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  • 1. Becker, Richard C.
    et al.
    Yang, Hongqiu
    Barrett, Yuchen
    Mohan, Puneet
    Wang, Jessie
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Alexander, John H.
    Chromogenic laboratory assays to measure the factor Xa-inhibiting properties of apixaban-an oral, direct and selective factor Xa inhibitor2011In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 32, no 2, p. 183-187Article in journal (Refereed)
    Abstract [en]

    An ability to readily determine an anticoagulant effect with an emerging class of direct, active site, oral factor Xa inhibitors is viewed by the medical community as attractive and by some as an absolute requirement for their use in clinical practice. We performed a pharmacokinetic and pharmacodynamic substudy in APPRAISE-1-a study of apixaban in patients with acute coronary syndrome(ACS). A total of 1691 patients had blood sampled for apixaban plasma concentrations using mass spectrometry/high performance liquid chromatography and anti-Xa activity using a chromogenic assay employing either low molecular weight heparin or apixaban as reference standards. Anti-Xa activity, determined by either anti-Xa-LMWH (r = 0.9671; P < 0.0001) or anti-Xa-apixaban (r = 0.9669; P < 0.0001) correlated strongly and in a linear fashion with apixaban plasma concentrations. The correlations for each method were equally strong at low (< 100 ng/ml) (r = 0.86, P < 0.0001; r = 0.85, P < 0.0001), intermediate(100-200 ng/ml) (r = 0.73, P < 0.0001; r = 0.69, P < 0.0001) and high (> 200 ng/ml) (r = 0.91, P < 0.0001; r = 0.91, P < 0.0001) plasma concentrations of apixaban, respectively. Our pharmacokinetic and pharmacodynamic substudy suggests that an apixaban-mediated anticoagulant effect can be detected even at very low plasma concentrations using a standard laboratory chromogenic anti-Xa assay with either LMWH or apixaban calibrators. While establishing parameters for safety and efficacy will require further investigation, an ability to discern the presence of a drug effect may provide clinically useful information.

  • 2.
    Damman, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research Center.
    Woudstra, Pier
    Kuijt, Wichert J
    de Winter, Robbert J
    James, Stefan K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research Center.
    P2Y12 platelet inhibition in clinical practice2012In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 33, no 2, p. 143-153Article in journal (Refereed)
    Abstract [en]

    Platelet adhesion, activation and aggregation play a pivotal role in atherothrombosis. Intracoronary atherothrombosis is the most common cause of the development of acute coronary syndrome (ACS), and plays a central role in complications occurring around percutaneous coronary intervention (PCI) including recurrent ACS, procedure-related myocardial infarction or stent thrombosis. Inhibition of platelet aggregation by medical treatment impairs formation and progression of thrombotic processes and is therefore of great importance in the prevention of complications after an ACS or around PCI. An essential part in the platelet activation process is the interaction of adenosine diphosphate (ADP) with the platelet P2Y12 receptor. The P2Y12 receptor is the predominant receptor involved in the ADP-stimulated activation of the glycoprotein IIb/IIIa receptor. Activation of the glycoprotein IIb/IIIa receptor results in enhanced platelet degranulation and thromboxane production, and prolonged platelet aggregation. The objectives of this review are to discuss the pharmacological limitations of the P2Y12 inhibitor clopidogrel, and describe the novel alternative P2Y12 inhibitors prasugrel and ticagrelor and the clinical implications of the introduction of these new medicines.

  • 3. Gharacholou, S. Michael
    et al.
    Lopes, Renato D.
    Washam, Jeffrey B.
    Newby, L. Kristin
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research center.
    Alexander, John H.
    Antithrombotic therapy in acute coronary syndromes: guidelines translated for the clinician2010In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 29, no 4, p. 516-528Article in journal (Refereed)
    Abstract [en]

    The use of anticoagulant and antiplatelet therapy during the management of acute coronary syndromes (ACS) has been associated with improvements in short- and long-term clinical outcomes, regardless of whether patients are managed conservatively or with acute coronary revascularization. Translating the existing evidence for selection of the most appropriate antithrombotic strategy has been summarized in available guideline recommendations. Given the breadth of antithrombotic recommendations across existing U.S. and European guidelines, synthesis of these recommendations for practicing clinicians who treat patients with ACS are increasingly desired. Providing a summary of the similarities across guidelines while noting the areas where divergence exists becomes an important facet in translating optimal antithrombotic management in ACS for the treating clinician. This review highlights the important aspects of clinical practice guidelines that practicing physicians should consider when selecting antithrombotic therapies to reduce ischemic risk while minimizing hemorrhagic risk across all ACS subtypes.

  • 4.
    Guimaraes, Patricia O.
    et al.
    Duke Clin Res Inst, Durham, NC 27705 USA.
    Lopes, Renato D.
    Duke Clin Res Inst, Durham, NC 27705 USA.
    Alexander, John H.
    Duke Clin Res Inst, Durham, NC 27705 USA.
    Thomas, Laine
    Duke Clin Res Inst, Durham, NC 27705 USA.
    Hellkamp, Anne S.
    Duke Clin Res Inst, Durham, NC 27705 USA.
    Hijazi, Ziad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Hylek, Elaine M.
    Boston Univ, Med Ctr, Boston, MA USA.
    Gersh, Bernard J.
    Mayo Clin, Coll Med, Dept Cardiovasc Med, Rochester, MN USA.
    Garcia, David A.
    Univ Washington, Sch Med, Med Ctr, Div Hematol,Dept Med, Seattle, WA 98195 USA.
    Verheugt, Freek W. A.
    Hartctr OLVG, Afdeling Cardiol, Amsterdam, Netherlands.
    Hanna, Michael
    Bristol Myers Squibb, Princeton, NJ USA.
    Flaker, Greg
    Univ Missouri, Sch Med, Columbia, MO USA.
    Vinereanu, Dragos
    Univ Med & Pharm Carol Davila, Bucharest, Romania.
    Granger, Christopher B.
    Duke Clin Res Inst, Durham, NC 27705 USA.
    International normalized ratio control and subsequent clinical outcomes in patients with atrial fibrillation using warfarin2019In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 48, no 1, p. 27-34Article in journal (Refereed)
    Abstract [en]

    We explored associations between INR measures and clinical outcomes in patients with AF using warfarin, and whether INR history predicted future INR measurements. We included patients in ARISTOTLE who were randomized to and received warfarin. Among patients who had events, we included those with ≥ 3 INR values in the 180 days prior to the event, with the most recent ≤ 60 days prior to the event, who were on warfarin at the time of event (n = 545). Non-event patients were included in the control group if they had ≥ 180 days of warfarin exposure with ≥ 3 INR measurements (n = 7259). The median (25th, 75th) number of INR values per patient was 29 (21, 38) over a median follow-up of 1.8 years. A total of 87% had at least one INR value < 1.5; 49% had at least one value > 4.0. The last INRs before events (median 14 [24, 7] days) were < 3.0 for at least 75% of patients with major bleeding and > 2.0 for half of patients with ischemic stroke. Historic time in therapeutic range (TTR) was weakly associated with future TTR (R2 = 0.212). Historic TTR ≥ 80% had limited predictive ability to discriminate future TTR ≥ 80% (C index 0.61). In patients with AF receiving warfarin, most bleeding events may not have been preventable despite careful INR control. Our findings suggest that INRs collected through routine management are not sufficiently predictive to provide reassurance about future time in therapeutic range or to prevent subsequent outcomes, and might be over-interpreted in clinical practice.

  • 5. Hamilos, Michalis
    et al.
    Muller, Olivier
    Ntalianis, Argyrios
    Trana, Catalina
    Bartunek, Jozef
    Sarno, Giovanna
    Cardiovascular Center Aalst, OLV Hospital, Aalst, Belgium.
    Mangiacapra, Fabio
    Dierickx, Karen
    Meeus, Peter
    Cuisset, Thomas
    De Bruyne, Bernard
    Wijns, William
    Barbato, Emanuele
    Relationship between peripheral arterial reactive hyperemia and residual platelet reactivity after 600 mg clopidogrel2011In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 32, no 1, p. 64-71Article in journal (Refereed)
    Abstract [en]

    Clopidogrel reduces long-term ischemic events in patients with acute coronary syndrome or stable angina (SA) undergoing percutaneous coronary intervention (PCI). Endothelial function improvement has been proposed, among other factors, for this beneficial effect of clopidogrel, but whether this might be associated to its anti-platelet action remains unclear. We tested the hypothesis that clopidogrel improvement of peripheral vascular endothelial function might be associated with inhibition of platelet aggregation. Endothelial function was evaluated before and at least 12 h after 600 mg clopidogrel in 43 SA pts undergoing elective PCI by: (a) reactive hyperemia peripheral arterial tonometry (measuring the Endoscore); (b) circulating endothelial microparticles (EMPs). Response to clopidogrel was measured with point-of-care VerifyNow P2Y12 assay and expressed as platelet reaction unit (PRU) and percent platelet inhibition (%PI). High platelet reactivity after clopidogrel was defined as PRU ≥ 240. Endothelial function improved after clopidogrel in 20 pts. Changes in Endoscore (Δ Endoscore) were significantly correlated with both PRU (r = -0.61, P < 0.001) and %PI (r = 0.57, P < 0.001). Endoscore significantly increased after clopidogrel in pts with PRU < 240 (0.38 ± 0.26 to 0.57 ± 0.33, P < 0.001), but did not in pts with PRU ≥ 240 (0.53 ± 0.31 to 0.40 ± 0.37, P = 0.12). EMPs were also significantly reduced in pts with PRU < 240 (222 [140-593] to 142 [83-371]/μl, P = 0.001), while no changes were observed in pts with PRU ≥ 240 (256 [178-531] to 388 [238-499]/μl, P = 0.55). In patients with stable coronary artery disease, a single 600 mg clopidogrel loading dose improves vascular endothelial function. This improvement is associated with optimal platelet inhibition and it is not observed in patients with post-clopidogrel high platelet reactivity.

  • 6.
    Helmersson-Karlqvist, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Karlsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Fredricsson, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Evaluation of the Alere D-dimer test for point of care testing2014In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 38, no 2, p. 250-252Article in journal (Refereed)
    Abstract [en]

    The primary care regularly sees patients that have symptoms that could be due to thromboembolic diseases. It would be valuable to be able to rule out deep venous thrombosis or pulmonary embolism using Wells score and a negative D-dimer testing already at the primary care unit. This requires a validated D-dimer assay suitable for primary care use. We compared D-dimer results obtained with the new point of care analyzer Alere Triage(®) and the central hospital laboratory STA-R Evolution analyzer from the same patient samples (n = 102). We also calculated the total coefficient of variation (CV) for the Alere method. The two methods showed a good linear correlation (R(2) = 0.977) and a slope of 0.975. CV for the Alere D-dimer method was well below 10 %. The study shows that the Alere D-dimer assay and the central laboratory standard assay show similar results. We suggest that the Alere D-dimer assay could be used in primary care in combination with Wells score to reduce referrals to the emergency unit.

  • 7. Lindh, Jonatan D
    et al.
    Holm, Lennart
    Dahl, Marja-Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Alfredsson, Lars
    Rane, Anders
    Incidence and predictors of severe bleeding during warfarin treatment2008In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 25, no 2, p. 151-159Article in journal (Refereed)
    Abstract [en]

    Background Optimal warfarin prescription requires correct, individualized assessment of the warfarin-related bleeding risk, which randomised controlled trials may underestimate . Observational studies have reported a range of bleeding risks that differ 40-fold. This variation may be caused by time trends, variation in bleeding definition and study subject selection. We investigated the incidence of, and risk factors for severe bleeding in un-selected warfarin-treated patients from Sweden. Methods Between 2001 and 2005, 40 centres recruited warfarin-naive patients commencing warfarin therapy and followed them prospectively with continuous registration of clinical data. The primary outcome was severe bleeding, according to the WHO universal definition of severe adverse drug reactions. The influence of potential risk factors was investigated by means of a Cox proportional-hazards model. Result A total of 1523 patients contributed 1276 warfarin-exposed patient-years. The incidence of first-time severe bleeding was 2.3 per 100 patient-years (95% confidence interval 1.4 to 3.1). Male sex and use of drugs potentially interacting with warfarin were the only independent risk factors of severe bleeding, with hazard ratios of 2.8 and 2.3, respectively. Age, target International Normalized Ratio (INR), time spent outside target INR range, and warfarin dose requirement were not significantly associated with bleeding risk. Conclusions The risk of severe bleeding in a large naturalistic, prospective cohort of first-time warfarin users was lower than reported in some previous reports. Male gender was an independent predictor of severe bleeding as was the receipt of warfarin-interacting medications at the onset of anticoagulation therapy. Further studies are required to evaluate the effect these findings may have on the quality of current risk-benefit analysis involved in warfarin prescription.

  • 8. Lopes, Renato D.
    et al.
    Becker, Richard C.
    Alexander, John H.
    Armstrong, Paul W.
    Califf, Robert M.
    Chan, Mark Y.
    Crowther, Mark
    Granger, Christopher B.
    Harrington, Robert A.
    Hylek, Elaine M.
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jolicoeur, E. Marc
    Mahaffey, Kenneth W.
    Newby, L. Kristin
    Peterson, Eric D.
    Pieper, Karen S.
    Van de Werf, Frans
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    White, Harvey D.
    Carvalho, Antonio C.
    Giraldez, Roberto R.
    Guimaraes, Helio P.
    Nader, Helena B.
    Kalil, Renato A. K.
    Bizzachi, Joyce M. A.
    Lopes, Antonio C.
    Garcia, David A.
    Highlights from the III International Symposium of Thrombosis and Anticoagulation (ISTA), October 14-16, 2010, Sao Paulo, Brazil2011In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 32, no 2, p. 242-266Article in journal (Refereed)
    Abstract [en]

    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.

  • 9.
    Lowenstern, Angela
    et al.
    Duke Univ, Med Ctr, Duke Clin Res Inst, DUMC Box 2845, Durham, NC 27710 USA..
    Storey, Robert F.
    Univ Sheffield, Dept Infect Immun & Cardiovasc Dis, Sheffield, S Yorkshire, England..
    Neely, Megan
    Duke Univ, Med Ctr, Duke Clin Res Inst, DUMC Box 2845, Durham, NC 27710 USA..
    Sun, Jie-Lena
    Duke Univ, Med Ctr, Duke Clin Res Inst, DUMC Box 2845, Durham, NC 27710 USA..
    Angiolillo, Dominick J.
    Univ Florida, Coll Med Jacksonville, Div Cardiol, Jacksonville, FL USA..
    Cannon, Christopher P.
    Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA..
    Himmelmann, Anders
    AstraZeneca Res & Dev, Gothenburg, Sweden..
    Huber, Kurt
    Wilhelminen Hosp, Dept Med Cardiol & Intens Care 3, Vienna, Austria.;Sigmund Freud Private Univ, Sch Med, Vienna, Austria..
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Katus, Hugo A.
    Univ Klinikum Heidelberg, Med Klin, Heidelberg, Germany..
    Morais, Joao
    Leiria Hosp Ctr, Leiria, Portugal..
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Steg, Phillippe Gabriel
    Hop Bichat Claude Bernard, AP HP, Dept Hosp Univ FIRE, Paris, France.;Paris Diderot Univ, Sorbonne Paris Cite, Paris, France.;NHLI Imperial Coll, ICMS, Royal Brompton Hosp, London, England.;FACT, INSERM, U1148, Paris, France..
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Becker, Richard C.
    Univ Cincinnati, Coll Med, Heart Lung & Vasc Inst, Div Cardiovasc Hlth & Dis, Cincinnati, OH USA..
    Platelet-related biomarkers and their response to inhibition with aspirin and p2y12-receptor antagonists in patients with acute coronary syndrome2017In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 44, no 2, p. 145-153Article in journal (Refereed)
    Abstract [en]

    The PLATelet inhibition and patient Outcomes (PLATO) trial showed that treatment with ticagrelor reduced the rate of death due to vascular causes, myocardial infarction and stroke when compared to clopidogrel in patients with ST-elevation or non-ST-elevation acute coronary syndrome (ACS). While the comparative benefit of ticagrelor over clopidogrel increased over time, event rates accrued in both groups during the study period. The purpose of our biomarker-based exploratory analysis was to determine whether long-term platelet inhibition may be associated with platelet adaptation. A sample of 4000 participants from the PLATO trial also consented to participate in a prospectively designed biomarker substudy. Blood samples were procured at baseline, immediately prior to hospital discharge and at 1 and 6 months. Markers of platelet activity, including platelet count, serum CD40-ligand and soluble P-selectin were analyzed. Mean levels were compared at discharge, 1 and 6 months following study drug initiation-first for all patients and subsequently stratified by treatment group. A linear mixed model was used to estimate the short-term change rate (baseline to 1 month) and long-term change rate (1-6 months) for each biomarker. A Cox proportional hazards model was used to calculate hazard ratios for each change in biomarker over the two time periods examined: baseline to 1 month and 1 to 6 months. Prior to randomized treatment (baseline), sCD40 ligand and sP-selectin levels were elevated above the normal range of the assay (0.39 and 33.5 A μg/L, respectively). The mean level of each biomarker was significantly different at 1 month compared to baseline (p < 0.0001). When stratified by treatment group, at 1 month patients treated with ticagrelor had a larger increase in platelet count compared to those treated with clopidogrel (p < 0.0001). Similarly, when comparing biomarker levels for all patients at 6 months with those at 1 month, each differed significantly (p < 0.05). There was no significant difference between treatment groups during this time period. The rate of change for both platelet count and sP-selectin were significantly different between baseline and 1 month when compared to the 1 to 6-month time period (p < 0.0001). When comparing treatment groups, the rate of increase in platelets from baseline to 1 month was greater for patients treated with ticagrelor (p < 0.0001). This was no longer observed in the 1 to 6-month interval. Using a Cox proportional hazard model, the increase in platelet count from 1 to 6 months was associated with ischemic-thrombotic events, while sCD40 ligand decrease from 1 to 6 months was associated with hemorrhagic events. There were no differences between treatment groups for the associations with clinical endpoints. Dynamic changes in platelet count, sCD-40 ligand and sP-selectin occur over time among patients with ACS. Platelet-directed therapy with a P2Y12 receptor inhibitor in combination with aspirin modestly impacts the expression of these biomarkers. Platelet count and sCD40 ligand may offer modest overall predictive value for future ischemic-thrombotic or hemorrhagic clinical events, respectively. The existence of a platelet adaptome and its overall clinical significance among patients at risk for thrombotic events will require a more in-depth and platelet-biology specific investigation.

  • 10. Lubenow, Norbert
    et al.
    Greinacher, A
    Management of patients with heparin-induced thrombocytopenia: focus on recombinant hirudin.2000In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 10 Suppl 1, p. 47-57Article in journal (Refereed)
  • 11.
    Sandén, Per
    et al.
    Umea Univ, Dept Publ Hlth & Clin Med, Sundsvall, Sweden..
    Renlund, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Svensson, Peter J.
    Lund Univ, Dept Coagulat Disorders, Malmo, Sweden..
    Sjalander, Anders
    Umea Univ, Dept Publ Hlth & Clin Med, Sundsvall, Sweden..
    Bleeding complications in venous thrombosis patients on well-managed warfarin2016In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 41, no 2, p. 351-358Article in journal (Refereed)
    Abstract [en]

    Anticoagulation treatment is effective in preventing both death and recurrence in patients with venous thromboembolism (VTE), but at the same time confers a substantial risk of bleeding complications. The aim of this study was to examine the rate of and predictors for bleeding complications in VTE patients on warfarin with high treatment quality. In total 13,859 patients on warfarin for VTE between January 1st 2006 and December 31th 2011 were retrieved from the national quality register Auricula. The cohort was matched with the Swedish National Patient Register for complications and background characteristics, the Cause of Death Register for date and cause of death and the Swedish Prescribed Drug Register for retrieved medication. The rate of major bleeding was 2.36 per 100 treatment years, increasing with age from 1.25 to 4.33 for those under 60 or over 80 years of age, respectively. Factors found to independently increase the risk of bleeding complications were increasing age HR 1.02, cardiac failure HR 1.39, Chronic pulmonary disease HR 1.41, alcohol abuse HR 3.33, anaemia HR 1.75, hypertension HR 1.29 and a history of major bleeding HR 1.69. Warfarin as treatment for VTE is safe with a low rate of bleeding complications at least for the younger patient. In an era of NOAK, warfarin has a comparable safety profile among VTE patients and is still a valid treatment option.

  • 12. Toss, Henrik
    et al.
    Ernofsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    No Prognostic Importance of Resistance to Activated Protein C in Unstable Coronary Artery Disease Despite Signs of Thrombin Activation1998In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 5, no 1, p. 3-7Article in journal (Refereed)
    Abstract [en]

    Resistance to activated protein C (APC resistance) is the single most important hemostatic defect associated with venous thromboembolic disease. However, little is. Known about this defect in arterial disease. The aim of this study was thus to investigate the frequency and prognostic importance of APC resistance and its influence on the coagulation system in one type of arterial thrombosis. In this study, 323 patients admitted to hospital because of unstable coronary artery disease, that is, unstable angina pectoris or non-Q-wave myocardial infarction, were investigated and compared with a reference group of apparently healthy individuals. The patients participated in a prospective, multicenter, randomized, and placebo-controlled investigation evaluating the protective value of low molecular weight heparin (dalteparin) in unstable coronary artery disease. The APC ratio was assayed using a modified activated partial thromboplastin time reaction method to measure the response to activated protein C. APC resistance was defined as an APC ratio </=2.2. Signs of thrombin activation were measured by prothrombin fragment 1+2 levels. The 7.2% (23/318) occurrence of APC resistance found in patients did not differ from the 5.8% (4/69) level in the reference population (P = 0.16). A significant elevation of the prothrombin fragment 1+2 median level of 2.5 nM (interquartile range, 1.9-3.2 nM) was found in the patients with APC resistance compared with 1.7 nM (interquartile range, 1.2-2.4nM) in the group with a normal APC ratio (P < 0.01). During the 150-day follow-up period, there was no increased risk of cardiac events in patients with APC resistance. Although accompanied by signs of increased thrombin formation, APC resistance doesnot seem to be an important risk factor for the development of instability in coronary artery disease.

  • 13. van Diepen, Sean
    et al.
    Roe, Matthew T.
    Lopes, Renato D.
    Stebbins, Amanda
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Newby, L. Kristin
    Moliterno, David J.
    Neumann, Franz-Josef
    Ezekowitz, Justin A.
    Mahaffey, Kenneth W.
    Hochman, Judith S.
    Hamm, Christian W.
    Armstrong, Paul W.
    Theroux, Pierre
    Granger, Christopher B.
    Baseline NT-proBNP and biomarkers of inflammation and necrosis in patients with ST-segment elevation myocardial infarction: insights from the APEX-AMI trial2012In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 34, no 1, p. 106-113Article in journal (Refereed)
    Abstract [en]

    Coronary plaque rupture is associated with a systemic inflammatory response. The relationship between baseline N-terminal pro B-type natriuretic peptide (NT-proBNP), a prognostic marker in patients with acute coronary syndromes, and systemic inflammatory mediators in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI) is not well described. Of 5,745 STEMI patients treated with primary PCI in the APEX-AMI trial, we evaluated the relationship between baseline NT-proBNP levels and baseline levels of inflammatory markers and markers of myonecrosis in a subset of 772 who were enrolled in a biomarker substudy. Spearman correlations (r (s)) were calculated between baseline NT-proBNP levels and a panel of ten systemic inflammatory biomarkers. Interleukin (IL)-6, a pro-inflammatory cytokine, was significantly positively correlated with NT-proBNP (r (s) = 0.317, P < 0.001). In a sensitivity analysis excluding all heart failure patients, the correlation between baseline IL-6 and NT-proBNP remained significant (n = 651, r (s) = 0.296, P < 0.001). A positive association was also observed with high sensitivity C-reactive protein (r (s) = 0.377, P < 0.001) and there was a weak negative correlation with the anti-inflammatory cytokine IL-10 (r (s) = -0.109, P = 0.003). No other significant correlations were observed among the other testes inflammatory cytokines and chemokines. In STEMI patients undergoing primary PCI, the pro-inflammatory cytokine IL-6 was modestly correlated with baseline NT-proBNP levels. This relationship remained significant in patients without heart failure. This finding is consistent with pre-clinical and clinical research suggesting that systemic inflammation may influence NT-proBNP expression independently of myocardial stretch.

  • 14. Wagner, Henrik
    et al.
    Angiolillo, Dominick J.
    ten Berg, Jurrien M.
    Bergmeijer, Thomas O.
    Jakubowski, Joseph A.
    Small, David S.
    Moser, Brian A.
    Zhou, Chunmei
    Brown, Patricia
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Winters, Kenneth J.
    Erlinge, David
    Higher body weight patients on clopidogrel maintenance therapy have lower active metabolite concentrations, lower levels of platelet inhibition, and higher rates of poor responders than low body weight patients2014In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 38, no 2, p. 127-136Article in journal (Refereed)
    Abstract [en]

    Body weight is a predictor of clopidogrel response. However, no prospective studies have compared pharmacodynamic (PD) and pharmacokinetic (PK) data based on body weight. We compared PD and PK effects of clopidogrel 75 mg in low body weight (LBW, <60 kg) and higher body weight (HBW, >= 60 kg) patients with stable coronary artery disease. LBW (n = 34, 56.4 +/- 3.7 kg) and HBW (n = 38, 84.7 +/- 14.9 kg) aspirin-treated patients received clopidogrel 75 mg for 10-14 days. The area under the concentration-time curve of active metabolite (Clop-AM) calculated through the last quantifiable concentration up to 4 h postdose, AUC((0-tlast)), was calculated by non-compartmental methods. Light transmission aggregometry (LTA) (maximum platelet aggregation and inhibition of platelet aggregation to 20 mu M adenosine diphosphate (ADP), and residual platelet aggregation to 5 mu M ADP), VerifyNow (R) P2Y12 reaction units (PRU), and vasodilator-associated stimulated phosphoprotein phosphorylation platelet reactivity index (VASP-PRI) were performed. Mean AUC((0-tlast)) was lower in HBW than LBW patients: 12.8 versus 17.9 ng h/mL. HBW patients had higher platelet reactivity as measured by LTA (all p <= 0.01), PRU (207 +/- 68 vs. 152 +/- 57, p < 0.001), and VASP-PRI (56 +/- 18 vs. 39 +/- 17, p < 0.001). More HBW patients exhibited high on-treatment platelet reactivity (HPR) using PRU (35 vs. 9 %) and VASP-PRI (65 vs. 27 %). Body weight correlated with PRU and VASP-PRI (both p < 0.001), and inversely with log transformed AUC((0-tlast)) (p < 0.001). In conclusion, HBW patients had lower levels of Clop-AM, and higher platelet reactivity and rates of HPR than LBW subjects, contributing to their suboptimal response to clopidogrel.

  • 15.
    Washam, Jeffrey B.
    et al.
    Duke Univ, Sch Med, Duke Clin Res Inst, Duke Heart Ctr, Box 3943 DUMC, Durham, NC 27710 USA.
    Hohnloser, Stefan H.
    Goethe Univ Frankfurt, Frankfurt, Germany.
    Lopes, Renato D.
    Duke Univ, Sch Med, Duke Clin Res Inst, Duke Heart Ctr, Box 3943 DUMC, Durham, NC 27710 USA.
    Wojdyla, Daniel M.
    Duke Univ, Sch Med, Duke Clin Res Inst, Duke Heart Ctr, Box 3943 DUMC, Durham, NC 27710 USA.
    Vinereanu, Dragos
    Univ & Emergency Hosp Bucharest, Bucharest, Romania.
    Alexander, John H.
    Duke Univ, Sch Med, Duke Clin Res Inst, Duke Heart Ctr, Box 3943 DUMC, Durham, NC 27710 USA.
    Gersh, Bernard J.
    Mayo Clin, Coll Med, Rochester, MN USA.
    Hanna, Michael
    Bristol Myers Squibb Co, Princeton, NJ USA.
    Horowitz, John
    Univ Adelaide, Basil Hetzel Inst, Queen Elizabeth Hosp, Adelaide, SA, Australia.
    Hylek, Elaine M.
    Boston Univ, Sch Med, Boston, MA 02118 USA.
    Xavier, Denis
    St Johns Res Inst, Bengaluru, India.
    Verheugt, Freek W. A.
    Univ Med Ctr Nijmegen, Nijmegen, Netherlands.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Granger, Christopher B.
    Duke Univ, Sch Med, Duke Clin Res Inst, Duke Heart Ctr, Box 3943 DUMC, Durham, NC 27710 USA.
    Interacting medication use and the treatment effects of apixaban versus warfarin: results from the ARISTOTLE Trial2019In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 47, no 3, p. 345-352Article in journal (Refereed)
    Abstract [en]

    Warfarin is dependent on multiple hepatic enzymes for metabolism while apixaban is a substrate for P-glycoprotein (P-gp) transport and hepatic CYP3A4 metabolism. The aim of this analysis was to assess the impact of interacting medication use on the treatment effects of apixaban versus warfarin. Outcomes were compared between apixaban and warfarin using Cox proportional hazards modeling according to the use of interacting medications at randomization in ARISTOTLE (n=18,201). Interacting medications for apixaban were identified as combined P-gp and 3A4 inhibitors or inducers while interacting medications for warfarin were defined as those highly probable for warfarin potentiation or inhibition. At randomization, 5547 (30.5%) patients were on an interacting medication, including 2722 on apixaban and 2825 on warfarin. Patients using an interacting medication were more likely to be female, taking aspirin, and have a history of prior bleeding and were less likely to have a prior stroke or transient ischemic attack. No significant differences were observed on the treatment effect of apixaban compared with warfarin in patients on and off interacting medications for outcomes including the primary efficacy outcome of stroke or systemic embolism (P for interaction=0.79) or the primary safety outcome of major bleeding (P for interaction=0.75). Use of interacting medications with anticoagulants occurs often in patients with atrial fibrillation. Despite the potential for altered exposure, interacting medication use was not associated with a significant change in the efficacy or safety of apixaban compared with warfarin in the ARISTOTLE trial.Trial registration ClinicalTrials.gov, NCT00412984

  • 16. Yeo, Leonard L L
    et al.
    Andersson, Tommy
    Yee, Kong Wan
    Tan, Benjamin Y Q
    Paliwal, Prakash
    Gopinathan, Anil
    Nadarajah, Mahendran
    Ting, Eric
    Teoh, Hock L
    Cherian, Robin
    Lundström, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Tay, Edgar L W
    Sharma, Vijay K
    Synchronous cardiocerebral infarction in the era of endovascular therapy: which to treat first?2017In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 44, no 1, p. 104-111Article in journal (Refereed)
    Abstract [en]

    A cardiocerebral ischemic attack (CCI) or a concurrent acute ischemic stroke (AIS) and myocardial infarction (AMI) is a severe event with no clear recommendations for ideal management because of the rarity of the scenario. The narrow time window for treatment and complexity of the treatment decision puts immense pressure on the treating physician. We evaluated this challenging situation at our tertiary center. Using our prospective stroke database out of a total of 555 patients with acute ischemic stroke between 2009 and 2014, we identified five consecutive cases with CCI (incidence 0.009%). Demography, risk factor characteristics, vascular occlusions and treatment approach were recorded. Good functional outcome was defined by the modified Rankin scale (mRS) score of 0-2 points. Out of five patients, AIS was treated with endovascular treatment in three cases, while two were treated with intravenous thrombolysis only. One out of three patients had embolectomy of the brain performed prior to the coronary intervention, while the other two patients underwent coronary intervention first. One patient developed sudden cardiac arrest on day-2 and passed away. CCI is an uncommon and devastating clinical scenario, further research is needed for the ideal management strategy that provides the best outcomes. However, the rarity of the disease does not lend itself to the conduct of a trial easily. We have proposed a considered treatment algorithm based on the current literature and our experience.

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