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  • 1. Andersson, B
    et al.
    Blomström-Lundqvist, C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hedner, T
    Waagstein, F
    Exercise hemodynamics and myocardial metabolism during long-term beta-adrenergic blockade in severe heart failure1991In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 18, no 4, p. 1059-1066Article in journal (Refereed)
    Abstract [en]

    Hemodynamics and myocardial metabolism at rest and during exercise were investigated in 21 patients with heart failure. The patients were evaluated before and after long-term treatment (14 +/- 7 months) with the beta-adrenergic blocking agent metoprolol. Clinical improvement with increased functional capacity occurred during treatment. Maximal work load increased by 25% (104 to 130 W; p less than 0.001). Hemodynamic data showed an increased cardiac index (3.8 to 4.6 liters/min per m2; p less than 0.02) during exercise. Pulmonary capillary wedge pressure decreased at rest (20 to 13 mm Hg; p less than 0.01) and during exercise (32 to 28 mm Hg; p = NS). Stroke volume index (30 to 39 g.m/m2; p less than 0.006) and stroke work index (28 to 46 g.m/m2; p less than 0.006) increased during exercise and long-term metoprolol treatment. The arterial norepinephrine concentration decreased at rest (3.72 to 2.19 nmol/liter; p less than 0.02) but not during exercise (13.2 to 11.1 nmol/liter; p = NS). The arterial-coronary sinus norepinephrine difference suggested a decrease in myocardial spillover during metoprolol treatment (-0.28 to -0.13 nmol/liter; p = NS at rest and -1.13 to -0.27 nmol/liter; p less than 0.05 during exercise). Coronary sinus blood flow was unchanged during treatment. Four patients produced myocardial lactate before the study, but none produced lactate after beta-blockade (p less than 0.05). There was no obvious improvement in a subgroup of patients with ischemic cardiomyopathy. In summary, there were signs of increased myocardial work load without higher metabolic costs after treatment with metoprolol.

  • 2. Bansilal, Sameer
    et al.
    Wiviott, Stephen
    Becker, Richard
    Harrington, Robert
    Himmelmann, Anders
    Neely, Benjamin
    Husted, Steen
    Storey, Robert
    Steg, Philippe
    Katus, Hugo
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Cannon, Christopher
    The efficacy and safety of ticagrelor as compared to clopidogrel, with and without a glycoprotein iib/iia inhibitor in patients with acute coronary syndromes undergoing percutaneous intervention: a PLATO (study of platelet inhibition and patient outcomes) analysis2013In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 61, no 10, p. E1858-E1858Article in journal (Other academic)
  • 3.
    Baron, Tomasz
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Orndahl, Lovisa Holm
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Kero, Tanja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Bjerner, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Hedin, Eva-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Ståhle, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Flachskampf, Frank
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Volumetric quantification of regurgitant volume in asymptomatic severe degenerative mitral regurgitation by echocardiography and cardiac mri with independent validation of forward stroke volume by positron emission tomography2017In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 69, no 11 Suppl, p. 1973-1973Article in journal (Other academic)
  • 4.
    Batra, Gorav
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Friberg, Leif
    Department of Clinical Sciences, Danderyd Hospital, Stockholm, Sweden.
    Erlinge, David
    Kardiologi, Lunds universitet, Sweden.
    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.
    Jernberg, Tomas
    Institutionen för medicinsk epidemiologi och biostatistik (MEB), Karolinska Institutet, Stockholm, Sweden..
    Svennblad, Bodil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wallentin, Lars
    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.
    Oldgren, Jonas
    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.
    Antithrombotic Medication And Outcomes After Myocardial Infarction In Patients With Atrial Fibrillation Not Undergoing Percutaneous Coronary Intervention2015In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 65, no 10, p. A207-A207Article in journal (Other academic)
  • 5.
    Batra, Gorav
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Friberg, Leif
    Department of Clinical Sciences, Danderyd Hospital, Stockholm, Sweden.
    Erlinge, David
    Kardiologi, Lunds universitet, Sweden.
    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.
    Jernberg, Tomas
    Institutionen för medicinsk epidemiologi och biostatistik (MEB), Karolinska Institutet, Stockholm, Sweden..
    Svennblad, Bodil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wallentin, Lars
    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.
    Oldgren, Jonas
    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.
    Outcome In Relation To Antithrombotic Therapy After Myocardial Infarction And Percutaneous Coronary Intervention In Patients With Atrial Fibrillation2015In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 65, no 10, p. A16-A16Article in journal (Other academic)
  • 6. Bax, Jeroen J
    et al.
    Casadei, Barbara
    Di Mario, Carlo
    Fagard, Robert
    Filippatos, Gerasimos
    Fox, Keith A
    Metra, Marco
    Nihoyannopoulos, Petros
    Perk, Joep
    University of Kalmar, School of Human Sciences.
    Rademakers, Frank
    Rosenhek, Raphael
    Vardas, Panos E
    Pinto, Fausto J
    Ferrari, Roberto
    Highlights of the 2009 scientific sessions of the European Society of Cardiology (Open Access)2009In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 54, no 25, p. 2447-2458Article in journal (Refereed)
  • 7.
    Bilchick, Kenneth C.
    et al.
    University of Virginia Health Syst, VA USA.
    Wang, Yongfei
    Yale New Haven Medical Centre, CT 06504 USA; Yale University, CT USA.
    Cheng, Alan
    Johns Hopkins Medical Institute, MD 21205 USA.
    Curtis, Jeptha P.
    Yale New Haven Medical Centre, CT 06504 USA; Yale University, CT USA.
    Dharmarajan, Kumar
    Yale New Haven Medical Centre, CT 06504 USA; Yale University, CT USA.
    Stukenborg, George J.
    University of Virginia, VA USA.
    Shadman, Ramin
    Southern Calif Permanente Medical Grp, CA USA.
    Anand, Inder
    University of Minnesota, MN USA.
    Lund, Lars H.
    Karolinska University Hospital, Sweden.
    Dahlström, Ulf
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Sartipy, Ulrik
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Maggioni, Aldo
    Italian Assoc Hospital Cardiologists, Italy.
    Swedberg, Karl
    University of Gothenburg, Sweden; Imperial Coll, England.
    OConner, Chris
    Inova Healthcare Syst, VA USA.
    Levy, Wayne C.
    University of Washington, WA USA.
    Seattle Heart Failure and Proportional Risk Models Predict Benefit From Implantable Cardioverter-Defibrillators2017In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 69, no 21, p. 2606-2618Article in journal (Refereed)
    Abstract [en]

    BACKGROUND Recent clinical trials highlight the need for better models to identify patients at higher risk of sudden death. OBJECTIVES The authors hypothesized that the Seattle Heart Failure Model (SHFM) for overall survival and the Seattle Proportional Risk Model (SPRM) for proportional risk of sudden death, including death from ventricular arrhythmias, would predict the survival benefit with an implantable cardioverter-defibrillator (ICD). METHODS Patients with primary prevention ICDs from the National Cardiovascular Data Registry (NCDR) were compared with control patients with heart failure (HF) without ICDs with respect to 5-year survival using multivariable Cox proportional hazards regression. RESULTS Among 98,846 patients with HF (87,914 with ICDs and 10,932 without ICDs), the SHFM was strongly associated with all-cause mortality (p amp;lt; 0.0001). The ICD-SPRM interaction was significant (p amp;lt; 0.0001), such that SPRM quintile 5 patients had approximately twice the reduction in mortality with the ICD versus SPRM quintile 1 patients (adjusted hazard ratios [HR]: 0.602; 95% confidence interval [CI]: 0.537 to 0.675 vs. 0.793; 95% CI: 0.736 to 0.855, respectively). Among patients with SHFM-predicted annual mortality amp;lt;= 5.7%, those with a SPRM-predicted risk of sudden death below the median had no reduction in mortality with the ICD (adjusted ICD HR: 0.921; 95% CI: 0.787 to 1.08; p = 0.31), whereas those with SPRM above the median derived the greatest benefit (adjusted HR: 0.599; 95% CI: 0.530 to 0.677; p amp;lt; 0.0001). CONCLUSIONS The SHFM predicted all-cause mortality in a large cohort with and without ICDs, and the SPRM discriminated and calibrated the potential ICD benefit. Together, the models identified patients less likely to derive a survival benefit from primary prevention ICDs. (J Am Coll Cardiol 2017;69:2606-18) (C) 2017 by the American College of Cardiology Foundation.

  • 8. Bjurman, Christian
    et al.
    Larsson, Mårten
    Johanson, Per
    Petzold, Max
    Lindahl, Bertil
    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.
    Fu, Michael Lx
    Hammarsten, Ola
    Small changes in Troponin T levels are common in patients with non-ST-elevation myocardial infarction and are linked to higher mortality2013In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 62, no 14, p. 1231-1238Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    To examine the extent of change in Troponin T levels in patients with non-ST-elevation myocardial infarction (NSTEMI).

    BACKGROUND:

    Changes in cardiac troponin levels are required for the diagnosis of NSTEMI, according to the new universal definition of acute myocardial infarction. A relative change of 20-230 % and an absolute change of 7- 9 ng/L have been suggested as cut-off points.

    METHOD:

    In a clinical setting, where a change in cTnT was not mandatory for the diagnosis of NSTEMI, serial samples of cTnT were measured with a high-sensitive cTnT (hs-cTnT) assay, and 37 clinical parameters were evaluated in 1178 patients with a final diagnosis of NSTEMI presenting <24h after symptom onset.

    RESULTS:

    After six hours of observation, the relative change in the hs-cTnT level remained <20 % in 26 % and the absolute change <9 ng/L in 12 % of the NSTEMI patients. A relative hs-cTnT change <20% was linked to higher long-term mortality across quartiles (p=0.002) and in multivariate analyses (HR 1.61 (1.17-2.21) p=0.004), whereas 30-day mortality was similar across quartiles of relative hs-cTnT change

    CONCLUSION:

    Because stable hs-TnT levels are common in patients with a clinical diagnosis of NSTEMI in our hospital, a small hs-cTnT change may not be useful to exclude NSTEMI, particularly as these patients show both short-term and long-term mortality at least as high as patients with large changes in hs-cTnT.

  • 9. Boehm, Michael
    et al.
    Ezekowitz, Michael D.
    Connolly, Stuart J.
    Eikelboom, John W.
    Hohnloser, Stefan H.
    Reilly, Paul A.
    Schumacher, Helmut
    Brueckmann, Martina
    Schirmer, Stephan H.
    Kratz, Mario T.
    Yusuf, Salim
    Diener, Hans-Christoph
    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.
    Wallentin, Lars
    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.
    Changes in Renal Function in Patients With Atrial Fibrillation An Analysis From the RE-LY Trial2015In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 65, no 23, p. 2481-2493Article in journal (Refereed)
    Abstract [en]

    BACKGROUND Vitamin K-dependent factors protect against vascular and renovascular calcification, and vitamin K antagonists may be associated with a decreased glomerular filtration rate (GFR). OBJECTIVES This study analyzed changes in GFR during long-term treatment with warfarin or dabigatran etexilate (DE) in patients enrolled in the RE-LY (Randomized Evaluation of Long Term Anticoagulation Therapy) trial. METHODS Of the 18,113 patients in the RE-LY study randomized to receive DE (110 mg or 150 mg twice daily) or warfarin, 16,490 patients with atrial fibrillation had creatinine values measured at baseline and at least 1 follow-up visit. Changes in GFR for up to 30 months were evaluated. RESULTS GFR declined in all treatment groups. After an average of 30 months, the mean +/- SE decline in GFR was significantly greater with warfarin (-3.68 +/- 0.24 ml/min) compared with DE 110 mg (-2.57 +/- 0.24 ml/min; p = 0.0009 vs. warfarin) and DE 150 mg (-2.46 +/- 0.23 ml/min; p = 0.0002 vs. warfarin). A decrease in GFR >25% was less likely with DE 110 mg (hazard ratio: 0.81 [95% confidence interval: 0.69 to 0.96]; p = 0.017) or DE 150 mg (hazard ratio: 0.79 [95% confidence interval: 0.68 to 0.93]; p = 0.0056) than with warfarin in the observation period >18 months. Patients with poor international normalized ratio control (i.e., time in therapeutic range <65%) exhibited a faster decline in GFR. A more pronounced decline in GFR was associated with previous warfarin use and with the presence of diabetes. CONCLUSIONS Patients with atrial fibrillation receiving oral anticoagulation exhibited a decline in renal function that was greater in those taking warfarin versus DE, and it was amplified by diabetes and previous vitamin K antagonist use.

  • 10.
    Bolger, Ann F
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Univ Calif San Francisco, CA USA.
    Preventing Endocarditis No Rest for the Worrier2018In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 72, no 20, p. 2455-2456Article in journal (Other academic)
    Abstract [en]

    n/a

  • 11. Bonaca, Marc P
    et al.
    Steg, Philippe Gabriel
    Feldman, Laurent J
    Canales, John F
    Ferguson, James J
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Califf, Robert M
    Harrington, Robert A
    Giugliano, Robert P
    Antithrombotics in acute coronary syndromes2009In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 54, no 11, p. 969-984Article in journal (Refereed)
    Abstract [en]

    Antithrombotic agents are an integral component of the medical regimens and interventional strategies currently recommended to reduce thrombotic complications in patients with acute coronary syndromes (ACS). Despite great advances with these therapies, associated high risks for thrombosis and hemorrhage remain as the result of complex interactions involving patient comorbidities, drug combinations, multifaceted dosing adjustments, and the intricacies of the care environment. As such, the optimal combinations of antithrombotic therapies, their timing, and appropriate targeted subgroups remain the focus of intense research. During the last several years a number of new antithrombotic treatments have been introduced, and new data regarding established therapies have come to light. Although treatment guidelines include the most current available data, subsequent findings can be challenging to integrate. This challenge is compounded by the complexity associated with different efficacy and safety measures and the variability in study populations, presenting syndromes, physician, and patient preferences. In this work we review recent data regarding clinically available antiplatelet and anticoagulation agents used in the treatment of patients with ACS. We address issues including relative efficacy, safety, and timing of therapies with respect to conservative and invasive treatment strategies. In specific cases we will highlight remaining questions and controversies and ongoing trials, which will hopefully shed light in these areas. In addition to reviewing existing agents, we take a look forward at the most promising new antithrombotics currently in late-stage clinical development and their potential role in the context of ACS management.

  • 12. Brilakis, Emmanouil
    et al.
    Held, Claes
    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.
    Meier, Bernhard
    Cools, Frank
    Claeys, Marc
    Cornel, Jan
    Aylward, Philip
    Lewis, Basil
    Weaver, Douglas
    Brandrup-Wognsen, Gunnar
    Stevens, Susanna
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Effect of Ticagrelor on the Outcomes of Patients With Prior Coronary Artery Bypass Graft Surgery: Insights From The PLATelet inhibition and patient Outcomes (PLATO) trial2012In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 60, no 17, p. B215-B216Article in journal (Other academic)
  • 13. Bräsen, Jan Hinrich
    et al.
    Leppänen, Olli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Inkala, Matias
    Heikura, Tommi
    Levin, Max
    Ahrens, Fabian
    Rutanen, Juha
    Pietsch, Hubertus
    Bergqvist, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Levonen, Anna-Liisa
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Zeller, Thomas
    Klöppel, Günter
    Laukkanen, Mikko O
    Ylä-Herttuala, Seppo
    Extracellular superoxide dismutase accelerates endothelial recovery and inhibits in-stent restenosis in stented atherosclerotic Watanabe heritable hyperlipidemic rabbit aorta2007In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 50, no 23, p. 2249-2253Article in journal (Refereed)
    Abstract [en]

    This study examined whether local gene therapy with extracellular superoxide dismutase (EC-SOD) could inhibit in-stent restenosis in atherosclerotic Watanabe heritable hyperlipidemic rabbits.

    Background

    Stenting causes an acute increase in superoxide anion production and oxidative stress; EC-SOD is a major component of antioxidative defense in blood vessels and has powerful cardioprotective effects in ischemic myocardium.

    Methods

    Endothelial denudation and stenting were done in 36 adult (15 to 18 months old) rabbits. Catheter-mediated intramural delivery of clinical good manufacturing practice-grade adenoviruses encoding rabbit EC-SOD were done simultaneously with stenting. Control animals received adenovirus-encoding nuclear-targeted β-galactosidase (AdLacZ). Circulating markers for oxidative stress (nonesterified 8-iso-prostaglandin F2 alpha) were measured. Analysis of 6-day, 28-day, and 90-day vessel histology, radical production, oxidation-specific epitopes, and expression studies were performed.

    Results

    The EC-SOD treatment reduced oxidant production in stented vessels compared with control vessels. Early systemic recovery of total SOD activity was observed in the treated rabbits. The EC-SOD significantly accelerated endothelial recovery (67.4% ± 10.8% vs. 24.2.1% ± 4.6% at 6 days, p < 0.05; 89.3% ± 3.7% vs. 45.1% ± 9.6% at 28 days, p < 0.05), and the beneficial effect involved increased proliferation of regenerating endothelium. The EC-SOD group showed a 61.3% lower (p < 0.05) neointimal formation at 28 days, with a similar, albeit nonsignificant trend at 90 days (1.20 ± 0.32 mm2 vs. 1.88 ± 0.24 mm2, p = 0.06).

    Conclusions

    The results suggest a central pathogenetic role of oxidation sensitive signaling processes in endothelial recovery and developing in-stent restenosis in atherosclerotic vessels. Local therapy against oxidative stress represents a promising therapeutic strategy in stent-induced vascular injury.

    Extracellular Superoxide Dismutase Accelerates Endothelial Recovery and Inhibits In-Stent Restenosis in Stented Atherosclerotic Watanabe Heritable Hyperlipidemic Rabbit Aorta

    Jan Hinrich Bräsen, Olli Leppänen, Matias Inkala, Tommi Heikura, Max Levin, Fabian Ahrens, Juha Rutanen, Hubertus Pietsch, David Bergqvist, Anna-Liisa Levonen, Samar Basu, Thomas Zeller, Günter Klöppel, Mikko O. Laukkanen, Seppo Ylä-Herttuala

    Percutaneous coronary interventions induce oxidative stress in vessels that already have compromised antioxidative defenses. Extracellular superoxide dismutase (EC-SOD) is a major antioxidant in healthy arteries, and exogenous EC-SOD confers powerful vasculoprotective and cardioprotective effects. However, the effects of EC-SOD therapy on stent-induced vascular injury have not been assessed. We present evidence showing that local therapy with EC-SOD, delivered using clinical-grade adenoviruses, attenuated tissue oxidant production, suppressed developing in-stent restenosis, and accelerated endothelial recovery.

  • 14.
    Bytyci, Ibadete
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Clinic of Cardiology, Prishtina, Albania.
    Bajraktari, Gani
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Clinic of Cardiology, Prishtina, Albania.
    Ibrahimi, Pranvera
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Clinic of Cardiology, Prishtina, Albania.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Clinic of Cardiology, Prishtina, Albania.
    Henein, Michael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Clinic of Cardiology, Prishtina, Albania.
    The relationship between left atrial measurements and cavity pressure: a systematic review and meta-analysis2018In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 71, no 11, p. 911-911Article in journal (Other academic)
  • 15. Böhm, Michael
    et al.
    Ezekowitz, Michael D
    Connolly, Stuart J
    Eikelboom, John W
    Hohnloser, Stefan H
    Reilly, Paul A
    Schumacher, Helmut
    Brueckmann, Martina
    Schirmer, Stephan H
    Kratz, Mario T
    Yusuf, Salim
    Diener, Hans-Christoph
    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.
    Wallentin, Lars
    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.
    Reply: Anticoagulant-Related Nephropathy2015In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 66, no 23, p. 2682-Article in journal (Refereed)
  • 16. Caglayan, Evren
    et al.
    Vantler, Marius
    Leppänen, Olli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Gerhardt, Felix
    Mustafov, Lenard
    ten Freyhaus, Henrik
    Kappert, Kai
    Odenthal, Margarete
    Zimmermann, Wolfram H.
    Tallquist, Michelle D.
    Rosenkranz, Stephan
    Disruption of Platelet-Derived Growth Factor-Dependent Phosphatidylinositol 3-Kinase and Phospholipase C gamma 1 Activity Abolishes Vascular Smooth Muscle Cell Proliferation and Migration and Attenuates Neointima Formation In Vivo2011In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 57, no 25, p. 2527-2538Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: We tested the hypothesis whether selective blunting of platelet-derived growth factor (PDGF)-dependent vascular smooth muscle cell (VSMC) proliferation and migration is sufficient to prevent neointima formation after vascular injury.

    BACKGROUND: To prevent neointima formation and stent thrombosis after coronary interventions, it is essential to inhibit VSMC proliferation and migration without harming endothelial cell function. The role of PDGF-a potent mitogen and chemoattractant for VSMC that does not affect endothelial cells-for neointima formation remains controversial.

    METHODS: To decipher the signaling pathways that control PDGF beta receptor (βPDGFR)-driven VSMC proliferation and migration, we characterized 2 panels of chimeric CSF1R/βPDGFR mutants in which the binding sites for βPDGFR-associated signaling molecules (Src, phosphatidylinositol 3-kinase [PI3K], GTPase activating protein of ras, SHP-2, phospholipase Cγ 1 [PLCγ]) were individually mutated. Based on in vitro results, the importance of PDGF-initiated signals for neointima formation was investigated in genetically modified mice.

    RESULTS: Our results indicate that the chemotactic response to PDGF requires the activation of Src, PI3K, and PLCγ, whereas PDGF-dependent cell cycle progression is exclusively mediated by PI3K and PLCγ. These 2 signaling molecules contribute to signal relay of the βPDGFR by differentially regulating cyclin D1 and p27(kip1). Blunting of βPDGFR-induced PI3K and PLCγ signaling by a combination mutant (F3) completely abolished the mitogenic and chemotactic response to PDGF. Disruption of PDGF-dependent PI3K and PLCγ signaling in mice expressing the F3 receptor led to a profound reduction of neointima formation after balloon injury.

    CONCLUSIONS: Signaling by the activated βPDGFR, particularly through PI3K and PLCγ, is crucial for neointima formation after vascular injury. Disruption of these specific signaling pathways is sufficient to attenuate pathogenic processes such as vascular remodeling in vivo.

  • 17. Calais, Fredrik
    et al.
    Lagerqvist, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Leppert, Jerzy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Fröbert, Ole
    Proximal Coronary Artery Stenting: DES Versus BMS and LAD Versus the Rest2012In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 60, no 17, p. B174-B175Article in journal (Other academic)
  • 18.
    Calais, Fredrik
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Lagerqvist, Bo
    University Hospital Uppsala, Uppsala, Sweden.
    Leppert, Jerzy
    Uppsala University, Västerås, Sweden.
    James, Stefan
    Uppsala Clinical Research Center, Uppsala, Sweden.
    Fröbert, Ole
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital, Örebro, Sweden.
    Thrombus aspiration in patients with large anterior myocardial infarction: a TASTE trial substudy2015In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 66, no 15, p. B2-B2Article in journal (Other academic)
  • 19.
    Calais, Fredrik
    et al.
    Univ Orebro, Fac Hlth, SE-70182 Orebro, Sweden..
    Lagerqvist, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Leppert, Jerzy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    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.
    Frobert, Ole
    Orebro Univ Hosp, Orebro, Sweden..
    Thrombus aspiration in patients with large anterior myocardial infarction: a TASTE trial substudy2015In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 66, no 15, p. B2-B2Article in journal (Other academic)
  • 20.
    Carlhäll, Carljohan
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Physiology . Östergötlands Läns Landsting, Heart Centre, Department of Clinical Physiology.
    Lindström, Lena
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Physiology .
    Wranne, Bengt
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Physiology . Östergötlands Läns Landsting, Heart Centre, Department of Clinical Physiology.
    Nylander, Eva
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Physiology . Östergötlands Läns Landsting, Heart Centre, Department of Clinical Physiology.
    Atrioventricular plane displacement correlates closely to circulatory dimensions but not to ejection fraction in normal subjects2001In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 37, no 2, p. 388A-388AConference paper (Other academic)
  • 21. Carlsson, Jörg
    et al.
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindbäck, Johan
    Scherstén, Fredrik
    Nilsson, Tage
    Stenestrand, Ulf
    Lagerqvist, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Outcome of drug-eluting versus bare-metal stenting used according to on- and off-label criteria2009In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 53, no 16, p. 1389-1398Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: The aim of this study was to investigate the outcome of bare-metal stents (BMS) versus drug-eluting stents (DES) after on-label as well as off-label use. BACKGROUND: DES lower restenosis rates while not influencing the risk for death and myocardial infarction when used in Federal Food and Drug Administration (FDA)-approved indications. It is debated whether the clinical results of this so-called on-label use might be extrapolated to off-label situations. METHODS: The SCAAR (Swedish Coronary Angiography and Angioplasty Registry) was used to investigate the outcomes in 17,198 patients who underwent stenting with an on-label indication (10,431 BMS and 6,767 DES patients) and 16,355 patients in the context of an off-label indication (9,907 BMS and 6,448 DES patients). The patients were included from 2003 to 2005 with a minimum follow-up of 1 year and a maximum of 4 years. The analysis was adjusted for differences in baseline characteristics. RESULTS: There were not significant differences between on-label DES and BMS (adjusted hazard ratio: 1.02; 95% confidence interval: 0.92 to 1.13) or between off-label DES and BMS (adjusted hazard ratio: 0.95; 95% confidence interval: 0.87 to 1.04) use with regard to the incidence of myocardial infarction and death. Off-label use of DES did not lead to significant differences in the combined risk of death and myocardial infarction compared with BMS throughout the whole spectrum of clinical indications. CONCLUSIONS: In contemporary Swedish practice, neither on- nor off-label use of DES is associated with worse outcome than use of BMS.

  • 22. Carlsson, Marcus
    et al.
    Heiberg, Einar
    Ostenfeld, Ellen
    Steding-Ehrenborg, Katarina
    Kovács, Sándor J
    Flachskampf, Frank
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Arheden, Håkan
    Functional Contribution of Circumferential Versus Longitudinal Strain: Different Concepts Suggest Conflicting Results.2018In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 71, no 2, p. 254-255, article id S0735-1097(17)41601-9Article in journal (Refereed)
  • 23.
    Carr, Hanna
    et al.
    Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Cnattingius, Sven
    Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Granath, Fredrik
    Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Ludvigsson, Jonas F.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Bonamy, Anna-Karin Edstedt
    Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Department of Women ’ s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.
    Preterm Birth and Risk of Heart Failure Up to Early Adulthood2017In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 69, no 21, p. 2634-2642Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In small clinical studies, preterm birth was associated with altered cardiac structure and increased cardiovascular mortality in the young.

    OBJECTIVES: The goal of this study was to determine the association between preterm birth and risk of incident heart failure (HF) in children and young adults.

    METHODS: This register-based cohort study included 2,665,542 individuals born in Sweden from 1987 to 2012 who were followed up from 1 year of age to December 31, 2013. The main study outcome was diagnosis of HF in the National Patient Register or the Cause of Death Register. The association between preterm birth and risk of incident HF was analyzed by using a Poisson regression model. Estimates were adjusted for maternal and pregnancy characteristics, socioeconomic status, and maternal and paternal cardiovascular disease.

    RESULTS: During 34.8 million person-years of follow-up (median 13.1 years), there were 501 cases of HF. After exclusion of 52,512 individuals with malformations (n = 196 cases), 305 cases of HF remained (0.88 per 100,000 person-years). Gestational age was inversely associated with the risk of HF. Compared with individuals born at term (>= 37 weeks' gestation), adjusted incidence relative risks for HF were 17.0 (95% confidence interval [CI]: 7.96 to 36.3) after extremely preterm birth (<28 weeks) and 3.58 (95% CI: 1.57 to 8.14) after very preterm birth (28 to 31 weeks). There was no risk increase after moderately preterm birth (32 to 36 weeks) (relative risk: 1.36; 95% CI: 0.87 to 2.13).

    CONCLUSIONS: There was a strong association between preterm birth before 32 weeks of gestation and HF in childhood and young adulthood. Although the absolute risk of HF is low in young age, our findings indicate that preterm birth may be a previously unknown risk factor for HF. (J Am Coll Cardiol 2017;69:2634-42) (C) 2017 by the American College of Cardiology Foundation.

  • 24. Chan, M. C.
    et al.
    Gaballa, M.
    Williams, R.
    Sivakumaran, S.
    O'Reilly, K.
    van der Linden, J.
    Brodin, Lars-Åke
    Hui, W.
    Tissue Doppler guided optimization of A-V and V-V delay of biventricular pacemaker improves response to cardiac resynchronization therapy in heart failure patients2005In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 45, no 3, p. 274A-274AArticle in journal (Other academic)
  • 25.
    Charytan, David M.
    et al.
    NYU Langone Med Ctr, NY USA; Brigham and Womens Hosp, MA 02115 USA; Harvard Med Sch, MA 02115 USA.
    Sabatine, Marc S.
    Brigham and Womens Hosp, MA 02115 USA; Harvard Med Sch, MA 02115 USA; Brigham and Womens Hosp, MA 02115 USA.
    Pedersen, Terje R.
    Oslo Univ Hosp, Norway.
    Im, KyungAh
    Brigham and Womens Hosp, MA 02115 USA; Harvard Med Sch, MA 02115 USA; Brigham and Womens Hosp, MA 02115 USA.
    Park, Jeong-Gun
    Brigham and Womens Hosp, MA 02115 USA; Harvard Med Sch, MA 02115 USA; Brigham and Womens Hosp, MA 02115 USA.
    Pineda, Armando Lira
    Amgen Inc, CA USA.
    Wasserman, Scott M.
    Amgen Inc, CA USA.
    Deedwania, Prakash
    Vet Affairs Cent Calif Healthcare Syst, CA USA.
    Olsson, Anders G.
    Univ Calif San Francisco, CA USA.
    Sever, Peter S.
    Not Found:Linkoping Univ, Dept Med and Hlth Sci, Linkoping, Sweden.
    Keech, Anthony C.
    Imperial Coll London, England; Univ Sydney, Australia.
    Giugliano, Robert P.
    Brigham and Womens Hosp, MA 02115 USA; Harvard Med Sch, MA 02115 USA; Brigham and Womens Hosp, MA 02115 USA.
    Efficacy and Safety of Evolocumab in Chronic Kidney Disease in the FOURIER Trial2019In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 73, no 23, p. 2961-2970Article in journal (Refereed)
    Abstract [en]

    BACK GROUND Data on PCSK9 inhibition in chronic kidney disease (CKD) is limited. OBJECTIVES The purpose of this study was to compare outcomes with evolocumab and placebo according to kidney function. METHODS The FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial randomized individuals with clinically evident atherosclerosis and low-density lipoprotein cholesterol (LDL-C) amp;gt;= 70 mg/dl or non-high-density lipoprotein cholesterol amp;gt;= 100 mg/dl to evolocumab or placebo. The primary endpoint (cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization), key secondary endpoint (cardiovascular death, myocardial infarction, or stroke), and safety were analyzed according to chronic kidney disease (CKD) stage estimated from CKD-epidemiology estimated glomerular filtration rate. RESULTS There were 8,077 patients with preserved kidney function, 15,034 with stage 2 CKD, and 4,443 with amp;gt;= stage 3 CKD. LDL-C reduction with evolocumab compared with placebo at 48 weeks was similar across CKD groups at 59%, 59%, and 58%, respectively. Relative risk reduction for the primary endpoint was similar for preserved function (hazard ratio [HR]: 0.82; 95% CI: 0.71 to 0.94), stage 2 (HR: 0.85; 95% CI: 0.77 to 0.94), and stage amp;gt;= 3 CKD (HR: 0.89; 95% CI: 0.76 to 1.05); p(int) = 0.77. Relative risk reduction for the secondary endpoint was similar across CKD stages (p(int) = 0.75)-preserved function (HR: 0.75; 95% CI: 0.62 to 0.90), stage 2 (HR: 0.82; 95% CI: 0.72 to 0.93), stage amp;gt;= 3 (HR: 0.79; 95% CI: 0.65 to 0.95). Absolute RRs at 30 months for the secondary endpoint were -2.5% (95% CI: -0.4% to -4.7%) for stage amp;gt;= 3 CKD compared with -1.7% (95% CI: 0.5% to -2.8%) with preserved kidney function. Adverse events, including estimated glomerular filtration rate decline, were infrequent and similar regardless of CKD stage. CONCLUSIONS LDL-C lowering and relative clinical efficacy and safety of evolocumab versus placebo were consistent across CKD groups. Absolute reduction in the composite of cardiovascular death, MI, or stroke with evolocumab was numerically greater with more advanced CKD. (C) 2019 by the American College of Cardiology Foundation.

  • 26. Chen, Yuqing
    et al.
    Rao, Fangwen
    Rodriguez-Flores, Juan L
    Mahata, Manjula
    Fung, Maple M.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Vaingankar, Sucheta M
    Wen, Gen
    Salem, Rany M.
    Das, Madhusudan
    Cockburn, Myles G.
    Schork, Nicholas J.
    Ziegler, Michael G.
    Hamilton, Bruce A.
    Mahata, Sushil K.
    Taupenot, Laurent
    O'Connor, Daniel T.
    Naturally occurring human genetic variation in the 3'-untranslated region of the secretory protein chromogranin A is associated with autonomic blood pressure regulation and hypertension in a sex-dependent fashion2008In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 52, no 18, p. 1468-81Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: We aimed to determine whether the common variation at the chromogranin A (CHGA) locus increases susceptibility to hypertension. BACKGROUND: CHGA regulates catecholamine storage and release. Previously we systematically identified genetic variants across CHGA. METHODS: We carried out dense genotyping across the CHGA locus in >1,000 individuals with the most extreme blood pressures (BPs) in the population, as well as twin pairs with autonomic phenotypes. We also characterized the function of a trait-associated 3'-untranslated region (3'-UTR) variant with transfected CHGA 3'-UTR/luciferase reporter plasmids. RESULTS: CHGA was overexpressed in patients with hypertension, especially hypertensive men, and CHGA predicted catecholamines. In individuals with extreme BPs, CHGA genetic variants predicted BP, especially in men, with a peak association occurring in the 3'-UTR at C+87T, accounting for up to approximately 12/ approximately 9 mm Hg. The C+87T genotype predicted CHGA secretion in vivo, with the +87T allele (associated with lower BP) also diminishing plasma CHGA by approximately 10%. The C+87T 3'-UTR variant also predicted the BP response to environmental (cold) stress; the same allele (+87T) that diminished basal BP in the population also decreased the systolic BP response to stress by approximately 12 mm Hg, and the response was smaller in women (by approximately 6 mm Hg). In a chromaffin cell-transfected CHGA 3'-UTR/luciferase reporter plasmid, the +87T allele associated with lower BP also decreased reporter expression by approximately 30%. In cultured chromaffin cells, reducing endogenous CHGA expression by small interfering ribonucleic acid caused approximately two-thirds depletion of catecholamine storage vesicles. CONCLUSIONS: Common variant C+87T in the CHGA 3'-UTR is a functional polymorphism causally associated with hypertension especially in men of the population, and we propose steps ("intermediate phenotypes") whereby in a sex-dependent fashion this genetic variant influences the ultimate disease trait. These observations suggest new molecular strategies to probe the pathophysiology, risk, and rational treatment of hypertension.

  • 27. Chockalingam, Priya
    et al.
    Crotti, Lia
    Girardengo, Giulia
    Johnson, Jonathan N
    Harris, Katy M
    van der Heijden, Jeroen F
    Hauer, Richard NW
    Beckmann, Britt M
    Spazzolini, Carla
    Rordorf, Roberto
    Rydberg, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Clur, Sally-Ann B
    Fischer, Markus
    van den Heuvel, Freek
    Kaeaeb, Stefan
    Blom, Nico A
    Ackerman, Michael J
    Schwartz, Peter J
    Wilde, Arthur AM
    Not all beta-blockers are equal in the management of Long QT Syndrome types 1 and 2: higher recurrence of events under metoprolol2012In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 60, no 20, p. 2092-2099Article in journal (Refereed)
    Abstract [en]

    Objectives The purpose of this study was to compare the efficacy of beta-blockers in congenital long QT syndrome (LQTS). Background Beta-blockers are the mainstay in managing LQTS. Studies comparing the efficacy of commonly used beta-blockers are lacking, and clinicians generally assume they are equally effective.

    Methods Electrocardiographic and clinical parameters of 382 LQT1/LQT2 patients initiated on propranolol (n = 134), metoprolol (n = 147), and nadolol (n = 101) were analyzed, excluding patients <1 year of age at beta-blocker initiation. Symptoms before therapy and the first breakthrough cardiac events (BCEs) were documented.

    Results Patients (56% female, 27% symptomatic, heart rate 76 +/- 16 beats/min, QTc 472 +/- 46 ms) were started on beta-blocker therapy at a median age of 14 years (interquartile range: 8 to 32 years). The QTc shortening with propranolol was significantly greater than with other beta-blockers in the total cohort and in the subset with QTc >480 ms. None of the asymptomatic patients had BCEs. Among symptomatic patients (n = 101), 15 had BCEs (all syncopes). The QTc shortening was significantly less pronounced among patients with BCEs. There was a greater risk of BCEs for symptomatic patients initiated on metoprolol compared to users of the other 2 beta-blockers combined, after adjustment for genotype (odds ratio: 3.95, 95% confidence interval: 1.2 to 13.1, p = 0.025). Kaplan-Meier analysis showed a significantly lower event-free survival for symptomatic patients receiving metoprolol compared to propranolol/nadolol.

    Conclusions Propranolol has a significantly better QTc shortening effect compared to metoprolol and nadolol, especially in patients with prolonged QTc. Propranolol and nadolol are equally effective, whereas symptomatic patients started on metoprolol are at a significantly higher risk for BCEs. Metoprolol should not be used for symptomatic LQT1 and LQT2 patients.

    (J Am Coll Cardiol 2012;60:2092-9) (C) 2012 by the American College of Cardiology Foundation

  • 28.
    Costa, Francesco
    et al.
    Univ Messina, Dept Clin & Expt Med, Policlin G Martino, Messina, Italy;Bern Univ Hosp, Swiss Cardiovasc Ctr Bern, CH-3010 Bern, Switzerland.
    Van Klaveren, David
    Leiden Univ, Med Ctr, Dept Med Stat & Bioinformat, Leiden, Netherlands;Tufts Med Ctr, Inst Clin Res & Hlth Policy Studies, Boston, MA 02111 USA.
    Feres, Fausto
    Ist Dante Pazzanese Cardiol, Sao Paulo, Brazil.
    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.
    Raber, Lorenz
    Bern Univ Hosp, Swiss Cardiovasc Ctr Bern, CH-3010 Bern, Switzerland.
    Pilgrim, Thomas
    Bern Univ Hosp, Swiss Cardiovasc Ctr Bern, CH-3010 Bern, Switzerland.
    Hong, Myeong-Ki
    Yonsei Univ, Coll Med, Severance Cardiovasc Hosp, Seoul, South Korea;Yonsei Univ, Severance Biomed Sci Inst, Coll Med, Seoul, South Korea.
    Kim, Hyo-Soo
    Seoul Natl Univ Hosp, Dept Internal Med, Seoul, South Korea.
    Colombo, Antonio
    Ist Sci San Raffaele, Intervent Cardiol Unit, Milan, Italy;EMO GVM Ctr Cuore Columbus, Intervent Cardiol Unit, Milan, Italy.
    Steg, Philippe Gabriel
    AP HP, FACT, Paris, France;Univ Paris Diderot, Bichat Hosp, Paris, France.
    Bhatt, Deepak L.
    Brigham & Womens Hosp, Heart & Vasc Ctr, 75 Francis St, Boston, MA 02115 USA;Harvard Med Sch, Boston, MA USA.
    Stone, Gregg W.
    Columbia Univ, Med Ctr, New York Presbyterian Hosp, New York, NY USA;Cardiovasc Res Fdn, New York, NY USA.
    Windecker, Stephan
    Bern Univ Hosp, Swiss Cardiovasc Ctr Bern, CH-3010 Bern, Switzerland.
    Steyerberg, Ewout W.
    Leiden Univ, Med Ctr, Dept Med Stat & Bioinformat, Leiden, Netherlands.
    Valgimigli, Marco
    Bern Univ Hosp, Swiss Cardiovasc Ctr Bern, CH-3010 Bern, Switzerland.
    Dual Antiplatelet Therapy Duration Based on Ischemic and Bleeding Risks After Coronary Stenting2019In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 73, no 7, p. 741-754Article in journal (Refereed)
    Abstract [en]

    BACKGROUND

    Complex percutaneous coronary intervention (PCI) is associated with higher ischemic risk, which can be mitigated by long-term dual antiplatelet therapy (DAPT). However, concomitant high bleeding risk (HBR) may be present, making it unclear whether short-or long-term DAPT should be prioritized.

    OBJECTIVES

    This study investigated the effects of ischemic (by PCI complexity) and bleeding (by PRECISE-DAPT [PREdicting bleeding Complications in patients undergoing stent Implantation and SubsequEnt Dual AntiPlatelet Therapy] score) risks on clinical outcomes and on the impact of DAPT duration after coronary stenting.

    METHODS

    Complex PCI was defined as $ 3 stents implanted and/or $ 3 lesions treated, bifurcation stenting and/or stent length > 60 mm, and/or chronic total occlusion revascularization. Ischemic and bleeding outcomes in high ($ 25) or nonhigh (< 25) PRECISE-DAPT strata were evaluated based on randomly allocated duration of DAPT.

    RESULTS

    Among 14,963 patients from 8 randomized trials, 3,118 underwent complex PCI and experienced a higher rate of ischemic, but not bleeding, events. Long-term DAPT in non-HBR patients reduced ischemic events in both complex (absolute risk difference:-3.86%; 95% confidence interval:-7.71 to thorn0.06) and noncomplex PCI strata (absolute risk difference:-1.14%; 95% confidence interval:-2.26 to-0.02), but not among HBR patients, regardless of complex PCI features. The bleeding risk according to the Thrombolysis In Myocardial Infarction scale was increased by long-term DAPT only in HBR patients, regardless of PCI complexity.

    CONCLUSIONS

    Patients who underwent complex PCI had a higher risk of ischemic events, but benefitted from long-term DAPT only if HBR features were not present. These data suggested that when concordant, bleeding, more than ischemic risk, should inform decision-making on the duration of DAPT.

  • 29.
    Cowper, Patricia A.
    et al.
    Duke University, NC USA.
    Pan, Wenqin
    Duke University, NC USA.
    Anstrom, Kevin J.
    Duke University, NC USA.
    Kaul, Padma
    University of Alberta, Canada.
    Wallentin, Lars
    Uppsala University, Sweden.
    Davidson-Ray, Linda
    Duke University, NC USA.
    Lundborg, Elisabet
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Medicine and Health Sciences.
    Janzon, Magnus
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Levin, Lars-Åke
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Medicine and Health Sciences.
    Cannon, Christopher P.
    Brigham and Womens Hospital, MA 02115 USA.
    Harrington, Robert A.
    Stanford University, CA 94305 USA.
    Mark, Daniel B.
    Duke University, NC USA.
    Economic Analysis of Ticagrelor Therapy From a US Perspective2015In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 65, no 5, p. 465-476Article in journal (Refereed)
    Abstract [en]

    BACKGROUND Based on results of the PLATO (Platelet Inhibition and Patient Outcomes) trial comparing ticagrelor with clopidogrel therapy, the U.S. Food and Drug Administration approved ticagrelor in 2011 for reducing thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) with the proviso that it be taken with low-dose aspirin. OBJECTIVES This study sought to assess the cost and cost effectiveness of ticagrelor therapy relative to clopidogrel in treating ACS patients from the perspective of the U.S. health care system. METHODS We estimated within-trial resource use and costs using U.S. low-dose aspirin patients in PLATO (n = 547). Quality-adjusted life expectancy was estimated using the total PLATO population (n = 18,624), combined with baseline risk and long-term survival data from an external ACS patient cohort. Study drugs were valued at current costs. Cost effectiveness was assessed, as was the sensitivity of results to sampling and methodological uncertainties. RESULTS One year of ticagrelor therapy, relative to that of generic clopidogrel, cost $29,665/quality-adjusted life-year gained, with 99% of bootstrap estimates falling under a $100,000 willingness-to-pay threshold. Results were robust to extensive sensitivity analyses, including variations in clopidogrel cost, exclusion of costs in extended years of life, and a recalibrated estimate of survival reflecting a lower underlying mortality risk in the United States. CONCLUSIONS For PLATO-eligible ACS patients, a U.S. perspective comparison of the current standard of dual antiplatelet therapy of aspirin with clopidogrel versus aspirin plus ticagrelor showed that the ticagrelor regimen increased life expectancy at an incremental cost well within accepted benchmarks of good value for money. (C) 2015 by the American College of Cardiology Foundation.

  • 30. Cowper, Patricia A
    et al.
    Pan, Wenqin
    Anstrom, Kevin J
    Kaul, Padma
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Davidson-Ray, Linda
    Nikolic, Elisabet
    Janzon, Magnus
    Levin, Lars-Åke
    Cannon, Christopher P
    Harrington, Robert A
    Mark, Daniel B
    Economic Analysis of Ticagrelor Therapy From a U.S. Perspective: Results From the PLATO Study2015In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 65, no 5, p. 465-476Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Based on results of the PLATO (Platelet Inhibition and Patient Outcomes) trial comparing ticagrelor with clopidogrel therapy, the U.S. Food and Drug Administration approved ticagrelor in 2011 for reducing thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) with the proviso that it be taken with low-dose aspirin.

    OBJECTIVES: This study sought to assess the cost and cost effectiveness of ticagrelor therapy relative to clopidogrel in treating ACS patients from the perspective of the U.S. health care system.

    METHODS: We estimated within-trial resource use and costs using U.S. low-dose aspirin patients in PLATO (n = 547). Quality-adjusted life expectancy was estimated using the total PLATO population (n = 18,624), combined with baseline risk and long-term survival data from an external ACS patient cohort. Study drugs were valued at current costs. Cost effectiveness was assessed, as was the sensitivity of results to sampling and methodological uncertainties.

    RESULTS: One year of ticagrelor therapy, relative to that of generic clopidogrel, cost $29,665/quality-adjusted life-year gained, with 99% of bootstrap estimates falling under a $100,000 willingness-to-pay threshold. Results were robust to extensive sensitivity analyses, including variations in clopidogrel cost, exclusion of costs in extended years of life, and a recalibrated estimate of survival reflecting a lower underlying mortality risk in the United States.

    CONCLUSIONS: For PLATO-eligible ACS patients, a U.S. perspective comparison of the current standard of dual antiplatelet therapy of aspirin with clopidogrel versus aspirin plus ticagrelor showed that the ticagrelor regimen increased life expectancy at an incremental cost well within accepted benchmarks of good value for money. (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872).

  • 31. Damman, Peter
    et al.
    Held, Claes
    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.
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Jeppsson, Anders
    Jernberg, Tomas
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Invasive Strategies And Outcomes For Non-ST-segment Elevation Acute Coronary Syndromes: A Twelve-year Experience From SWEDEHEART2012In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 60, no 17, p. B133-B133Article in journal (Other academic)
  • 32.
    Damman, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research Center.
    Varenhorst, Christoph
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research Center.
    Koul, Sasha
    Eriksson, Peter
    Erlinge, David
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research Center.
    Patient characteristics and bleeding outcomes in invasively treated acute coronary syndrome patients treated with prasugrel or clopidogrel2012In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 59, no 13, p. E271-E271Article in journal (Other academic)
  • 33. Danad, Ibrahim
    et al.
    Uusitalo, Valtteri
    Kero, Tanja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Saraste, Antti
    Raijmakers, Pieter G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Lammertsma, Adriaan A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Heymans, Martijn W.
    Kajander, Sami A.
    Pietilae, Mikko
    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.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Knaapen, Paul
    Knuuti, Juhani
    Quantitative Assessment of Myocardial Perfusion in the Detection of Significant Coronary Artery Disease Cutoff Values and Diagnostic Accuracy of Quantitative [O-15]H2O PET Imaging2014In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 64, no 14, p. 1464-1475Article in journal (Refereed)
    Abstract [en]

    BACKGROUND Recent studies have demonstrated improved diagnostic accuracy for detecting coronary artery disease (CAD) when myocardial blood flow (MBF) is quantified in absolute terms, but there are no uniformly accepted cutoff values for hemodynamically significant CAD. OBJECTIVES The goal of this study was to determine cutoff values for absolute MBF and to evaluate the diagnostic accuracy of quantitative [O-15]H2O positron emission tomography (PET). METHODS A total of 330 patients underwent both quantitative [O-15]H2O PET imaging and invasive coronary angiography in conjunction with fractional flow reserve measurements. A stenosis >90% and/or fractional flow reserve <= 0.80 was considered obstructive; a stenosis <30% and/or fractional flow reserve >0.80 was nonobstructive. RESULTS Hemodynamically significant CAD was diagnosed in 116 (41%) of 281 patients who fulfilled study criteria for CAD. Resting perfusion was 1.00 +/- 0.25 and 0.92 +/- 0.23 ml/min/g in regions supplied by nonstenotic and significantly stenosed vessels, respectively (p < 0.001). During stress, perfusion increased to 3.26 +/- 1.04 ml/min/g and 1.73 +/- 0.67 ml/min/g, respectively (p < 0.001). The optimal cutoff values were 2.3 and 2.5 for hyperemic MBF and myocardial flow reserve, respectively. For MBF, these cutoff values showed a sensitivity, specificity, and accuracy for detecting significant CAD of 89%, 84%, and 86%, respectively, at a per-patient level and 87%, 85%, and 85% at a per-vessel level. The corresponding myocardial flow reserve values were 86%, 72%, and 78% (per patient) and 80%, 82%, and 81% (per vessel). Age and sex significantly affected diagnostic accuracy of quantitative PET. CONCLUSIONS Quantitative MBF measurements with the use of [O-15]H2O PET provided high diagnostic performance, but both sex and age should be taken into account.

  • 34. De Caterina, Raffaele
    et al.
    Husted, Steen
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Andreotti, Felicita
    Arnesen, Harald
    Bachmann, Fedor
    Baigent, Colin
    Huber, Kurt
    Jespersen, Jorgen
    Kristensen, Steen Dalby
    Lip, Gregory Y. H.
    Morais, Joao
    Rasmussen, Lars Hvilsted
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Verheugt, Freek W. A.
    Weitz, Jeffrey I.
    New Oral Anticoagulants in Atrial Fibrillation and Acute Coronary Syndromes: ESC Working Group on Thrombosis - Task Force on Anticoagulants in Heart Disease Position Paper2012In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 59, no 16, p. 1413-1425Article, review/survey (Refereed)
    Abstract [en]

    Until recently, vitamin K antagonists were the only available oral anticoagulants, but with numerous limitations that prompted the introduction of new oral anticoagulants targeting the single coagulation enzymes thrombin (dabigatran) or factor Xa (apixaban, rivaroxaban, and edoxaban) and given in fixed doses without coagulation monitoring. Here we review the pharmacology and the results of clinical trials with these new agents in stroke prevention in atrial fibrillation and secondary prevention after acute coronary syndromes, providing perspectives on their future incorporation into clinical practice. In phase III trials in atrial fibrillation, compared with warfarin, dabigatran etexilate 150 mg B.I.D. reduced the rates of stroke/systemic embolism without any difference in major bleeding; dabigatran etexilate 110 mg B.I.D. had similar efficacy with decreased bleeding; apixaban 5 mg B.I.D. reduced stroke, systemic embolism, and mortality as well as major bleeding; and rivaroxaban 20 mg Q.D. was noninferior to warfarin for stroke and systemic embolism without a difference in major bleeding. All these agents reduced intracranial hemorrhage. Edoxaban is currently being evaluated in a further large phase III trial. Apixaban and rivaroxaban were evaluated in phase III trials for prevention of recurrent ischemia in patients with acute coronary syndromes who were mostly receiving dual antiplatelet therapy, with conflicting results on efficacy but consistent results for increased major bleeding. Overall, the new oral anticoagulants are poised to replace vitamin K antagonists for many patients with atrial fibrillation and may have a role after acute coronary syndromes. Although convenient to administer and manage, they present challenges that need to be addressed.

  • 35.
    Dondo, Tatendashe B.
    et al.
    Univ Leeds, Leeds Inst Cardiovasc & Metab Med, MRC, Bioinformat Ctr, Level 11,Worsley Bldg, Leeds LS2 9JT, W Yorkshire, England..
    Hall, Marlous
    Univ Leeds, Leeds Inst Cardiovasc & Metab Med, MRC, Bioinformat Ctr, Level 11,Worsley Bldg, Leeds LS2 9JT, W Yorkshire, England..
    West, Robert M.
    Univ Leeds, Leeds Inst Hlth Sci, Leeds, W Yorkshire, England..
    Jernberg, Tomas
    Karolinska Univ Hosp, Karolinska Inst, Dept Cardiol, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Lindahl, Bertil
    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.
    Bueno, Hector
    Ctr Nacl Invest Cardiovasc, Madrid, Spain.;Hosp Univ 12 Octubre, Inst Invest i 12, Madrid, Spain.;Hosp Univ 12 Octubre, Cardiol Dept, Madrid, Spain.;Univ Complutense Madrid, Fac Med, Madrid, Spain..
    Danchin, Nicolas
    Hop Europeen Georges Pompidou, Dept Cardiol, Paris, France.;AP HP, Paris, France.;Univ Paris 05, Paris, France..
    Deanfield, John E.
    UCL, Natl Inst Cardiovasc Outcomes Res, London, England..
    Hemingway, Harry
    UCL, London, England.;Farr Inst Hlth Informat Res, London, England..
    Fox, Keith A. A.
    Univ Edinburgh, Ctr Cardiovasc Sci, Edinburgh, Midlothian, Scotland..
    Timmis, Adam D.
    Barts Heart Ctr, Biomed Res Unit, Natl Inst Hlth, London, England..
    Gale, Chris P.
    Univ Leeds, Leeds Inst Cardiovasc & Metab Med, MRC, Bioinformat Ctr, Level 11,Worsley Bldg, Leeds LS2 9JT, W Yorkshire, England.;York Teaching Hosp NHS Fdn Trust, Dept Cardiol, York, N Yorkshire, England..
    beta-Blockers and Mortality After Acute Myocardial Infarction in Patients Without Heart Failure or Ventricular Dysfunction2017In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 69, no 22, p. 2710-2720Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: For acute myocardial infarction (AMI) without heart failure (HF), it is unclear if beta-blockers are associated with reduced mortality.

    OBJECTIVES: The goal of this study was to determine the association between beta-blocker use and mortality in patients with AMI without HF or left ventricular systolic dysfunction (LVSD).

    METHODS: This cohort study used national English and Welsh registry data from the Myocardial Ischaemia National Audit Project. A total of 179,810 survivors of hospitalization with AMI without HF or LVSD, between January 1, 2007, and June 30, 2013 (final follow-up: December 31, 2013), were assessed. Survival-time inverse probability weighting propensity scores and instrumental variable analyses were used to investigate the association between the use of beta-blockers and 1-year mortality.

    RESULTS: Of 91,895 patients with ST-segment elevation myocardial infarction and 87,915 patients with non-ST-segment elevation myocardial infarction, 88,542 (96.4%) and 81,933 (93.2%) received beta-blockers, respectively. For the entire cohort, with> 163,772 person-years of observation, there were 9,373 deaths (5.2%). Unadjusted 1-year mortality was lower for patients who received beta-blockers compared with those who did not (4.9% vs. 11.2%; p < 0.001). However, after weighting and adjustment, there was no significant difference in mortality between those with and without beta-blocker use (average treatment effect [ATE] coefficient: 0.07; 95% confidence interval [CI]: -0.60 to 0.75; p = 0.827). Findings were similar for ST-segment elevation myocardial infarction (ATE coefficient: 0.30; 95% CI: -0.98 to 1.58; p = 0.637) and non-ST-segment elevation myocardial infarction (ATE coefficient: -0.07; 95% CI: -0.68 to 0.54; p = 0.819).

    CONCLUSIONS: Among survivors of hospitalization with AMI who did not have HF or LVSD as recorded in the hospital, the use of beta-blockers was not associated with a lower risk of death at any time point up to 1 year.

  • 36.
    Ebeling Barbier, Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Bjerner, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Myocardial scars more frequent than expected - Magnetic resonance imaging detects potential risk group2006In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 48, no 4, p. 765-771Article in journal (Refereed)
    Abstract [en]

    Objectives: The aim of this study was to investigate the prevalence of clinically recognized myocardial infarctions (RMIs) and unrecognized myocardial infarctions (UMIs) in 70-year-old subjects, assessed with magnetic resonance imaging (MRI), and to relate the findings to cardiac function and morbidity. Background: Late enhancement MRI identifies myocardial scars and thereby has the potential to detect UMI. Methods: Cardiac MRI was performed on 259 randomly chosen 70-year-old subjects. Late enhancement and cine sequences were acquired, and the ejection fraction and left ventricular (LV) mass were calculated. Late enhancement involving the subendocardial layer was considered to represent myocardial infarction (MI) scars, and their volumes were calculated. Information on cardiac morbidity and risk factors was collected from medical records and from a health examination. Subjects with MI scars, with or without a hospital diagnosis of MI were classified as RMI or UMI, respectively. Results: The images from 248 subjects (123 women, 125 men) were assessable. Myocardial infarction scars were found in 60 subjects (24.2%), in 49 of whom (19.8%) they were UMIs. The volumes of the UMIs were significantly smaller than those of the RMIs. There was an increased frequency of chest pain symptoms among the subjects with UMI or RMI compared with those without MI scars. Ejection fraction was significantly lower and LV mass significantly larger in the subjects with UMI or RMI than in those without MI scars. Conclusions: Unrecognized MI detected with MRI was more frequent than expected in 70-year-old subjects. The subjects displaying these UMIs may represent a previously unknown potential risk group for future cardiovascular events.

  • 37.
    Ebeling Barbier, Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Nylander, Ruta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Themudo, Raquel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Bjerner, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Prevalence of unrecognized myocardial infarction detected with magnetic resonance imaging and its relationship to cerebral ischemic lesions in both sexes2011In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 58, no 13, p. 1372-1377Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: The purpose of this study was to investigate the prevalence of unrecognized myocardial infarction (UMI) detected with magnetic resonance imaging (MRI) and whether it is related to cerebral ischemic lesions on MRI in an elderly population-based cohort.

    BACKGROUND: There is a correlation between stroke and recognized myocardial infarction (RMI) and between stroke and UMI detected with electrocardiography, whereas the prevalence of stroke in subjects with MRI-detected UMI is unknown.

    METHODS: Cerebral MRI and cardiac late-enhancement MRI were performed on 394 randomly selected 75-year-old subjects (188 women, 206 men). Images were assessed for cerebral ischemic lesions and myocardial infarction (MI) scars. Medical records were scrutinized. Subjects with MI scars, with or without a hospital diagnosis of MI, were classified as RMI or UMI, respectively.

    RESULTS: UMIs were found in 120 subjects (30%) and RMIs in 21 (5%). The prevalence of UMIs (p = 0.004) and RMIs (p = 0.02) was greater in men than in women. Men with RMI displayed an increased prevalence of cortical and lacunar cerebral infarctions, whereas women with UMI more frequently had cortical cerebral infarctions (p = 0.003).

    CONCLUSIONS: MI scars are more frequent in men than in women at 75 years of age. The prevalence of RMI is related to that of cerebral infarctions.

  • 38.
    Eggers, Kai M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Mental Stress and Cardiac Troponin2013In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 62, no 18, p. 1702-1703Article in journal (Other academic)
  • 39.
    Eggers, Kai M.
    et al.
    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.
    Jernberg, Tomas
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden.
    Lindahl, Bertil
    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.
    Cardiac Troponin Elevation in Patients Without a Specific Diagnosis2019In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 73, no 1, p. 1-9Article in journal (Refereed)
    Abstract [en]

    BACKGROUND Cardiac troponin (cTn) elevation is a common finding in acutely admitted patients, even in the absence of acute coronary syndrome. In some of these patients, no etiology of cTn elevation can be identified. The term troponinemia is sometimes used to describe this scenario.

    OBJECTIVES This study aimed to investigate the associations of cTn levels with clinical findings and long-term outcome in acutely admitted patients with suspected acute coronary syndrome who had been discharged without a specified diagnosis.

    METHODS Retrospective registry-based cohort study investigating 48,872 patients (SWEDEHEART [Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies] registry). Patients were stratified into cohorts with cTn levels less than or equal to the assay-specific 99th percentile and separated by assay-specific cTn tertiles in case of higher levels.

    RESULTS A cTn level >99th percentile was noted in 9,800 (20.1%) patients. The prevalence of cardiovascular risk factors as well as cardiovascular and noncardiovascular comorbidities increased across higher cTn strata. In total, 7,529 (15.4%) patients had a major adverse event (MAE), defined as the composite of all-cause mortality, myocardial infarction, readmission for heart failure, or stroke (median follow-up 4.9 years). MAE risk was associated with higher cTn strata (hazard ratio for highest assay-specific cTn tertile: 2.59; 95% confidence interval: 2.39 to 2.80; hazard ratio in patients without cardiovascular comorbidities, renal dysfunction, left ventricular dysfunction, or significant coronary stenosis: 3.57; 95% confidence interval: 2.30 to 5.54).

    CONCLUSIONS cTn elevation is associated with cardiovascular and noncardiovascular comorbidities and predicts major adverse events in acutely admitted patients, in whom no definite diagnosis could have been established. The term troponinemia is trivializing and should be avoided. Instead, careful work-up is required in these patients.

  • 40.
    Eggers, Kai M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Jernberg, Tomas
    Danderyd Hospital.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    REPLY: The Validity of "Without a Specific Diagnosis" in Patients With Chest Pain and Troponin Elevation2019In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 73, no 17, p. 2240-2241Article in journal (Other academic)
  • 41.
    Eggers, Kai M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lagerqvist, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Prognostic value of biomarkers during and after non-ST-segment elevation acute coronary syndrome2009In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 54, no 4, p. 357-364Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: The aim of this study was to assess risk prediction by different biomarkers in patients with an ongoing non-ST-segment elevation acute coronary syndrome (NSTE-ACS) and after clinical stabilization. BACKGROUND: Different biomarkers reflect different aspects of the pathobiology in NSTE-ACS. However, there is little information regarding their relative prognostic value during the time course of disease. METHODS: The N-terminal pro-brain natriuretic peptide (NT-proBNP), C-reactive protein (CRP), cardiac troponin I (cTnI), and the estimated glomerular filtration rate (eGFR) were measured at randomization and after 6 weeks and 6 months in 877 NSTE-ACS patients included in the FRISC (FRagmin and fast revascularization during InStability in Coronary artery disease) II trial. The biomarkers' prognostic value during 5-year follow-up was evaluated by Cox regression models, calculation of the c-statistics, and estimation of the net reclassification improvement (NRI). RESULTS: Among the biomarkers measured at randomization, NT-proBNP was the strongest predictor for mortality (adjusted hazard ratio [HR]: 1.7; 95% confidence interval [CI]: 1.3 to 2.1; p < 0.001). Even during follow-up, NT-proBNP demonstrated the strongest association to the composite end point of death/myocardial infarction (adjusted HR at 6 weeks: 1.5; 95% CI: 1.3 to 1.7; p < 0.001; adjusted HR at 6 months: 1.4; 95% CI: 1.2 to 1.7; p = 0.001). Even CRP was independently predictive at 6 months for the composite end point (adjusted HR: 1.3; 95% CI: 1.1 to 1.5; p = 0.003). Only 6-week results of NT-proBNP provided significant incremental prognostic value to established risk indicators regarding the composite end point (c-statistics 0.69 [p = 0.03]; NRI 0.11 [p = 0.03]). CONCLUSIONS: The NT-proBNP is an independent risk predictor in patients with ongoing NSTE-ACS and after clinical stabilization. The CRP exhibits increasing predictive value at later measurements. However, only NT-proBNP provided incremental prognostic value and might therefore be considered as a complement for early follow-up controls after NSTE-ACS.

  • 42.
    Eggers, Kai M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Lindahl, Bertil
    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.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Cardiac troponin I levels measured with a high-sensitive assay increase over time and are strong predictors of mortality in an elderly population2013In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 61, no 18, p. 1906-1913Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Cardiac troponin levels are often detectable in community-dwellers when sensitive assays are applied. However, information on the course of troponin levels over time is limited.

    OBJECTIVES:

    We assessed changes in troponin levels, underlying conditions and the prognostic implications thereof in elderly subjects from the community.

    METHODS:

    Cardiac troponin I (cTnI) was measured using a novel high-sensitive assay from Abbott Laboratories in community-dwellers aged 70 years (PIVUS study). Measurements were performed at baseline (n=1004) and after 5 years (n=814). Total follow-up was 8.0 years.

    RESULTS:

    cTnI levels were detectable in 968 (96.4%) subjects at baseline, and independently predicted all-cause mortality (adjusted HR 1.44 [95% CI 1.18-1.77]) and cardiovascular mortality (adjusted HR 1.66 [95% CI 1.20-2.29]) when levels from baseline and 5-year follow-up were used as updated covariates. The integrated discrimination improvement of cTnI regarding all-cause mortality was 0.014 (p=0.04) and the category-free net reclassification improvement was 0.231 (p=0.02). Median cTnI levels increased by 45% between both measurements. The change in cTnI levels was significantly related to male sex (p=0.02), body mass index (p=0.01), HDL-cholesterol (p=0.005), N-terminal pro B-type natriuretic peptide (p=0.004) and the left-ventricular ejection fraction (p=0.04), and independently predicted all-cause mortality occurring after 5-year follow-up (adjusted HR 1.97 [1.14-3.40]; p=0.02).

    CONCLUSIONS:

    Using a novel high-sensitive assay, cTnI levels could be determined in nearly all elderly subjects. cTnI levels increased over time and were a strong marker of mortality risk. Our data suggest that cTnI might offer utility for clinical assessment of subjects in the general population.

  • 43. Eikelboom, John W.
    et al.
    Connolly, Stuart J.
    Hart, Robert G.
    Wallentin, Lars
    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.
    Reilly, Paul
    Oldgren, Jonas
    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.
    Yang, Sean
    Yusuf, Salim
    Balancing the Benefits and Risks of 2 Doses of Dabigatran Compared With Warfarin in Atrial Fibrillation2013In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 62, no 10, p. 900-908Article in journal (Refereed)
    Abstract [en]

    Objectives This study sought to compare the net clinical benefit of dabigatran 110 mg bid and 150 mg bid with that of warfarin in patients with atrial fibrillation (AF). Background In patients with AF, dabigatran 110 mg bid and 150 mg bid are associated with similar rates of death. However, the higher dose reduces ischemic stroke and increases bleeding compared with the lower dose. Therefore, there is uncertainty about how to evaluate the overall benefit of the 2 doses. Methods In 18,113 AF patients in the RE-LY (Randomized Evaluation of Long Term Anticoagulant Therapy) trial, we used a previously developed method for integrating ischemic and bleeding events as "ischemic stroke equivalents" in order to compare a weighted benefit of 2 doses of dabigatran with each other, and with that of warfarin. Results Compared with warfarin, there was a significant decrease in ischemic stroke equivalents with both dabigatran doses: -0.92 per 100 patient years (95% confidence interval [CI]: -1.74 to -0.21, p = 0.02) with dabigatran 110 mg bid and -1.08 (95% CI: -1.86 to -0.34, p = 0.01) with dabigatran 150 mg bid. There was no significant difference in ischemic stroke equivalents between the 2 doses: -0.16 (95% CI: -0.80 to 0.43) comparing dabigatran 150 mg bid with 110 bid. When including death in the weighted benefit calculations, the results were similar. Conclusions On a group level both doses of dabigatran as compared with warfarin have similar benefits when considering a weighted estimate including both efficacy and safety. The similar overall benefits of the 2 doses of dabigatran versus warfarin support individualizing the dose based on patient characteristics and physician and patient preferences. (Randomized Evaluation of Long Term Anticoagulant Therapy [RE-LY] With Dabigatran Etexilate; NCT00262600)

  • 44. Erlinge, D.
    et al.
    Ten Berg, J.
    Foley, D.
    Angiolillo, D. J.
    Wagner, H.
    Brown, P. B.
    Zhou, C.
    Luo, J.
    Jakubowski, J. A.
    Moser, B.
    Small, D. S.
    Bergmeijer, T.
    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, K. J.
    Reduction in platelet reactivity with prasugrel 5 mg in low-body-weight patients is noninferior to prasugrel 10 mg in higher-body-weight patients2012In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 60, no 20, p. 2032-2040Article in journal (Refereed)
    Abstract [en]

    Objectives: The aim of this study was to confirm prior modeling data suggesting that prasugrel 5 mg in low-body-weight (LBW) patients would be noninferior to prasugrel 10 mg in higher-body-weight (HBW) patients as assessed by maximal platelet aggregation (MPA). Background: Prasugrel 10 mg reduced ischemic events compared with clopidogrel 75 mg but increased bleeding, particularly in LBW patients. Methods: In this blinded, 3-period, crossover study in stable patients with coronary artery disease (CAD) taking aspirin, prasugrel 5 and 10 mg and clopidogrel 75 mg were administered to LBW (56.4 ± 3.7 kg; n = 34) and HBW patients (84.7 ± 14.9 kg; n = 38). Assays included light transmission aggregometry (LTA), VerifyNow P2Y12 (VN), and vasodilator-associated stimulated phosphoprotein (VASP) level measured predose and after each 12-day treatment. Results: Median MPA by LTA for prasugrel 5 mg in LBW patients was noninferior to the 75th percentile for prasugrel 10 mg in HBW patients (primary endpoint) and mean MPA was similar, but active metabolite exposure was lowered by 38%. Within LBW patients, prasugrel 5 mg lowered MPA more than clopidogrel (least squares mean difference [95% confidence interval]: -3.7% [-6.72%, -0.69%]) and resulted in lower rates of high on-treatment platelet reactivity (HPR). Within HBW patients, prasugrel 10 mg lowered MPA more than clopidogrel (-16.9% [-22.3%, -11.5%]). Similar results were observed by VN and VASP. Prasugrel 10 mg in LBW patients was associated with more mild to moderate bleeding (mainly bruising) compared with prasugrel 5 mg and clopidogrel. Conclusions: In aspirin-treated patients with CAD, prasugrel 5 mg in LBW patients reduced platelet reactivity to a similar extent as prasugrel 10 mg in HBW patients and resulted in greater platelet inhibition, lower HPR, and similar bleeding rates compared with clopidogrel. (Comparison of Prasugrel and Clopidogrel in Low Body Weight Versus Higher Body Weight With Coronary Artery Disease [FEATHER]; NCT01107925)

  • 45. Erlinge, David
    et al.
    Gotberg, Matthias
    Lang, Irene
    Holzer, Michael
    Noc, Marko
    Clemmensen, Peter
    Jensen, Ulf
    Metzler, Bernhard
    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.
    Botker, Hans Erik
    Omerovic, Elmir
    Engblom, Henrik
    Carlsson, Marcus
    Arheden, Hakan
    Östlund, Ollie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wallentin, Lars
    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.
    Harnek, Jan
    Olivecrona, Goran K.
    Rapid Endovascular Catheter Core Cooling Combined With Cold Saline as an Adjunct to Percutaneous Coronary Intervention for the Treatment of Acute Myocardial Infarction The CHILL-MI Trial: A Randomized Controlled Study of the Use of Central Venous Catheter Core Cooling Combined With Cold Saline as an Adjunct to Percutaneous Coronary Intervention for the Treatment of Acute Myocardial Infarction2014In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 63, no 18, p. 1857-1865Article in journal (Refereed)
    Abstract [en]

    Objectives The aim of this study was to confirm the cardioprotective effects of hypothermia using a combination of cold saline and endovascular cooling. Background Hypothermia has been reported to reduce infarct size (IS) in patients with ST-segment elevation myocardial infarctions. Methods In a multicenter study, 120 patients with ST-segment elevation myocardial infarctions (<6 h) scheduled to undergo percutaneous coronary intervention were randomized to hypothermia induced by the rapid infusion of 600 to 2,000 ml cold saline and endovascular cooling or standard of care. Hypothermia was initiated before percutaneous coronary intervention and continued for 1 h after reperfusion. The primary end point was IS as a percent of myocardium at risk (MaR), assessed by cardiac magnetic resonance imaging at 4 +/- 2 days. Results Mean times from symptom onset to randomization were 129 +/- 56 min in patients receiving hypothermia and 132 +/- 64 min in controls. Patients randomized to hypothermia achieved a core body temperature of 34.7 degrees C before reperfusion, with a 9-min longer door-to-balloon time. Median IS/MaR was not significantly reduced (hypothermia: 40.5% [interquartile range: 29.3% to 57.8%; control: 46.6% [interquartile range: 37.8% to 63.4%]; relative reduction 13%; p = 0.15). The incidence of heart failure was lower with hypothermia at 45 +/- 15 days (3% vs. 14%, p < 0.05), with no mortality. Exploratory analysis of early anterior infarctions (0 to 4 h) found a reduction in IS/MaR of 33% (p < 0.05) and an absolute reduction of IS/left ventricular volume of 6.2% (p = 0.15). Conclusions Hypothermia induced by cold saline and endovascular cooling was feasible and safe, and it rapidly reduced core temperature with minor reperfusion delay. The primary end point of IS/MaR was not significantly reduced. Lower incidence of heart failure and a possible effect in patients with early anterior ST-segment elevation myocardial infarctions need confirmation. (Efficacy of Endovascular Catheter Cooling Combined With Cold Saline for the Treatment of Acute Myocardial Infarction [CHILL-MI]; NCT01379261)

  • 46. Erlinge, David
    et al.
    Gurbel, Paul A.
    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.
    Lindahl, Tomas L.
    Svensson, Peter
    Ten Berg, Jurrien M.
    Foley, David P.
    Wagner, Henrik
    Brown, Patricia B.
    Luo, Junxiang
    Zhou, Chunmei
    Moser, Brian A.
    Jakubowski, Joseph A.
    Small, David S.
    Winters, Kenneth J.
    Angiolillo, Dominick J.
    Prasugrel 5 mg in the Very Elderly Attenuates Platelet Inhibition But Maintains Noninferiority to Prasugrel 10 mg in Nonelderly Patients2013In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 62, no 7, p. 577-583Article in journal (Refereed)
    Abstract [en]

    Objectives This study assessed pharmacodynamic (PD) response to the reduced prasugrel maintenance dose of 5 mg in very elderly (VE) patients (>= 75 years of age). Background In the TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial Infarction 38) study prasugrel 10 mg reduced ischemic events versus clopidogrel 75 mg, but increased bleeding in VE patients. Methods We examined PD and active metabolite pharmacokinetics (PKs) with prasugrel 5 and 10 mg and clopidogrel 75 mg in a 3-period (12 days each) blinded, crossover study in VE (n = 73; mean: 79 +/- 3 years of age) or (n 82) nonelderly (NE) (>= 45 to <65 years of age; mean: 56 +/- 5 years of age) stable coronary artery disease (CAD) patients receiving background aspirin. Assays included light transmission aggregometry (LTA), VerifyNow P2Y12 (VN-P2Y12), and vasodilator-associated stimulated phosphoprotein (VASP). The primary comparison was noninferiority of maximum platelet aggregation (MPA) comparing the median for prasugrel 5 mg in VE versus the 75th percentile for prasugrel 10 mg in NE, using a pre-specified 1-sided 97.5% confidence interval for the difference <15%. Results Prasugrel 5 mg in VE met the primary PD noninferiority criterion versus prasugrel 10 mg in NE. For prasugrel 5 mg, MPA was significantly lower (57 +/- 14%) than clopidogrel (63 +/- 14%; p < 0.001) in VE but higher than prasugrel 10 mg in NE (46 +/- 12%; p < 0.001). PD response by LTA, VN-P2Y12, and VASP during all treatments appeared similar between age cohorts. Prasugrel 5 mg resulted in fewer VE poor responders than clopidogrel. Rates of mild bleeding were higher with prasugrel 10 mg but similar for prasugrel 5 mg versus clopidogrel 75 mg. Conclusions In aspirin-treated stable CAD patients, prasugrel 5 mg in VE attenuated platelet inhibition while meeting pre-specified noninferiority criterion versus prasugrel 10 mg in NE, with significantly better PD response and fewer poor responders compared to clopidogrel 75 mg in VE. (Comparison of Prasugrel and Clopidogrel in Very Elderly and Non-Elderly Patients With Stable Coronary Artery Disease [GENERATIONS]; NCT01107912)

  • 47.
    Erlinge, David
    et al.
    Lund University, Sweden .
    Gurbel, Paul A.
    Sinai Centre Thrombosis Research, MD USA .
    James, Stefan
    Uppsala University, Sweden .
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Svensson, Peter
    Lund University, Sweden .
    Ten Berg, Jurrien M.
    St Antonius Hospital, Netherlands .
    Foley, David P.
    Beaumont Hospital, Ireland .
    Wagner, Henrik
    Lund University, Sweden .
    Brown, Patricia B.
    Eli Lilly and Co, IN USA .
    Luo, Junxiang
    Eli Lilly and Co, IN USA .
    Zhou, Chunmei
    Eli Lilly and Co, IN USA .
    Moser, Brian A.
    Eli Lilly and Co, IN USA .
    Jakubowski, Joseph A.
    Eli Lilly and Co, IN USA .
    Small, David S.
    Eli Lilly and Co, IN USA .
    Winters, Kenneth J.
    Eli Lilly and Co, IN USA .
    Angiolillo, Dominick J.
    University of Florida, FL USA .
    Prasugrel 5 mg in the Very Elderly Attenuates Platelet Inhibition But Maintains Noninferiority to Prasugrel 10 mg in Nonelderly Patients2013In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 62, no 7, p. 577-583Article in journal (Refereed)
    Abstract [en]

    Objectives This study assessed pharmacodynamic (PD) response to the reduced prasugrel maintenance dose of 5 mg in very elderly (VE) patients (andgt;= 75 years of age). less thanbrgreater than less thanbrgreater thanBackground In the TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial Infarction 38) study prasugrel 10 mg reduced ischemic events versus clopidogrel 75 mg, but increased bleeding in VE patients. less thanbrgreater than less thanbrgreater thanMethods We examined PD and active metabolite pharmacokinetics (PKs) with prasugrel 5 and 10 mg and clopidogrel 75 mg in a 3-period (12 days each) blinded, crossover study in VE (n = 73; mean: 79 +/- 3 years of age) or (n 82) nonelderly (NE) (andgt;= 45 to andlt;65 years of age; mean: 56 +/- 5 years of age) stable coronary artery disease (CAD) patients receiving background aspirin. Assays included light transmission aggregometry (LTA), VerifyNow P2Y12 (VN-P2Y12), and vasodilator-associated stimulated phosphoprotein (VASP). The primary comparison was noninferiority of maximum platelet aggregation (MPA) comparing the median for prasugrel 5 mg in VE versus the 75th percentile for prasugrel 10 mg in NE, using a pre-specified 1-sided 97.5% confidence interval for the difference andlt;15%. less thanbrgreater than less thanbrgreater thanResults Prasugrel 5 mg in VE met the primary PD noninferiority criterion versus prasugrel 10 mg in NE. For prasugrel 5 mg, MPA was significantly lower (57 +/- 14%) than clopidogrel (63 +/- 14%; p andlt; 0.001) in VE but higher than prasugrel 10 mg in NE (46 +/- 12%; p andlt; 0.001). PD response by LTA, VN-P2Y12, and VASP during all treatments appeared similar between age cohorts. Prasugrel 5 mg resulted in fewer VE poor responders than clopidogrel. Rates of mild bleeding were higher with prasugrel 10 mg but similar for prasugrel 5 mg versus clopidogrel 75 mg. less thanbrgreater than less thanbrgreater thanConclusions In aspirin-treated stable CAD patients, prasugrel 5 mg in VE attenuated platelet inhibition while meeting pre-specified noninferiority criterion versus prasugrel 10 mg in NE, with significantly better PD response and fewer poor responders compared to clopidogrel 75 mg in VE. (Comparison of Prasugrel and Clopidogrel in Very Elderly and Non-Elderly Patients With Stable Coronary Artery Disease [GENERATIONS]; NCT01107912)

  • 48. Erlinge, David
    et al.
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Duvvuru, Suman
    Jakubowski, Joseph
    Wanger, Henrik
    Varenhorst, Christoph
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Tantry, Udaya
    Brown, Patricia
    Small, David
    Moser, Brian
    Sundseth, Scott
    Walker, Joseph
    Winters, Kenneth
    Gurbel, Paul
    Point-of-Care Genetic Testing of Eleven CYP2C19 Single Nucleotide Polymorphisms Identifies Extensive and Reduced Metabolizers of Clopidogrel With High Accuracy in Patients With Coronary Artery Disease2012In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 60, no 17, p. B211-B212Article in journal (Other academic)
  • 49. Erlinge, David
    et al.
    Varenhorst, Christoph
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Braun, Oscar O
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Winters, Kenneth J
    Jakubowski, Joseph A
    Brandt, John T
    Sugidachi, Atsuhiro
    Siegbahn, Agneta
    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.
    Patients with poor responsiveness to thienopyridine treatment or with diabetes have lower levels of circulating active metabolite, but their platelets respond normally to active metabolite added ex vivo2008In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 52, no 24, p. 1968-77Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: We evaluated the prevalence and mechanism of poor responsiveness to clopidogrel and prasugrel in coronary artery disease patients with and without diabetes. BACKGROUND: Low platelet inhibition by clopidogrel is associated with ischemic clinical events. A higher 600-mg loading dose (LD) has been advocated to increase responsiveness to clopidogrel. METHODS: In this study, 110 aspirin-treated patients were randomized to double-blind treatment with clopidogrel 600 mg LD/75 mg maintenance dose (MD) for 28 days or prasugrel 60 mg LD/10 mg MD for 28 days. Pharmacodynamic (PD) response was evaluated by light transmission aggregometry and vasodilator-stimulated phosphoprotein phosphorylation. The PD poor responsiveness was defined with 4 definitions previously associated with worse clinical outcomes. Active metabolites (AM) of clopidogrel and prasugrel were measured. Clopidogrel AM was added ex vivo. RESULTS: The proportion of patients with poor responsiveness was greater in the clopidogrel group for all definitions at all time points from 1 h to 29 days. Poor responders had significantly lower plasma AM levels compared with responders. Patients with diabetes were over-represented in the poor-responder groups and had significantly lower levels of AM. Platelets of both poor responders and diabetic patients responded fully to AM added ex vivo. CONCLUSIONS: Prasugrel treatment results in significantly fewer PD poor responders compared with clopidogrel after a 600-mg clopidogrel LD and during MD. The mechanism of incomplete platelet inhibition in clopidogrel poor-responder groups and in diabetic patients is lower plasma levels of its AM and not differences in platelet P2Y(12) receptor function.

  • 50.
    Evans, Marie
    et al.
    Karolinska Inst, Renal Med, CLINTEC, Stockholm, Sweden..
    Carrero, Juan-Jesus
    Karolinska Inst, Renal Med, CLINTEC, Stockholm, Sweden.;Karolinska Inst, Inst Mol Med, Stockholm, Sweden..
    Szummer, Karolina
    Karolinska Inst, Dept Med, Cardiol Sect, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Cardiol, Stockholm, Sweden..
    Åkerblom, Axel
    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.
    Edfors, Robert
    Karolinska Inst, Dept Med, Cardiol Sect, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Cardiol, Stockholm, Sweden..
    Spaak, Jonas
    Karolinska Inst, Dept Clin Sci, Danderyd Univ Hosp, Stockholm, Sweden..
    Jacobson, Stefan H.
    Karolinska Inst, Dept Clin Sci, Danderyd Univ Hosp, Stockholm, Sweden..
    Andell, Pontus
    Lund Univ, Dept Cardiol, Clin Sci, Lund, Sweden..
    Lindhagen, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Jernberg, Tomas
    Karolinska Inst, Dept Med, Cardiol Sect, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Cardiol, Stockholm, Sweden..
    Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Myocardial Infarction Patients With Renal Dysfunction2016In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 67, no 14, p. 1687-1697Article in journal (Refereed)
    Abstract [en]

    BACKGROUND There is no consensus whether angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) should be used for secondary prevention in all or in only high-risk patients after an acute myocardial infarction (AMI).

    OBJECTIVES This study sought to investigate whether ACEI/ARB treatment after AMI is associated with better outcomes across different risk profiles, including the entire spectrum of estimated glomerular filtration rates.

    METHODS This study evaluated discharge and continuous follow-up data on ACEI/ARB use among AMI survivors (2006 to 2009) included in a large Swedish registry. The association between ACEI/ARB treatment and outcomes (mortality, myocardial infarction, stroke, and acute kidney injury [AKI]) was studied using Cox proportional hazards models (intention-to-treat and as treated).

    RESULTS In total, 45,697 patients (71%) were treated with ACEI/ARB. The 3-year mortality was 19.8% (17.4% of ACEI/ARB users and 25.4% of nonusers). In adjusted analysis, significantly better survival was observed for patients treated with ACEI/ARB (3-year hazard ratio: 0.80; 95% confidence interval: 0.77 to 0.83). The survival benefit was consistent through all kidney function strata, including dialysis patients. Overall, those treated with ACEI/ARB also had lower 3-year risk for myocardial infarction (hazard ratio: 0.91; 95% confidence interval: 0.87 to 0.95), whereas treatment had no significant effect on stroke risk. The crude risk for AKI was in general low (2.5% and 2.0% for treated and nontreated, respectively) and similar across estimated glomerular filtration rate categories but was significantly higher with ACEI/ARB treatment. However, the composite outcome of AKI and mortality favored ACEI/ARB treatment.

    CONCLUSIONS Treatment with ACEI/ARB after AMI was associated with improved long-term survival, regardless of underlying renal function, and was accompanied by low rates of adverse renal events.

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