, 1977-, et al.
(author)
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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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In: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 30:14, s. 1744-1752
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Journal article (peer-reviewed)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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| 464. |
- Varenhorst, Christoph, 1977-, et al.
(author)
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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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In: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 162:2, s. 363-371
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Journal article (peer-reviewed)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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| 465. |
- Végvári, Ákos, et al.
(author)
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Clinical and Biomedical Mass Spectrometry - New Frontiers in Drug Developments and Diagnosis
- 2013
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In: Bioinformatics of Human Proteomics. - Dordrecht : Springer Netherlands. - 9789400758117 ; Translational Bioinformatics 3, s. 169-186
-
Book chapter (peer-reviewed)abstract
- Healthcare systems today are undergoing major restructuring. From the patient’s perspective, expectations focusing on high quality treatments for most common diseases – such as cancer, cardiovascular diseases, neurodegenerative diseases, diabetes, and others – have gone unmet in most countries throughout the world. Today, a number of protein expression and analysis platforms is available, which can generate large-scale maps of proteins related to healthy and diseased states. These mass spectrometry-based technologies are used on a daily basis by thousands of research laboratories around the world. The major interest is focused on discovery and validation of novel biomarkers in various diseases, as well as on targeted proteomics where quantification of multiple protein biomarkers is achieved. We present these technological developments in relation to disease diagnosis and treatment and provide two examples where significant progress has been made.
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| 466. |
- Venetsanos, Dimitrios, et al.
(author)
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Bivalirudin versus heparin with primary percutaneous coronary intervention
- 2018
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In: American Heart Journal. - Philadelphia, United States : Mosby, Inc.. - 0002-8703 .- 1097-6744. ; 201, s. 9-16
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Journal article (peer-reviewed)abstract
- Background: Optimal adjunctive therapy in ST-segment elevation myocardial infarction (STEMI) patients treated with primary PCI (PPCI) remains a matter of debate. Our aim was to compare the efficacy and safety of bivalirudin to unfractionated heparin (UFH), with or without glycoprotein IIb/IIIa inhibitors (GPI) in a large real-world population, using data from the Swedish national registry, SWEDEHEART. Method: From 2008 to 2014 we identified 23,800 STEMI patients presenting within 12 hours from symptom onset treated with PPCI and UFH +/- GPI or bivalirudin +/- GPI. Primary outcomes included 30-day all-cause mortality and major in-hospital bleeding. Multivariable regression models and propensity score modelling were utilized to study adjusted association between treatment and outcome. Results: Treatment with UFH +/- GPI was associated with similar risk of 30-day mortality compared to bivalirudin +/- GPI (5.3% vs 5.5%, adjusted HR 0.94; 95% CI 0.82-1.07). The adjusted risk for 1-year mortality, 30-day and 1-year stent thrombosis and re-infarction did not differ significantly between UFH +/- GPI and bivalirudin +/- GPI. In contrast, treatment with UFH +/- GPI was associated with a significant higher risk of major in-hospital bleeding (adjusted OR 1.62; 95% CI 1.30-2.03). When including GPI use in the multivariable analysis, the difference was attenuated and no longer significant (adjusted OR 1.25; 95% CI 0.92-1.70). Conclusion: Bivalirudin +/- GPI was associated with significantly lower risk for major in hospital bleeding but no significant difference in 30-day or one year mortality, stent thrombosis or re-infarction compared with UFH +/- GPI. The bleeding reduction associated with bivalirudin could be explained by the greater GPI use with UFH. (C) 2018 Elsevier Inc. All rights reserved.
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| 467. |
- Venetsanos, Dimitrios, et al.
(author)
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Prasugrel versus ticagrelor in patients with myocardial infarction undergoing percutaneous coronary intervention
- 2021
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In: Heart. - : BMJ Publishing Group Ltd. - 1355-6037 .- 1468-201X. ; 107:14, s. 1145-1151
-
Journal article (peer-reviewed)abstract
- Objective: The comparative efficacy and safety of prasugrel and ticagrelor in patients with myocardial infarction (MI) treated with percutaneous coronary intervention (PCI) remain unclear. We aimed to investigate the association of treatment with clinical outcomes.Methods: In the SWEDEHEART (Swedish Web-system for enhancement and development of evidence-based care in heart disease evaluated according to recommended therapies) registry, all patients with MI treated with PCI and discharged on prasugrel or ticagrelor from 2010 to 2016 were included. Outcomes were 1-year major adverse cardiac and cerebrovascular events (MACCE, death, MI or stroke), individual components and bleeding. Multivariable adjustment, inverse probability of treatment weighting (IPTW) and propensity score matching (PSM) were used to adjust for confounders.Results: We included 37 990 patients, 2073 in the prasugrel group and 35 917 in the ticagrelor group. Patients in the prasugrel group were younger, more often admitted with ST elevation MI and more likely to have diabetes. Six to twelve months after discharge, 20% of patients in each group discontinued the P2Y12 receptor inhibitor they received at discharge. The risk for MACCE did not significantly differ between prasugrel-treated and ticagrelor-treated patients (adjusted HR 1.03, 95% CI 0.86 to 1.24). We found no significant difference in the adjusted risk for death, recurrent MI or stroke alone between the two treatments. There was no significant difference in the risk for bleeding with prasugrel versus ticagrelor (2.5% vs 3.2%, adjusted HR 0.92, 95% CI 0.69 to 1.22). IPTW and PSM analyses confirmed the results.Conclusion: In patients with MI treated with PCI, prasugrel and ticagrelor were associated with similar efficacy and safety during 1-year follow-up.
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| 468. |
- Venetsanos, Dimitrios, et al.
(author)
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Pretreatment with ticagrelor may offset additional inhibition of platelet and coagulation activation with bivalirudin compared to heparin during primary percutaneous coronary intervention
- 2018
-
In: Thrombosis Research. - : Elsevier BV. - 0049-3848 .- 1879-2472. ; 171, s. 38-44
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Journal article (peer-reviewed)abstract
- Background: It remains unknown if bivalirudin compared to heparin confers any additional inhibition of platelet and coagulation activation during primary percutaneous coronary intervention (PPCI) after pretreatment with ticagrelor. Methods: In this substudy of VALIDATE-SWEDEHEART trial, 103 patients pretreated with ticagrelor were randomized before PPCI to heparin or bivalirudin. Blood samples were collected before and 1 and 12 h after PPCI. We measured platelet reactivity (PR) using Multiplate, soluble P-selectin, thrombin-antithrombin complexes (TAT) and prothrombin fragments 1 + 2 (F1 + 2) as markers of platelet and coagulation activation. Results: The median (IQR) time from ticagrelor administration to randomization was 63 (29) vs 60 (24) minutes, p = 0.28. ADP-induced PR did not significantly differ between groups over time (heparin vs bivalirudin, AUC 73 (62) vs 74 (68), p = 0.74, 32 (42) vs 43 (51), p = 0.38, 15 (15) vs 19 (15), p = 0.29, before, 1 and 12 h after PPCI). Soluble P-selectin did not significantly differ between groups. At 1 h TAT significantly increased with bivalirudin (3.0 (1.3) to 4.3 (4.2) ug/L; p < 0.01), but not with UFH (3.1 (2.1) to 3.5 (1.6) ug/L, p = 0.24). F1 + 2 increased in both groups but the rise was numerically higher with bivalirudin (170 (85) to 213 (126) pmol/L vs 168 (118) to 191 (103) pmol/L). At 12 h, a comparable significant increase in thrombin generation was observed in both groups. Conclusion: In patients treated with ticagrelor, we found no major differences between bivalirudin and heparin in platelet aggregation or coagulation markers, which is in agreement with the neutral clinical results of the VALIDATE-SWEDEHEART study.
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| 469. |
- Venetsanos, Dimitrios, et al.
(author)
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Uninterrupted Oral Anticoagulant Therapy in Patients Undergoing Unplanned Percutaneous Coronary Intervention
- 2021
-
In: JACC. - : ELSEVIER SCIENCE INC. - 1936-8798 .- 1876-7605. ; 14:7, s. 754-763
-
Journal article (peer-reviewed)abstract
- OBJECTIVES This study sought to compare interrupted and uninterrupted oral anticoagulant therapy (I-OAC vs. U-OAC) in patients on OAC undergoing percutaneous coronary intervention. BACKGROUND There is a paucity of data regarding the optimal peri-procedural management of OAC-treated patients. METHODS In the SWEDEHEART registry, all patients on OAC who were admitted acutely and underwent percutaneous coronary intervention or coronary angiography with a diagnostic procedure, from 2005 to 2017, were included. Outcomes were major adverse cardiac and cerebrovascular events (MACCE; death, myocardial infarction, or stroke) and bleeds at 120 days. Propensity score was used to adjust for the nonrandomized treatment selection. RESULTS The study included 6,485 patients: 3,322 in the I-OAC group and 3,163 in the U-OAC group. The cumulative incidence of MACCE was 8.2% (269 events) versus 8.2% (254 events) in the I-OAC and the U-OAC groups, respectively. The adjusted risk for MACCE did not differ between the groups (I-OAC vs. U-OAC hazard ratio: 0.89; 95% confidence interval: 0.71 to 1.12). Similarly, no difference was found in the risk for MACCE or bleeds (12.6% vs. 12.9%, adjusted hazard ratio: 0.87; 95% confidence interval: 0.70 to 1.07). The risk for major or minor in-hospital bleeds did not differ between the groups. However, U-OAC was associated with a significantly shorter duration of hospitalization: 4 (3 to 7) days versus 5 (3 to 8) days; p < 0.01. CONCLUSIONS I-OAC and U-OAC were associated with equivalent risk for MACCE and bleeding complications. An U-OAC strategy was associated with shorter length of hospitalization. These data support U-OAC as the preferable strategy in patients on OAC undergoing coronary intervention. (c) 2021 by the American College of Cardiology Foundation.
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| 470. |
- von Koch, Sacharias, et al.
(author)
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Intracoronary Imaging of Proximal Coronary Artery Lesions – A Nationwide Lesion-Level Analysis From SCAAR
- 2023
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In: Journal of the Society for Cardiovascular Angiography & Interventions. - : Elsevier. - 2772-9303. ; 2:3
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Journal article (peer-reviewed)abstract
- Background: Current evidence suggests that use of intracoronary imaging during percutaneous coronary intervention (PCI) of the left main coronary artery (LMCA) reduces mortality. However, there is a scarcity of data on the overall role of intracoronary imaging, particularly in other non-LMCA proximal coronary artery lesions. We aimed to investigate the association of use of intracoronary imaging on outcome in proximal lesions treated with PCI.Methods: The Swedish Coronary Angiography and Angioplasty Registry was used to identify all proximal coronary artery lesions treated with stent implantation between June 11, 2013, and January 16, 2021. Proximal coronary artery lesions (LMCA, proximal left anterior descending artery, left circumflex artery, and right coronary artery) assessed by intracoronary imaging before and/or after stent implantation were matched to control lesions treated based on angiography alone using propensity score matching. The primary end point was target lesion revascularization with PCI, and secondary end points included all-cause mortality and definite stent thrombosis within 3 years.Results: Among the 3623 matched pairs, intracoronary imaging was associated with significantly lower risk of target lesion revascularization, 3.7% vs 4.7%; hazard ratio (HR), 0.77; 95% CI, 0.61-0.97; P = .025, and all-cause mortality, 9.1% vs 12.8%; HR, 0.70; 95% CI, 0.61-0.81; P < .001, with no difference in definite stent thrombosis.Conclusions: The use of intracoronary imaging in proximal coronary artery lesions is associated with lower rates of repeat revascularization and better survival. The results appear to be primarily driven by improved outcome of LMCA lesions. These results reinforce the role of intracoronary imaging in assessing and treating proximal coronary lesions.
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